The Brain-Gut-Islet Connection
http://www.100md.com
《糖尿病学杂志》
the Department of Psychiatry and the Obesity Research Center, University of Cincinnati, Cincinnati, Ohio
ARC, arcuate nucleus; CCK, cholecystokinin
ABSTRACT
Peptide signals from the pancreatic islets and the gastrointestinal tract influence the regulation of energy homeostasis by the brain, and the brain in turn influences the secretions of both the islets and the gut. This article focuses on how insulin interacts with the brain to influence food intake, blood glucose, and cognitive behavior. Insulin is secreted in response to changes of ambient glucose, and the levels achieved are directly proportional to body adiposity. Hence, insulin, like leptin, is an adiposity signal. An increased insulin signal in the mediobasal hypothalamus indicates that ample or excess energy is available in the body and elicits responses that limit food intake and reduce hepatic glucose secretion. Increased insulin (and leptin as well) locally within the brain complements other signals that indicate a surfeit of energy in the body, including satiety signals generated by the gut during meals, glucose, and some fatty acids. There is compelling evidence that overlapping intracellular signaling pathways within the mediobasal hypothalamus mediate the overall catabolic response to these diverse metabolic signals. Insulin receptors are also densely expressed in the hippocampus, and insulin acts there to facilitate learning and memory. The function of insulin receptors in other brain areas is poorly understood. Obesity and/or the consumption of diets high in fat render the brain as well as the body insulin resistant. In the hypothalamus, this is manifest as a reduced ability of insulin to reduce food intake and body weight, and in the hippocampus, it is manifest as a reduced ability of insulin to improve learning and/or memory.
The brain-gut-islet connection refers to the myriad ways in which signals arising in the three arms of this important axis interact among themselves, and at least one overall function of this integrated control system is the regulation of energy homeostasis throughout the body. Many of the interactions of this triad are well known. The brain regulates activity in both the gut and the pancreatic islets directly via the autonomic nervous system and indirectly via changes in food intake and energy expenditure. Peptide hormones and other signals secreted from the gut, in addition to coordinating the digestion and absorption of nutrients, provide the incretin effect that augments prandial insulin secretion. Many of these peptides also serve as critical satiety signals to the brain that limit meal size. Islet hormones influence digestion and control the disposition of ingested nutrients in addition to providing key signals to the brain regarding the level of adiposity and circulating energy. This review focuses on one aspect of this complex network, i.e., the actions of pancreatic insulin within the brain and the pathologies that occur when insulin signaling within the brain is compromised. The topic is timely, with relevant new information appearing almost monthly, and it is also an area of knowledge where the basic tenets are being challenged, since insulin was historically thought not to interact with the brain and subsequently was thought to mainly influence the control of food intake and body weight.
CONTROL OF ENERGY INTAKE
The energy equation holds that for body weight to remain relatively stable over time, food intake must match energy expenditure, and deviations in either direction will result in weight gain or loss. Humans and most mammals consume food in discrete episodes or meals. When there are no restrictions on when or how much individuals are allowed to eat (i.e., when they are in a free-feeding or ad lib condition), the impetus to begin a meal is rarely if ever caused by a biological deficit or need such as insufficient glucose. Rather, evidence indicates that the timing of meals is based on psychological factors such as habit, time of day, the social situation, convenience, and others (1–3). Because of this, body weight regulation, the continuous process that ties energy intake to energy expenditure, must logically be manifest as a control over how many calories are consumed once a meal begins, i.e., on meal size. Consistent with this, during meals, the gut responds to ingested nutrients by secreting peptide signals proportional to the quantity and quality of calories consumed, and some of these secretions function as satiety signals to the brain to limit meal size (4–7). The prototypical satiety signal is the duodenal peptide cholecystokinin (CCK). Humans and animals that are administered CCK just before eating consume smaller meals, and when administered a selective CCK-1 receptor antagonist, they consume larger meals (5,8). Table 1 lists gut and islet signals secreted during meals that influence meal size and are considered to be satiety signals.
Adiposity signals are hormones secreted in direct proportion to body fat. In contrast to satiety signals that are secreted mainly during meals, adiposity signals are tonically present, providing a relatively continuous message to the brain concerning fat stored within the body. Pancreatic insulin and the adipocyte hormone leptin are the two best-known adiposity signals, and others such as amylin and adiponectin also circulate in proportion to body fat and share many of the same properties. Administering either insulin or leptin directly into the brain results in reduced food intake and body weight, and reductions of either insulin or leptin signaling locally within the brain results in overeating and weight gain. When an individual’s weight (i.e., body fat) changes, insulin and leptin secretion change in parallel, and this is manifest as an altered adiposity signal to the brain. There are many reviews of these phenomena (9–14).
The interaction of adiposity signals with satiety signals in the control of food intake is a topic of considerable interest and beyond the scope of this review. The basic principle is that adiposity signals modulate the sensitivity of the brain to meal-generated satiety signals (10,12,15). As an example, the administration of very low doses of either insulin or leptin directly into the brain enhances the efficacy of systemic CCK to reduce food intake (16–22), and a reduced leptin signal in the brain, which also reduces brain insulin signaling (23), lowers CCK sensitivity (24). The implication is that when an individual loses weight and insulin and leptin secretion are reduced, brain circuits that control meal size are consequently rendered less sensitive to meal-generated satiety signals such as CCK. As a result, more calories than normal must be consumed before a satiety signal of sufficient magnitude to terminate a meal is generated. Individuals consequently eat larger than normal meals until body weight returns to normal. Conversely, when an individual gains excess weight, the increased insulin and leptin signal in the brain causes increased sensitivity to satiety signals, and relatively small meals are consumed until the excess weight is lost.
INSULIN AS AN ADIPOSITY SIGNAL
Basal plasma insulin is low and increases during meals or when stimulated by glucose. Basal, prandial, and stimulated insulin levels are all direct functions of stored fat, with leaner individuals having lower levels and more obese individuals having higher levels (25–27). Plasma insulin is therefore positioned to convey an important signal to the brain indicating the degree of adiposity, and as discussed below, some insulin enters the brain from the circulation and provides a key negative feedback signal in the regulation of body fat as originally proposed by Kennedy (28) (Fig. 1). When exogenous insulin is administered near or directly into the mediobasal hypothalamus, animals behave as if they have excess fat, i.e., they eat less and lose weight. The response is dose dependent (17,29), occurs in all species assessed, and is not secondary to illness or incapacitation (30). When insulin levels in the brain are clamped by means of slow steady local infusions, body weight is maintained and defended at a level determined by the dose of insulin administered (rev. in 13,31–33). The response to changes of the insulin signal is bidirectional in that the administration of insulin antibodies into or near the mediobasal hypothalamus causes overeating and weight gain (34,35). Likewise, reducing hypothalamic insulin receptor activity either genetically by a neuronal-specific knockout of insulin receptors or pharmacologically via antisense oligonucleotides against the insulin receptor leads to increased food intake and body fat (36,37). Although insulin has not been administered directly into the brains of humans, certain formulations of insulin have been administered intranasally to humans with a consequent increase of cerebrospinal fluid but not plasma insulin. Humans receiving insulin in this way eat less food and lose body fat (38).
Insulin enters the brain via receptor-facilitated transport through capillary endothelial cells. The process is saturable, selective for insulin, and regulated (39–42). Insulin transport into the brain is reduced during fasting (43), by maintenance on a high-fat diet (44), and in genetic and dietary-induced obesity (45,46). Because brain insulin derives from plasma insulin, it should be the case that experimentally induced increases of plasma insulin enter the brain and result in reduced food intake and body weight. Such procedures are confounded by hypoglycemia and a consequent increased tendency to eat more food. However, when insulin is administered systemically at doses sufficiently low to preclude hypoglycemia, food intake is reduced (47). Likewise, when sufficient glucose is administered in conjunction with systemic insulin to circumvent hypoglycemia, food intake is also reduced (48).
Autoradiographic insulin binding, as well as immunohistochemical analyses, reveal that insulin receptors are selectively located in several brain regions (49–52). The areas of highest concentrations are the olfactory bulb, hypothalamus, cerebellum, cortex, and hippocampus (53–55), and most insulin receptor immunoreactivity occurs on neurons and not on glia.
INSULIN REGULATES ENERGY HOMEOSTASIS IN THE HYPOTHALAMUS
As discussed above, insulin reduces food intake and body weight when delivered into the third cerebral ventricle (i3vt) or directly into the hypothalamus in or near the arcuate nucleus (ARC). Conversely, reduction of insulin signaling has the opposite action. Insulin signaling in the ARC also initiates a signal via the vagus nerve to the liver to reduce glucose synthesis and secretion into the blood (56–58). Hence, insulin’s action in the hypothalamus is consistent with its better-known systemic actions, i.e., its net effect is to lower blood glucose (9,11). Reducing the amount of food consumed and neurally reducing hepatic glucose output both complement insulin’s ability to facilitate glucose uptake by muscle, liver, and other tissues, as well as complement insulin’s direct action in the liver. It has recently been reported that administering oleic acid or glucose into or near the ARC also reduces food intake (57,59–62). Leptin may also act there to influence glucose homeostasis (63). Hence, ARC neurons respond to diverse signals indicative of a surfeit of available energy (i.e., elevated insulin, fatty acids, or glucose) by reducing the ingestion of energy and decreasing the secretion of utilizable energy (especially glucose) into the blood. Rossetti’s group has postulated that manipulating intracellular metabolic signaling pathways, especially those involved with the oxidation of lipids, comprises the actual stimulus that is important in controlling both food intake and hepatic glucose production by the hypothalamus (61,64–67).
INSULIN AND LEPTIN AS ADIPOSITY SIGNALS
As discussed above, both leptin and insulin function as adiposity signals, and the two have overlapping actions with regard to the hypothalamic control of metabolism. While the existence of two or more adiposity signals might seem redundant, insulin and leptin in fact reflect different fat stores, sexes, and risk factors for developing type 2 diabetes, cardiovascular problems, and the metabolic syndrome.
Fat stores.
Insulin is secreted in proportion to visceral fat, whereas leptin reflects total fat mass and especially subcutaneous fat (68,69). This is an important distinction with regard to the message conveyed to the brain, since visceral fat carries a greater risk factor for the metabolic complications associated with obesity than does subcutaneous fat. Elevated visceral fat carries an increased risk for insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, and certain cancers (68,70,71). Hence, leptin and insulin each convey specific information to the brain regarding the distribution of fat, and the combination of the two additionally conveys information as to the total fat mass of the body.
Sex.
Women have relatively more subcutaneous fat and higher plasma leptin, whereas men have relatively more visceral fat and higher plasma insulin (68,70,71). Likewise, male rats have relatively more visceral fat and higher plasma insulin, whereas female rats have more subcutaneous fat and higher plasma leptin (72). We have found that the brain of females is more sensitive to the catabolic action of leptin, whereas the brain of males is more sensitive to the catabolic action of insulin (73), and that estrogen mediates this difference (72). These data are consistent with a growing literature documenting sex differences in the actions of many compounds that influence energy homeostasis, including CCK (74), insulin (38,73), leptin (73), and ghrelin (D.J.C., L.M. Brown, C.J. Kemp, A.D. Strader, S.C.B., S.C.W., M. Mangiarachina, N. Geary, unpublished data), and this may be manifest in the selection of foods (75,76) as well as the preferred strategy used by males and females to defend their body weight (77). The physiological basis of these sex differences is an important clinical issue, since males are far more likely to develop symptoms of the metabolic syndrome (70), whereas females are far more likely to develop eating disorders (78).
Risk factors for developing type 2 diabetes.
Although insulin and leptin each signal the degree of adiposity to the brain, and whereas each lowers food intake as well as hepatic glucose secretion, they do so by stimulating different ARC neurons and circuits (79) as well as by altering different hepatic enzyme systems (80). Further, each has important other functions. Insulin is a major controller of the levels and utilization of glucose throughout most of the body, including the brain (9,11). Leptin also influences glucose parameters via the brain, although via different neural circuits than stimulated by insulin (80). Low circulating leptin and the resultant decrease of leptin signaling have been hypothesized to regulate many vital systems when animals are severely hypocaloric and have low body fat (81–83). The secretion of insulin is adjusted in response to every acute change of metabolism (9,84), with levels increasing during meals or when glucose is elevated for some other reason and decreasing during stress and exercise. The half-life of insulin in the blood (2–3 min) is consistent with its role as a minute-to-minute indicator of ongoing metabolism, and all of its fluctuations are directly proportional to total body fat (26). Leptin is secreted from adipocytes in direct proportion to the amount of stored fat (85) (although the actual stimulus is related more to the metabolic activity of the fat cell than to actual fat storage [86] such that dissociations can occur between stored fat and leptin release, particularly during a fast [86–88]). Nonetheless, under normal conditions and with a half-life of 45 min, plasma leptin levels are a reliable and relatively stable indicator of body fat. Hence, insulin levels reflect the interaction of ongoing metabolic processes and body adiposity, whereas leptin levels reflect the activity of adipose cells more directly.
As described above, both insulin and leptin act in the ARC (and probably other brain areas) to reduce food intake and body weight, and both also act in the ARC to reduce hepatic output of glucose. In some instances, the overlap of function may result from common intracellular signaling pathways of insulin and leptin, since both activate a pathway using insulin receptor substrate 1 and 2, and both cause increased intracellular cAMP degradation (89–91). Insulin upregulates the expression of mRNA of the long form of the leptin receptor (OB-Rb) in neuronal but not other cell types (92), and insulin facilitates leptin’s ability to activate the JAK-STAT pathway in the hypothalamus (90,93). Both leptin (94,95) and insulin (94,95) exert their catabolic action through phosphatidylinositol 3-kinase.
INSULIN AND LEPTIN'S INTERACTION WITH CENTRAL NEUROPEPTIDES
Insulin and leptin interact with two populations of ARC neurons. Activity of those that synthesize proopiomelanocortin, the precursor molecule of the melanocortins, is stimulated by insulin and leptin, whereas activity of those that synthesize neuropeptide Y plus Agouti-related protein is inhibited by insulin and leptin. -Melanocyte–stimulating hormone is a melanocortin that is derived from ARC proopiomelanocortin and is an agonist at melanocortin receptors (MC3R and MC4R) in several hypothalamic nuclei; Agouti-related protein is an endogenous antagonist of these same melanocortin receptors. Central administration of insulin or leptin, or the administration of -melanocyte–stimulating hormone or synthetic agonists for melanocortin receptors, or the application of treatments that reduce ARC neuropeptide Y (e.g., antisense oligonucleotides administered directly into the ARC [96]), all result in reduced food intake and body weight. Conversely, the administration of neuropeptide Y, Agouti-related protein, or synthetic melanocortin antagonists, or the absence of endogenous insulin or leptin signaling, all result in a net increase of food intake and body weight (rev. in 11,83,97–101).
OTHER ACTIONS OF INSULIN WITHIN THE BRAIN
It is important to consider what a change in the insulin signal at its receptor in diverse brain areas actually signifies. The obvious answer is that acute changes of insulin reflect an increase (or decrease) in energy in the form of glucose interacting with the pancreas, whereas sustained changes additionally reflect the amount of fat stored in the visceral or abdominal region. Based on this, it is easy to generate an explanation for why neurons in the mediobasal hypothalamus express insulin receptors, since these neurons are intimately involved in the regulation of energy homeostasis. An intriguing related question, however, concerns the rationale for more remote areas of the brain to express insulin receptors, such as the hippocampus or the olfactory bulb.
In the hippocampus, immunoreactivity for insulin receptors is found in the molecular layer of the dentate gyrus and on dendrites of CA1 pyramidal cells (51,102). Insulin binding in the hippocampus is colocalized with immuno-labeled phosphotyrosine (54) and insulin receptor substrate 1 (103), and as is discussed above, these compounds are important for the insulin receptor’s intracellular signaling pathways (104). Thus, the binding of insulin in the hippocampus, as it is in the hypothalamus, appears to be closely associated with functional effects of insulin. Glucose metabolism in hippocampal cells is sensitive to application of exogenous insulin (105), and this sensitivity depends on the insulin receptor (106,107). Further, insulin receptors in the hippocampus are localized in dendritic fields, suggesting a neuromodulatory role (51,54,55). Furthermore, there is a relationship between certain metabolic disorders and cognitive decline (108). In diabetes, for example, patients must rely on exogenous insulin administration to keep blood glucose levels within a life-sustaining range. These patients also often exhibit increased cognitive impairment correlated with the progression of their diabetes (109). Other disease states are also accompanied by changes in metabolic status. The progression of diverse central nervous system disorders such as Huntington’s disease (110), Parkinson’s disease (111), and schizophrenia is correlated with changes in glucose levels, insulin, and metabolic activity. Likewise, the progression of Alzheimer’s disease is correlated with disturbances in basal insulin levels as well as glucose metabolism (112).
More striking is the finding that when Alzheimer’s patients are made hyperinsulinemic, their performance on several assessments of memorial tasks is improved (113). Importantly, this occurs even at doses of insulin that do not affect peripheral glucose levels. Further, hyperinsulinemic states do not appear to increase Alzheimer’s patients’ performance on visual-spatial or physical-coordination tasks. This finding adds support to the hypothesis that insulin levels are specific to cognitive process (e.g., memory) in Alzheimer’s patients. Finally, patients with type 2 diabetes who are insensitive to the effects of insulin (i.e., who are insulin resistant) are also impaired on some measures of cognitive ability (114–117). These and other findings encourage the hypothesis that insulin plays an important role in normal cognitive functions and memorial processes. Moreover, it encourages the hypothesis that alterations in insulin signaling may play an important role in neurodegenerative disease.
In addition to the epidemiological and clinical studies, a growing body of evidence from animal experiments also implicates insulin as an important factor in learning and memory (118). Experimental removal of insulin leads to disrupted learning and performance. For example, administration of streptozotocin leads to impaired learning on a number of learning tasks in mice (119). In rats, streptozotocin-induced diabetes leads to disrupted performance on avoidance tasks and in Morris water mazes (109,120–123). Central streptozotocin also produces impairment in working and reference memory in rats (124), and it alters intracellular signaling by N-methyl-D-aspartate (125) and -amino-3-hydroxy-5-methyl-4-isoxaziole-propionate (126) receptors that are implicated in the development of long-term potentiation (127). Thus, disruption of systemic insulin signaling is associated with impairments of memorial processes in rodents.
Importantly, administration of exogenous insulin improves performance on some learning tasks and corrects the learning and memory deficits produced by streptozotocin or diabetes. For example, administration of exogenous insulin improves rats’ performance in the one-trial learning of a passive avoidance task (128,129). It also ameliorates the diabetic impairments observed on radial-arm maze tasks and water mazes (122,123). A key point is that administration of insulin directly into the brain, where it does not improve peripheral glucose metabolism, also improves learning (128,130), although some studies have reported contradictory findings, i.e., that administration of insulin impairs learning and memory performance (131–134).
Therefore, data from both humans and animals support the hypothesis that insulin is an important factor in memorial processes. However, the exact nature of that role remains elusive. This is due, in part, to the fact that much of the previous work suffers from one or both of two serious confounds. First, it is often difficult to disentangle the effects of altered insulin from the effects of altered metabolism. Large changes in basal insulin levels can produce profound disruptions in metabolic status that might account for some of the observed disruptions in learning in and of themselves. Second, because most manipulations of insulin occur systemically, it is difficult to identify the effects of insulin uniquely in regions of the brain known to be important for learning and memory. Finally, the ability of insulin to improve cognitive behavior might be task or reinforcement specific. It might be, for example, that increased insulin in the hippocampus, which reflects an increase of available energy in the body, facilitates learning tasks that help procure food. That is, elevated insulin might well enable remembering where food is located, or the best time to access it, or related factors. Likewise, increased insulin activity in the olfactory bulb could help form associations between specific odors and food. The point is that any general hypothesis of insulin action in the brain must account for what changes of insulin actually reflect.
DIETARY FAT, OBESITY, AND INSULIN RESISTANCE
As previously mentioned, when leptin is administered into the brains of experimental animals, there is a selective reduction of body fat, with lean body mass being spared (135). Likewise, when insulin is administered into the brain, there is a reduction of the respiratory quotient, suggesting that the body is oxidizing relatively more fat (136). These observations suggest that one action of these adipose signals within the brain is to reduce body fat, and a corollary of this is that fat ingestion would be expected to be reduced as well. Consistent with this, we have observed that when insulin is administered into the third cerebral ventricle of rats, fat intake is selectively reduced (137). Hence, it is reasonable to hypothesize that leptin and insulin, acting in the brain, reduce body fat by increasing lipid mobilization and oxidation and simultaneously by reducing the consumption of dietary fat.
When animals become obese after exposure to high-fat diets, they become resistant to leptin and insulin’s ability to regulate food intake and body weight. The epidemiological data that increasing dietary fat accelerates the development of obesity are quite compelling and have been summarized in several reviews (138–140). Animal studies provide strong corroborative evidence, i.e., across numerous experiments, diets, and species, and the conclusion that increased consumption of high-fat diets leads to increased body fat is inescapable (141–148). Importantly, there are strong genetic influences that dictate whether or not a given individual will be prone or resistant to becoming obese when exposed to a high-fat diet (141,146,149–153). As Bray and Popkin (138) point out, a high-fat diet can be viewed as the environmental agent that acts on a susceptible host animal to produce the noninfectious disease obesity. Importantly, the consequences of obesity, including dietary-induced obesity, are well documented and include type 2 diabetes and insulin insensitivity. Further, some detrimental effects of dietary fat are not limited to obese individuals. For example, we have recently demonstrated that while high-fat diet–induced obesity decreases central sensitivity to the anorexic effects of central insulin administration, increased dietary fat, in the absence of frank obesity, also attenuates the potency of central insulin to reduce food intake and body weight (148; K. Gotoh, M.D. Wortman, S.C.B., D.J.C., D. D’Alessio, P. Tso, R.J. Seeley, S.C.W., unpublished data).
HIPPOCAMPAL INSULIN RESISTANCE
Consistent with the concept that insulin acts in multiple regions of the brain to influence multiple processes, dietary-induced insulin resistance has recently been linked to impaired cognitive function in both humans and animals. Specifically, high levels of dietary saturated fats and simple carbohydrates (which promote insulin resistance and obesity) have been demonstrated to reduce hippocampal-dependent memory processes. For example, Gomez-Pinilla and colleagues (154) have shown that long-term access to obesigenic diets impairs rats’ performance in the Morris water maze task, a classic measure of spatial memory. These deficits are associated with reductions in hippocampal expression of brain-derived neurotrophic factor mRNA (155). We and others have found that increased body weight and peripheral metabolic disruptions are also associated with reduced insulin receptor gene expression in the hippocampus. Several important questions remain unanswered, however, including the specific molecular mechanisms by which central insulin resistance might lead to decreased expression of such factors as brain-derived neurotrophic factor.
SUMMARY
To summarize, increased insulin in the mediobasal hypothalamus provides a signal that ample or excess energy is available in the body, and one consequence is a reduction of food intake. It has recently been reported that the increased hypothalamic insulin signal also elicits a vagal reflex to the liver that reduces glucose secretion. Increased insulin (and probably leptin) locally within the hypothalamus therefore can be considered to be analogous to other signals that indicate a surfeit of energy in the body. In addition to satiety and adiposity signals, this includes certain lipids and glucose, and there is compelling evidence that overlapping intracellular signaling pathways within the mediobasal hypothalamus mediate the overall catabolic response to these diverse metabolic signals. Insulin receptors are also densely expressed in the hippocampus, and there is evidence that insulin acts there to facilitate certain cognitive functions. The function of insulin receptors in other brain areas is poorly understood. Obesity and/or the consumption of diets high in fat render the brain as well as the body insulin resistant. In the hypothalamus, this is manifest as a reduced ability of insulin to reduce food intake and body weight, and in the hippocampus, it is manifest as a reduced ability of insulin to improve learning and/or memory. Figure 2 is a model depicting some of the feedback loops involving insulin in the brain.
FOOTNOTES
This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
REFERENCES
Strubbe JH, Woods SC: The timing of meals. Psychol Rev 111:128–141, 2004
Woods SC: The eating paradox: how we tolerate food. Psychol Rev 98:488–505, 1991
Woods SC, Strubbe JH: The psychobiology of meals. Psychol Bull Rev 1:141–155, 1994
Kaplan JM, Moran TH: Gastrointestinal signaling in the control of food intake. In Handbook of Behavioral Neurobiology: Neurobiology of Food and Fluid Intake. Vol. 4, no. 2. Stricker EM, Woods SC, Eds. New York, Kluwer Academic/Plenum, 2004, p.273–303
Moran TH, Kinzig KP: Gastrointestinal satiety signals II. Cholecystokinin. Am J Physiol Gastrointest Liver Physiol 286:G183–G188, 2004
Strader AD, Woods SC: Gastrointestinal hormones and food intake. Gastroenterology 128:175–191, 2005
Woods SC: Gastrointestinal satiety signals I. An overview of gastrointestinal signals that influence food intake. Am J Physiol Gastrointest Liver Physiol 286:G7–G13, 2004
Smith GP, Gibbs J: The development and proof of the cholecystokinin hypothesis of satiety. In Multiple Cholecystokinin Receptors in the CNS. Dourish CT, Cooper SJ, Iversen SD, Iversen LL, Eds. Oxford, U.K., Oxford University Press, 1992, p.166–182
Porte D Jr, Baskin DG, Schwartz MW: Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes 54:1264–1276, 2005
Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG: Central nervous system control of food intake. Nature 404:661–671, 2000
Schwartz MW, Porte D Jr: Diabetes, obesity, and the brain. Science 307:375–379, 2005
Woods SC, Seeley RJ, Porte D Jr, Schwartz MW: Signals that regulate food intake and energy homeostasis. Science 280:1378–1383, 1998
Woods SC, Seeley RJ: Insulin as an adiposity signal. Int J Obes Relat Metab Disord 25:S35–S38, 2001
Friedman JM: The function of leptin in nutrition, weight, and physiology. Nutr Rev 60:S1–S14, 2002
Woods SC, Seeley RJ: Adiposity signals and the control of energy homeostasis. Nutrition 16:894–902, 2000
Figlewicz DP, Sipols AJ, Seeley RJ, Chavez M, Woods SC, Porte DJ: Intraventricular insulin enhances the meal-suppressive efficacy of intraventricular cholecystokinin octapeptide in the baboon. Behav Neurosci 109:567–569, 1995
Riedy CA, Chavez M, Figlewicz DP, Woods SC: Central insulin enhances sensitivity to cholecystokinin. Physiol Behav 58:755–760, 1995
Emond M, Schwartz GJ, Ladenheim EE, Moran TH: Central leptin modulates behavioral and neural responsivity to CCK. Am J Physiol Regul Integr Comp Physiol 276:R1545–R1549, 1999
Matson CA, Wiater MF, Kuijper JL, Weigle DS: Synergy between leptin and cholecystokinin (CCK) to control daily caloric intake. Peptides 18:1275–1278, 1997
Matson CA, Reid DF, Cannon TA, Ritter RC: Cholecystokinin and leptin act synergistically to reduce body weight. Am J Physiol Regul Integr Comp Physiol 278:R882–R890, 2000
Morton GJ, Blevins JE, Williams DL, Niswender KD, Gelling RW, Rhodes CJ, Baskin DG, Schwartz MW: Leptin action in the forebrain regulates the hindbrain response to satiety signals. J Clin Invest 115:703–710, 2005
Barrachina MD, Martinez V, Wang L, Wei JY, Tache Y: Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice. Proc Natl Acad Sci U S A 94:10455–10460, 1997
Ikeda H, West DB, Pustek JJ, Figlewicz DP, Greenwood MRC, Porte D Jr, Woods SC: Intraventricular insulin reduces food intake and body weight of lean but not obese Zucker rats. Appetite 7:381–386, 1986
McMinn JE, Sindelar DK, Havel PJ, Schwartz MW: Leptin deficiency induced by fasting impairs the satiety response to cholecystokinin. Endocrinology 141:4442–4448, 2000
Bagdade JD, Bierman EL, Porte D Jr: The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest 46:1549–1557, 1967
Polonsky KS, Given E, Carter V: Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest 81:442–448, 1988
Woods SC, Decke E, Vasselli JR: Metabolic hormones and regulation of body weight. Psychol Rev 81:26–43, 1974
Kennedy GC: The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond (Biol ) 140:579–592, 1953
Woods SC, Lotter EC, McKay LD, Porte D Jr: Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282:503–505, 1979
Chavez M, Seeley RJ, Woods SC: A comparison between the effects of intraventricular insulin and intraperitoneal LiCl on three measures sensitive to emetic agents. Behav Neurosci 109:547–550, 1995
Schwartz MW, Figlewicz DP, Baskin DG, Woods SC, Porte D Jr: Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev 13:387–414, 1992
Woods SC, Chavez M, Park CR, Riedy C, Kaiyala K, Richardson RD, Figlewicz DP, Schwartz MW, Porte D, Seeley RJ: The evaluation of insulin as a metabolic signal controlling behavior via the brain. Neurosci Biobehav Rev 20:139–144, 1995
Woods SC: Insulin and the brain: a mutual dependency. Prog Psychobiol Physiol Psychol 16:53–81, 1996
McGowan MK, Andrews KM, Grossman SP: Chronic intrahypothalamic infusions of insulin or insulin antibodies alter body weight and food intake in the rat. Physiol Behav 51:753–766, 1992
Strubbe JH, Mein CG: Increased feeding in response to bilateral injection of insulin antibodies in the VMH. Physiol Behav 19:309–313, 1977
Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Müller-Wieland D, Kahn CR: Role of brain insulin receptor in control of body weight and reproduction. Science 289:2122–2125, 2000
Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L: Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5:566–572, 2002
Hallschmid M, Benedict C, Schultes B, Fehm HL, Born J, Kern W: Intranasal insulin reduces body fat in men but not in women. Diabetes 53:3024–3029, 2004
Banks WA, Jaspan JB, Huang W, Kastin AJ: Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin. Peptides 18:1423–1429, 1997
Baura G, Foster D, Porte D Jr, Kahn SE, Bergman RN, Cobelli C, Schwartz MW: Saturable transport of insulin from plasma into the central nervous system of dogs in vivo: a mechanism for regulated insulin delivery to the brain. J Clin Invest 92:1824–1830, 1993
Schwartz MW, Bergman RN, Kahn SE, Taborsky GJ Jr, Fisher LD, Sipols AJ, Woods SC, Steil GM, Porte D Jr: Evidence for uptake of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. J Clin Invest 88:1272–1281, 1991
Woods SC, Seeley RJ, Baskin DG, Schwartz MW: Insulin and the blood-brain barrier. Curr Pharm Des 9:795–800, 2003
Strubbe JH, Porte DJ, Woods SC: Insulin responses and glucose levels in plasma and cerebrospinal fluid during fasting and refeeding in the rat. Physiol Behav 44:205–208, 1988
Kaiyala K, Prigeon RL, Kahn SE, Woods SC, Schwartz MW: Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes 49:1525–1533, 2000
Israel PA, Park CR, Schwartz MW, Green PK, Sipols AJ, Woods SC, Porte D Jr, Figewicz DP: Effect of diet-induced obesity and experimental hyperinsulinemia on insulin uptake into CSF of the rat. Brain Res Bull 30:571–575, 1993
Stein LJ, Dorsa DM, Baskin DG, Figlewicz DP, Ikeda H, Frankmann SP, Greenwood MR, Porte D Jr, Woods SC: Immunoreactive insulin levels are elevated in the cerebrospinal fluid of genetically obese Zucker rats. Endocrinology 113:2299–2301, 1983
Vanderweele DA, Haraczkiewicz E, Van Itallie TB: Elevated insulin and satiety in obese and normal weight rats. Appetite 3:99–109, 1982
Nicolaidis S, Rowland N: Metering of intravenous versus oral nutrients and regulation of energy balance. Am J Physiol 231:661–668, 1976
Baskin DG, Marks JL, Schwartz MW, Figewicz DP, Woods SC, Porte D Jr: Insulin and insulin receptors in the brain in relation to food intake and body weight. In Endocrine and Nutritional Control of Basic Biological Functions. Lehnert H, Murison R, Weiner H, Hellhammer D, Beyer J, Eds. Stuttgart, Hogrefe & Huber, 1990, p.202–222
Baskin DG, Woods SC, West DB, van HM, Posner BI, Dorsa DM, Porte D Jr: Immunocytochemical detection of insulin in rat hypothalamus and its possible uptake from cerebrospinal fluid. Endocrinology 113:1818–1825, 1983
Corp ES, Woods SC, Porte D Jr, Dorsa DM, Figlewicz DP, Baskin DG: Localization of 125I-insulin binding sites in the rat hypothalamus by quantitative autoradiography. Neurosci Lett 70:17–22, 1986
Havrankova J, Brownstein M, Roth J: Insulin and insulin receptors in the rodent brain. Diabetologia 20:268–273, 1981
Unger J, McNeil TH, Moxley RTI, White M, Moss A, Livingston JN: Distribution of insulin receptor-like immunoreactivity in the rat forebrain. Neuroscience 31:143–157, 1989
Unger JW, Moss AM, Livingston JN: Immunohistochemical localization of insulin receptors and phosphotyrosine in the brainstem of the adult rat. Neuroscience 42:853–861, 1991
Unger JW, Livingston JN, Moss AM: Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Neurobiol 36:343–362, 1991
Obici S, Zhang BB, Karkanias G, Rossetti L: Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376–1382, 2002
Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L: Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 11:320–327, 2005
Lin X, Taguchi A, Park S, Kushner JA, Li F, Li Y, White MF: Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes. J Clin Invest 114:886–888, 2004
Levin BE, Routh VH, Kang L, Sanders NM, Dunn-Meynell AA: Neuronal glucosensing: what do we know after 50 years Diabetes 53:2521–2528, 2004
Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L: Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51:271–275, 2002
Obici S, Feng Z, Arduini A, Conti R, Rossetti L: Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 9:756–761, 2003
Obici S, Rossetti L: Minireview: nutrient sensing and the regulation of insulin action and energy balance. Endocrinology 144:5172–5178, 2003
Pocai A, Morgan K, Buettner C, Gutierrez-Juarez R, Obici S, Rossetti L: Central leptin acutely reverses diet-induced hepatic insulin resistance. Diabetes 54:3182–3189, 2005
He W, Lam TK, Obici S, Rossetti L: Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat Neurosci 9:227–233, 2006
Pocai A, Obici S, Schwartz GJ, Rossetti L: A brain-liver circuit regulates glucose homeostasis. Cell Metab 1:53–61, 2005
Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L: Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434:1026–1031, 2005
Lam TK, Gutierrez-Juarez R, Pocai A, Rossetti L: Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309:943–947, 2005
Wajchenberg BL, Giannella-Neto D, da Silva ME, Santos RF: Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Horm Metab Res 34:616–621, 2002
Woods SC, Gotoh K, Clegg DJ: Gender differences in the control of energy homeostasis. Exp Biol Med 228:1175–1180, 2003
Bjorntorp P: Body fat distribution, insulin resistance, and metabolic diseases. Nutrition 13:795–803, 1997
Wajchenberg BL: Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 21:697–738, 2000
Clegg DJ, Brown LM, Woods SC, Benoit SC: Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes 55:978–987, 2006
Clegg DJ, Riedy CA, Smith KA, Benoit SC, Woods SC: Differential sensitivity to central leptin and insulin in male and female rats. Diabetes 52:682–687, 2003
Geary N: Estradiol, CCK and satiation. Peptides 22:1251–1263, 2001
Geary N: Is the control of fat ingestion sexually differentiated Physiol Behav 83:659–671, 2004
Yanovsky S: Sugar and fat: Cravings and aversions. J Nutr 133:835S–837S, 2003
Valle A, Catala-Niell A, Colom B, Garcia-Palmer FJ, Oliver J, Roca P: Sex related differences in energy balance in response to caloric restriction. Am J Physiol Endocrinol Metab 289:E15–E22, 2005
Bulik CM, Reba L, Siega-Riz AM, Reichborn-Kjennerud T: Anorexia nervosa: definition, epidemiology, and cycle of risk. Int J Eat Dis 37 (Suppl. 1):S2–S9, 2005
Xu AW, Kaelin CB, Takeda K, Akira S, Schwartz MW, Barsh GS: PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115:951–958, 2005
Guitterez-Juarez R, Obici S, Rossetti L: Melanocortin-independent effects of leptin on hepatic glucose fluxes. J Biol Chem 279:49704–49715, 2004
Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS: Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252, 1996
Ahima RS: Central actions of adipocyte hormones. Trends Endocrinol Metab 16:307–313, 2005
Kishi T, Elmquist JK: Body weight is regulated by the brain: a link between feeding and emotion. Mol Psychiatry 10:132–146, 2005
Porte DJ, Baskin DG, Schwartz MW: Leptin and insulin action in the central nervous system. Nutr Rev 60:S20–S29, 2002
Considine RV, Sinha MK, Heiman ML, Kriaucinas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF: Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295, 1996
Havel PJ: Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. Diabetes 53 (Suppl. 1):S143–S151, 2004
Wisse BE, Campfield LA, Marliss EB, Morais JA, Tenenbaum R, Gougeon R: Effect of prolonged moderate and severe energy restriction and refeeding on plasma leptin concentrations in obese women. Am J Clin Nutr 70:321–330, 1999
Ahren B, Mansson S, Gingerich RL, Havel PJ: Regulation of plasma leptin in mice: influence of age, high-fat diet and fasting. Am J Physiol Regul Integr Comp Physiol 273:R113–R120, 1997
Zhao AZ, Shinohara MM, Huang D, Shimizu H, Eldar-Finkelman H, Krebs EG, Beavo JA, Bornfeldt KE: Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes. J Biol Chem 275:11348–11354, 2000
Niswender KD, Schwartz MW: Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Front Neuroendocrinol 24:1–10, 2003
Niswender KD, Baskin DG, Schwartz MW: Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol Metab 15:362–369, 2004
Hikita M, Bujo H, Hirayama S, Takahashi K, Morisaki N, Saito Y: Differential regulation of leptin receptor expression by insulin and leptin in neuroblastoma cells. Biochem Biophys Res Commun 271:703–709, 2000
Carvalheira JB, Siloto RM, Ignacchitti I, Brenelli SL, Carvalho CR, Leite A, Velloso LA, Gontijo JA, Saad MJ: Insulin modulates insulin-induced STAT3 activation in rat hypothalamus. FEBS Lett 500:119–124, 2001
Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr, Schwartz MW: Intracellular signaling: key enzyme in leptin-induced anorexia. Nature 413:794–795, 2001
Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers MG Jr, Seeley RJ, Schwartz MW: Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52:227–231, 2003
Akabayashi A, Wahlestedt C, Alexander JT, Leibowitz SF: Specific inhibition of endogenous neuropeptide Y synthesis in arcuate nucleus by antisense oligonucleotides suppresses feeding behavior and insulin secretion. Brain Res 21:55–61, 1994
Flier JS: Obesity wars: molecular progress confronts an expanding epidemic. Cell 116:337–350, 2004
Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ: Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:480–484, 2001
Seeley RJ, Drazen DL, Clegg DJ: The critical role of the melanocortin system in the control of energy balance. Ann Rev Nutr 24:133–149, 2004
Benoit SC, Tracy AL, Air EL, Kinzig K, Seeley RJ, Davidson TL: The role of the hypothalamic melanocortin system in behavioral appetitive processes. Pharmacol Biochem Behav 69:603–609, 2001
Baskin DG, Hahn TM, Schwartz MW: Leptin sensitive neurons in the hypothalamus. Horm Metab Res 31:345–350, 1999
Baskin DG, Porte DJ, Guest K, Dorsa DM: Regional concentrations of insulin in the rat brain. Endocrinology 112:898–903, 1983
Baskin DG, Sipols AJ, Schwartz MW, White MF: Insulin receptor substrate-1 (IRS-1) expression in rat brain. Endocrinology 134:1952–1955, 1994
Baskin DG, Sipols AJ, Schwartz MW, White MF: Immunocytochemical detection of insulin receptor substrate-1 (IRS- 1) in rat brain: colocalization with phosphotyrosine. Reg Peptides 48:257–266, 1993
Henneberg N, Hoyer S: Short-term or long-term intracerebroventricular (i.c.v.) infusion of insulin exhibits a discrete anabolic effect on cerebral energy metabolism in the rat. Neurosci Letters 175:153–156, 1994
Palovcik R, Phillips M, Kappy M, Raizada M: Insulin inhibits pyramidal neurons in hippocampal slices. Brain Res 309:187–191, 1984
Phillips M, Palovcik R: Dose-response testing of peptides by hippocampal brain slice recording. Meth Enzymol 168:129–144, 1989
Beal MF: Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci 23:298–304, 2000
Biessels G: Cerebral complications of diabetes: clinical findings and pathogenetic mechanisms. Neth J Med 54:35–45, 1999
Podolsky S, Leopold N: Abnormal glucose tolerance and arginine tolerance tests in Huntington’s disease. Gerontology 23:55–63, 1977
Mattson M, Pedersen W, Duan W, Culmsee C, Camandola S: Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer’s and Parkinson’s diseases. Ann N Y Acad Sci 893:154–175, 1999
Nolan JH, Wright CE: Evidence of impaired glucose tolerance and insulin resistance in patients with Alzheimer’s disease. Curr Dir Psychol Sci 10:102–105, 2001
Craft S, Newcomer J, Kanne S, Dagogo-Jack S, Cryer P, Sheline Y, Luby J, Dagogo-Jack A, Alderson A: Memory improvement following induced hyperinsulinemia in Alzheimer’s disease. Neurobiol Aging 17:123–130, 1996
Kumari M, Brunner E, Fuhrer R: Minireview: mechanisms by which the metabolic syndrome and diabetes impair memory. J Gerontol Series A Biol Sci Med 55:B228–B232, 2000
Strachan M, Deary I, Ewing F, Frier B: Is type II diabetes associated with an increased risk of cognitive dysfunction A critical review of published studies. Diabetes Care 20:438–445, 1997
Stewart R, Liolitsa D: Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med 16:93–112, 1999
Richardson J: Cognitive function in diabetes mellitus. Neurosci Biobehav Rev 14:385–388, 1990
Park CR: Cognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev 25:311–323, 2001
Flood J, Mooradian A, Morley J: Characteristics of learning and memory in streptozocin-induced diabetic mice. Diabetes 39:1391–1398, 1990
Kamal A, Biessels G, Urban I, Gispen W: Hippocampal synaptic plasticity in streptozotocin-diabetic rats: impairment of long-term potentiation and facilitation of long-term depression. Neuroscience 90:737–745, 1999
Kamal A, Biessels G, Duis S, Gispen W: Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing. Diabetologia 43:500–506, 2000
Biessels G, Kamal A, Ramakers G, Urban I, Spruijt B, Erkelens D, Gispen W: Place learning and hippocampal synaptic plasticity in streptozotocin-induced diabetic rats. Diabetes 45:1259–1266, 1996
Biessels G, Kamal A, Urban I, Spruijt B, Erkelens D, Gispen W: Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res 800:125–135, 1998
Lannert H, Hoyer S: Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 112:1199–1208, 1998
Di Luca M, Ruts L, Gardoni F, Cattabeni F, Biessels G, Gispen W: NMDA receptor subunits are modified transcriptionally and post-translationally in the brain of streptozotocin-diabetic rats. Diabetologia 42:693–701, 1999
Chabot C, Massicotte G, Milot M, Trudeau F, Gagne J: Impaired modulation of AMPA receptors by calcium-dependent processes in streptozotocin-induced diabetic rats. Brain Res 768:249–256, 1997
Collingridge G: Synaptic plasticity: the role of NMDA receptors in learning and memory. Nature 330:604–605, 1987
Park C, Seeley R, Craft S, Woods S: Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav 68:509–514, 2000
Parkes M, White K: Glucose attenuation of memory impairments. Behav Neurosci 114:307–319, 2000
Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon M, Alkon D: Brain insulin receptors and spatial memory: correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 274:34893–34902, 1999
Blanchard J, Duncan P: Effect of combinations of insulin, glucose and scopolamine on radial arm maze performance. Pharmacol Biochem Behav 58:209–214, 1997
Kopf S, Baratti C: The impairment of retention induced by insulin in mice may be mediated by a reduction in central cholinergic activity. Neurobiol Learn Mem 63:220–228, 1995
Kopf S, Baratti C: Effects of posttraining administration of insulin on retention of a habituation response in mice: participation of a central cholinergic mechanism. Neurobiol Learn Mem 71:50–61, 1999
Schwarzberg H, Bernstein H, Reiser M, Gunther O: Intracerebroventricular administration of insulin attenuates retrieval of a passive avoidance response in rats. Neuropeptides 13:79–81, 1989
Chen G, Koyama K, Yuan X, Lee Y, Zhou YT, O’Doherty R, Newgard CB, Unger RH: Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proc Natl Acad Sci U S A 93:14795–14799, 1996
Park C, Chavez M, Woods SC: IVT insulin decreases respiratory quotient in rats. Soc Neurosci Abstr 22:939, 1992
Chavez M, Riedy CA, van Dijk G, Woods SC: Central insulin and macronutrient intake in the rat. Am J Physiol Regul Integr Comp Physiol 271:R727–R731, 1996
Bray GA, Popkin BM: Dietary fat does affect obesity. Am J Clin Nutr 68:1157–1173, 1998
Gibney MJ: Epidemiology of obesity in relation to nutrient intake. Int J Obes 19 (Suppl. 5):S1–S3, 1995
Samaras K, Kelly PJ, Chiano MN, Arden N, Spector TD, Campbell LV: Genes versus environment. Diabetes Care 21:2069–2076, 1998
Bray GA, Fisler J, York DA: Neuroendocrine control of the development of obesity: understanding gained from studies of experimental animal models. Front Neuroendocrinol 11:128–181, 1990
Golay A, Bobbioni E: The role of dietary fat in obesity. Int J Obes Rel Metab Dis 21 (Suppl. 3):S2–S11, 1997
Hill JO, Lin D, Yakubu F, Peters JC: Development of dietary obesity in rats: influence of amount and composition of dietary fat. Int J Obes 16:321–333, 1992
Warwick ZS, Schiffman SS: Role of dietary fat in calorie intake and weight gain. Neurosci Biobehav Rev 16:585–596, 1992
Warwick ZS: Probing the causes of high-fat diet hyperphagia: a mechanistic and behavioral dissection. Neurosci Biobehav Rev 20:155–161, 1996
West DB, York B: Dietary fat, genetic predisposition, and obesity: lessons from animal models. Am J Clin Nutr 67 (Suppl. 3):505S–512S, 1998
Woods SC, Seeley RJ, Rushing PA, D’Alessio DA, Tso P: A controlled high-fat diet induces an obese syndrome in rats. J Nutr 133:1081–1087, 2003
Woods SC, D’Alessio DA, Tso P, Rushing PA, Clegg DJ, Benoit SC, Gotoh K, Liu M, Seeley RJ: Consumption of a high-fat diet alters the homeostatic regulation of energy balance. Physiol Behav 83:573–578, 2004
Leibel RL, Chung WK, Chua SC Jr: The molecular genetics of rodent single gene obesities. J Biol Chem 272:31937–31940, 1997
Levin BE, Brown KL, Dunn-Meynell AA: Differential effects of diet and obesity on high and low affinity sulfonylurea binding sites in the rat brain. Brain Res 739:293–300, 1996
Levin BE, Dunn-Meynell AA, Balkan B, Keesey RE: Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am J Physiol Regul Integr Comp Physiol 273:R725–R730, 1997
Reed DR, Bachmanov AA, Beauchamp GK, Tordoff MG, Price RA: Heritable variation in food preferences and their contribution to obesity. Behav Genet 27:373–387, 1997
West DB: Genetics of obesity in humans and animal models. Endocrinol Metab Clin N Am 25:801–813, 1996
Molteni R, Barnard RJ, Ying Z, Roberts CK, Gomez-Pinilla F: A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 112:803–814, 2002
Wu A, Molteni R, Ying Z, Gomez-Pinilla F: A saturated-fat diet aggravates the outcome of traumatic brain injury on hippocampal plasticity and cognitive function by reducing brain-derived neurotrophic factor. Neuroscience 119:365–375, 2003(Stephen C. Woods, Stephen C. Benoit, and)
ARC, arcuate nucleus; CCK, cholecystokinin
ABSTRACT
Peptide signals from the pancreatic islets and the gastrointestinal tract influence the regulation of energy homeostasis by the brain, and the brain in turn influences the secretions of both the islets and the gut. This article focuses on how insulin interacts with the brain to influence food intake, blood glucose, and cognitive behavior. Insulin is secreted in response to changes of ambient glucose, and the levels achieved are directly proportional to body adiposity. Hence, insulin, like leptin, is an adiposity signal. An increased insulin signal in the mediobasal hypothalamus indicates that ample or excess energy is available in the body and elicits responses that limit food intake and reduce hepatic glucose secretion. Increased insulin (and leptin as well) locally within the brain complements other signals that indicate a surfeit of energy in the body, including satiety signals generated by the gut during meals, glucose, and some fatty acids. There is compelling evidence that overlapping intracellular signaling pathways within the mediobasal hypothalamus mediate the overall catabolic response to these diverse metabolic signals. Insulin receptors are also densely expressed in the hippocampus, and insulin acts there to facilitate learning and memory. The function of insulin receptors in other brain areas is poorly understood. Obesity and/or the consumption of diets high in fat render the brain as well as the body insulin resistant. In the hypothalamus, this is manifest as a reduced ability of insulin to reduce food intake and body weight, and in the hippocampus, it is manifest as a reduced ability of insulin to improve learning and/or memory.
The brain-gut-islet connection refers to the myriad ways in which signals arising in the three arms of this important axis interact among themselves, and at least one overall function of this integrated control system is the regulation of energy homeostasis throughout the body. Many of the interactions of this triad are well known. The brain regulates activity in both the gut and the pancreatic islets directly via the autonomic nervous system and indirectly via changes in food intake and energy expenditure. Peptide hormones and other signals secreted from the gut, in addition to coordinating the digestion and absorption of nutrients, provide the incretin effect that augments prandial insulin secretion. Many of these peptides also serve as critical satiety signals to the brain that limit meal size. Islet hormones influence digestion and control the disposition of ingested nutrients in addition to providing key signals to the brain regarding the level of adiposity and circulating energy. This review focuses on one aspect of this complex network, i.e., the actions of pancreatic insulin within the brain and the pathologies that occur when insulin signaling within the brain is compromised. The topic is timely, with relevant new information appearing almost monthly, and it is also an area of knowledge where the basic tenets are being challenged, since insulin was historically thought not to interact with the brain and subsequently was thought to mainly influence the control of food intake and body weight.
CONTROL OF ENERGY INTAKE
The energy equation holds that for body weight to remain relatively stable over time, food intake must match energy expenditure, and deviations in either direction will result in weight gain or loss. Humans and most mammals consume food in discrete episodes or meals. When there are no restrictions on when or how much individuals are allowed to eat (i.e., when they are in a free-feeding or ad lib condition), the impetus to begin a meal is rarely if ever caused by a biological deficit or need such as insufficient glucose. Rather, evidence indicates that the timing of meals is based on psychological factors such as habit, time of day, the social situation, convenience, and others (1–3). Because of this, body weight regulation, the continuous process that ties energy intake to energy expenditure, must logically be manifest as a control over how many calories are consumed once a meal begins, i.e., on meal size. Consistent with this, during meals, the gut responds to ingested nutrients by secreting peptide signals proportional to the quantity and quality of calories consumed, and some of these secretions function as satiety signals to the brain to limit meal size (4–7). The prototypical satiety signal is the duodenal peptide cholecystokinin (CCK). Humans and animals that are administered CCK just before eating consume smaller meals, and when administered a selective CCK-1 receptor antagonist, they consume larger meals (5,8). Table 1 lists gut and islet signals secreted during meals that influence meal size and are considered to be satiety signals.
Adiposity signals are hormones secreted in direct proportion to body fat. In contrast to satiety signals that are secreted mainly during meals, adiposity signals are tonically present, providing a relatively continuous message to the brain concerning fat stored within the body. Pancreatic insulin and the adipocyte hormone leptin are the two best-known adiposity signals, and others such as amylin and adiponectin also circulate in proportion to body fat and share many of the same properties. Administering either insulin or leptin directly into the brain results in reduced food intake and body weight, and reductions of either insulin or leptin signaling locally within the brain results in overeating and weight gain. When an individual’s weight (i.e., body fat) changes, insulin and leptin secretion change in parallel, and this is manifest as an altered adiposity signal to the brain. There are many reviews of these phenomena (9–14).
The interaction of adiposity signals with satiety signals in the control of food intake is a topic of considerable interest and beyond the scope of this review. The basic principle is that adiposity signals modulate the sensitivity of the brain to meal-generated satiety signals (10,12,15). As an example, the administration of very low doses of either insulin or leptin directly into the brain enhances the efficacy of systemic CCK to reduce food intake (16–22), and a reduced leptin signal in the brain, which also reduces brain insulin signaling (23), lowers CCK sensitivity (24). The implication is that when an individual loses weight and insulin and leptin secretion are reduced, brain circuits that control meal size are consequently rendered less sensitive to meal-generated satiety signals such as CCK. As a result, more calories than normal must be consumed before a satiety signal of sufficient magnitude to terminate a meal is generated. Individuals consequently eat larger than normal meals until body weight returns to normal. Conversely, when an individual gains excess weight, the increased insulin and leptin signal in the brain causes increased sensitivity to satiety signals, and relatively small meals are consumed until the excess weight is lost.
INSULIN AS AN ADIPOSITY SIGNAL
Basal plasma insulin is low and increases during meals or when stimulated by glucose. Basal, prandial, and stimulated insulin levels are all direct functions of stored fat, with leaner individuals having lower levels and more obese individuals having higher levels (25–27). Plasma insulin is therefore positioned to convey an important signal to the brain indicating the degree of adiposity, and as discussed below, some insulin enters the brain from the circulation and provides a key negative feedback signal in the regulation of body fat as originally proposed by Kennedy (28) (Fig. 1). When exogenous insulin is administered near or directly into the mediobasal hypothalamus, animals behave as if they have excess fat, i.e., they eat less and lose weight. The response is dose dependent (17,29), occurs in all species assessed, and is not secondary to illness or incapacitation (30). When insulin levels in the brain are clamped by means of slow steady local infusions, body weight is maintained and defended at a level determined by the dose of insulin administered (rev. in 13,31–33). The response to changes of the insulin signal is bidirectional in that the administration of insulin antibodies into or near the mediobasal hypothalamus causes overeating and weight gain (34,35). Likewise, reducing hypothalamic insulin receptor activity either genetically by a neuronal-specific knockout of insulin receptors or pharmacologically via antisense oligonucleotides against the insulin receptor leads to increased food intake and body fat (36,37). Although insulin has not been administered directly into the brains of humans, certain formulations of insulin have been administered intranasally to humans with a consequent increase of cerebrospinal fluid but not plasma insulin. Humans receiving insulin in this way eat less food and lose body fat (38).
Insulin enters the brain via receptor-facilitated transport through capillary endothelial cells. The process is saturable, selective for insulin, and regulated (39–42). Insulin transport into the brain is reduced during fasting (43), by maintenance on a high-fat diet (44), and in genetic and dietary-induced obesity (45,46). Because brain insulin derives from plasma insulin, it should be the case that experimentally induced increases of plasma insulin enter the brain and result in reduced food intake and body weight. Such procedures are confounded by hypoglycemia and a consequent increased tendency to eat more food. However, when insulin is administered systemically at doses sufficiently low to preclude hypoglycemia, food intake is reduced (47). Likewise, when sufficient glucose is administered in conjunction with systemic insulin to circumvent hypoglycemia, food intake is also reduced (48).
Autoradiographic insulin binding, as well as immunohistochemical analyses, reveal that insulin receptors are selectively located in several brain regions (49–52). The areas of highest concentrations are the olfactory bulb, hypothalamus, cerebellum, cortex, and hippocampus (53–55), and most insulin receptor immunoreactivity occurs on neurons and not on glia.
INSULIN REGULATES ENERGY HOMEOSTASIS IN THE HYPOTHALAMUS
As discussed above, insulin reduces food intake and body weight when delivered into the third cerebral ventricle (i3vt) or directly into the hypothalamus in or near the arcuate nucleus (ARC). Conversely, reduction of insulin signaling has the opposite action. Insulin signaling in the ARC also initiates a signal via the vagus nerve to the liver to reduce glucose synthesis and secretion into the blood (56–58). Hence, insulin’s action in the hypothalamus is consistent with its better-known systemic actions, i.e., its net effect is to lower blood glucose (9,11). Reducing the amount of food consumed and neurally reducing hepatic glucose output both complement insulin’s ability to facilitate glucose uptake by muscle, liver, and other tissues, as well as complement insulin’s direct action in the liver. It has recently been reported that administering oleic acid or glucose into or near the ARC also reduces food intake (57,59–62). Leptin may also act there to influence glucose homeostasis (63). Hence, ARC neurons respond to diverse signals indicative of a surfeit of available energy (i.e., elevated insulin, fatty acids, or glucose) by reducing the ingestion of energy and decreasing the secretion of utilizable energy (especially glucose) into the blood. Rossetti’s group has postulated that manipulating intracellular metabolic signaling pathways, especially those involved with the oxidation of lipids, comprises the actual stimulus that is important in controlling both food intake and hepatic glucose production by the hypothalamus (61,64–67).
INSULIN AND LEPTIN AS ADIPOSITY SIGNALS
As discussed above, both leptin and insulin function as adiposity signals, and the two have overlapping actions with regard to the hypothalamic control of metabolism. While the existence of two or more adiposity signals might seem redundant, insulin and leptin in fact reflect different fat stores, sexes, and risk factors for developing type 2 diabetes, cardiovascular problems, and the metabolic syndrome.
Fat stores.
Insulin is secreted in proportion to visceral fat, whereas leptin reflects total fat mass and especially subcutaneous fat (68,69). This is an important distinction with regard to the message conveyed to the brain, since visceral fat carries a greater risk factor for the metabolic complications associated with obesity than does subcutaneous fat. Elevated visceral fat carries an increased risk for insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, and certain cancers (68,70,71). Hence, leptin and insulin each convey specific information to the brain regarding the distribution of fat, and the combination of the two additionally conveys information as to the total fat mass of the body.
Sex.
Women have relatively more subcutaneous fat and higher plasma leptin, whereas men have relatively more visceral fat and higher plasma insulin (68,70,71). Likewise, male rats have relatively more visceral fat and higher plasma insulin, whereas female rats have more subcutaneous fat and higher plasma leptin (72). We have found that the brain of females is more sensitive to the catabolic action of leptin, whereas the brain of males is more sensitive to the catabolic action of insulin (73), and that estrogen mediates this difference (72). These data are consistent with a growing literature documenting sex differences in the actions of many compounds that influence energy homeostasis, including CCK (74), insulin (38,73), leptin (73), and ghrelin (D.J.C., L.M. Brown, C.J. Kemp, A.D. Strader, S.C.B., S.C.W., M. Mangiarachina, N. Geary, unpublished data), and this may be manifest in the selection of foods (75,76) as well as the preferred strategy used by males and females to defend their body weight (77). The physiological basis of these sex differences is an important clinical issue, since males are far more likely to develop symptoms of the metabolic syndrome (70), whereas females are far more likely to develop eating disorders (78).
Risk factors for developing type 2 diabetes.
Although insulin and leptin each signal the degree of adiposity to the brain, and whereas each lowers food intake as well as hepatic glucose secretion, they do so by stimulating different ARC neurons and circuits (79) as well as by altering different hepatic enzyme systems (80). Further, each has important other functions. Insulin is a major controller of the levels and utilization of glucose throughout most of the body, including the brain (9,11). Leptin also influences glucose parameters via the brain, although via different neural circuits than stimulated by insulin (80). Low circulating leptin and the resultant decrease of leptin signaling have been hypothesized to regulate many vital systems when animals are severely hypocaloric and have low body fat (81–83). The secretion of insulin is adjusted in response to every acute change of metabolism (9,84), with levels increasing during meals or when glucose is elevated for some other reason and decreasing during stress and exercise. The half-life of insulin in the blood (2–3 min) is consistent with its role as a minute-to-minute indicator of ongoing metabolism, and all of its fluctuations are directly proportional to total body fat (26). Leptin is secreted from adipocytes in direct proportion to the amount of stored fat (85) (although the actual stimulus is related more to the metabolic activity of the fat cell than to actual fat storage [86] such that dissociations can occur between stored fat and leptin release, particularly during a fast [86–88]). Nonetheless, under normal conditions and with a half-life of 45 min, plasma leptin levels are a reliable and relatively stable indicator of body fat. Hence, insulin levels reflect the interaction of ongoing metabolic processes and body adiposity, whereas leptin levels reflect the activity of adipose cells more directly.
As described above, both insulin and leptin act in the ARC (and probably other brain areas) to reduce food intake and body weight, and both also act in the ARC to reduce hepatic output of glucose. In some instances, the overlap of function may result from common intracellular signaling pathways of insulin and leptin, since both activate a pathway using insulin receptor substrate 1 and 2, and both cause increased intracellular cAMP degradation (89–91). Insulin upregulates the expression of mRNA of the long form of the leptin receptor (OB-Rb) in neuronal but not other cell types (92), and insulin facilitates leptin’s ability to activate the JAK-STAT pathway in the hypothalamus (90,93). Both leptin (94,95) and insulin (94,95) exert their catabolic action through phosphatidylinositol 3-kinase.
INSULIN AND LEPTIN'S INTERACTION WITH CENTRAL NEUROPEPTIDES
Insulin and leptin interact with two populations of ARC neurons. Activity of those that synthesize proopiomelanocortin, the precursor molecule of the melanocortins, is stimulated by insulin and leptin, whereas activity of those that synthesize neuropeptide Y plus Agouti-related protein is inhibited by insulin and leptin. -Melanocyte–stimulating hormone is a melanocortin that is derived from ARC proopiomelanocortin and is an agonist at melanocortin receptors (MC3R and MC4R) in several hypothalamic nuclei; Agouti-related protein is an endogenous antagonist of these same melanocortin receptors. Central administration of insulin or leptin, or the administration of -melanocyte–stimulating hormone or synthetic agonists for melanocortin receptors, or the application of treatments that reduce ARC neuropeptide Y (e.g., antisense oligonucleotides administered directly into the ARC [96]), all result in reduced food intake and body weight. Conversely, the administration of neuropeptide Y, Agouti-related protein, or synthetic melanocortin antagonists, or the absence of endogenous insulin or leptin signaling, all result in a net increase of food intake and body weight (rev. in 11,83,97–101).
OTHER ACTIONS OF INSULIN WITHIN THE BRAIN
It is important to consider what a change in the insulin signal at its receptor in diverse brain areas actually signifies. The obvious answer is that acute changes of insulin reflect an increase (or decrease) in energy in the form of glucose interacting with the pancreas, whereas sustained changes additionally reflect the amount of fat stored in the visceral or abdominal region. Based on this, it is easy to generate an explanation for why neurons in the mediobasal hypothalamus express insulin receptors, since these neurons are intimately involved in the regulation of energy homeostasis. An intriguing related question, however, concerns the rationale for more remote areas of the brain to express insulin receptors, such as the hippocampus or the olfactory bulb.
In the hippocampus, immunoreactivity for insulin receptors is found in the molecular layer of the dentate gyrus and on dendrites of CA1 pyramidal cells (51,102). Insulin binding in the hippocampus is colocalized with immuno-labeled phosphotyrosine (54) and insulin receptor substrate 1 (103), and as is discussed above, these compounds are important for the insulin receptor’s intracellular signaling pathways (104). Thus, the binding of insulin in the hippocampus, as it is in the hypothalamus, appears to be closely associated with functional effects of insulin. Glucose metabolism in hippocampal cells is sensitive to application of exogenous insulin (105), and this sensitivity depends on the insulin receptor (106,107). Further, insulin receptors in the hippocampus are localized in dendritic fields, suggesting a neuromodulatory role (51,54,55). Furthermore, there is a relationship between certain metabolic disorders and cognitive decline (108). In diabetes, for example, patients must rely on exogenous insulin administration to keep blood glucose levels within a life-sustaining range. These patients also often exhibit increased cognitive impairment correlated with the progression of their diabetes (109). Other disease states are also accompanied by changes in metabolic status. The progression of diverse central nervous system disorders such as Huntington’s disease (110), Parkinson’s disease (111), and schizophrenia is correlated with changes in glucose levels, insulin, and metabolic activity. Likewise, the progression of Alzheimer’s disease is correlated with disturbances in basal insulin levels as well as glucose metabolism (112).
More striking is the finding that when Alzheimer’s patients are made hyperinsulinemic, their performance on several assessments of memorial tasks is improved (113). Importantly, this occurs even at doses of insulin that do not affect peripheral glucose levels. Further, hyperinsulinemic states do not appear to increase Alzheimer’s patients’ performance on visual-spatial or physical-coordination tasks. This finding adds support to the hypothesis that insulin levels are specific to cognitive process (e.g., memory) in Alzheimer’s patients. Finally, patients with type 2 diabetes who are insensitive to the effects of insulin (i.e., who are insulin resistant) are also impaired on some measures of cognitive ability (114–117). These and other findings encourage the hypothesis that insulin plays an important role in normal cognitive functions and memorial processes. Moreover, it encourages the hypothesis that alterations in insulin signaling may play an important role in neurodegenerative disease.
In addition to the epidemiological and clinical studies, a growing body of evidence from animal experiments also implicates insulin as an important factor in learning and memory (118). Experimental removal of insulin leads to disrupted learning and performance. For example, administration of streptozotocin leads to impaired learning on a number of learning tasks in mice (119). In rats, streptozotocin-induced diabetes leads to disrupted performance on avoidance tasks and in Morris water mazes (109,120–123). Central streptozotocin also produces impairment in working and reference memory in rats (124), and it alters intracellular signaling by N-methyl-D-aspartate (125) and -amino-3-hydroxy-5-methyl-4-isoxaziole-propionate (126) receptors that are implicated in the development of long-term potentiation (127). Thus, disruption of systemic insulin signaling is associated with impairments of memorial processes in rodents.
Importantly, administration of exogenous insulin improves performance on some learning tasks and corrects the learning and memory deficits produced by streptozotocin or diabetes. For example, administration of exogenous insulin improves rats’ performance in the one-trial learning of a passive avoidance task (128,129). It also ameliorates the diabetic impairments observed on radial-arm maze tasks and water mazes (122,123). A key point is that administration of insulin directly into the brain, where it does not improve peripheral glucose metabolism, also improves learning (128,130), although some studies have reported contradictory findings, i.e., that administration of insulin impairs learning and memory performance (131–134).
Therefore, data from both humans and animals support the hypothesis that insulin is an important factor in memorial processes. However, the exact nature of that role remains elusive. This is due, in part, to the fact that much of the previous work suffers from one or both of two serious confounds. First, it is often difficult to disentangle the effects of altered insulin from the effects of altered metabolism. Large changes in basal insulin levels can produce profound disruptions in metabolic status that might account for some of the observed disruptions in learning in and of themselves. Second, because most manipulations of insulin occur systemically, it is difficult to identify the effects of insulin uniquely in regions of the brain known to be important for learning and memory. Finally, the ability of insulin to improve cognitive behavior might be task or reinforcement specific. It might be, for example, that increased insulin in the hippocampus, which reflects an increase of available energy in the body, facilitates learning tasks that help procure food. That is, elevated insulin might well enable remembering where food is located, or the best time to access it, or related factors. Likewise, increased insulin activity in the olfactory bulb could help form associations between specific odors and food. The point is that any general hypothesis of insulin action in the brain must account for what changes of insulin actually reflect.
DIETARY FAT, OBESITY, AND INSULIN RESISTANCE
As previously mentioned, when leptin is administered into the brains of experimental animals, there is a selective reduction of body fat, with lean body mass being spared (135). Likewise, when insulin is administered into the brain, there is a reduction of the respiratory quotient, suggesting that the body is oxidizing relatively more fat (136). These observations suggest that one action of these adipose signals within the brain is to reduce body fat, and a corollary of this is that fat ingestion would be expected to be reduced as well. Consistent with this, we have observed that when insulin is administered into the third cerebral ventricle of rats, fat intake is selectively reduced (137). Hence, it is reasonable to hypothesize that leptin and insulin, acting in the brain, reduce body fat by increasing lipid mobilization and oxidation and simultaneously by reducing the consumption of dietary fat.
When animals become obese after exposure to high-fat diets, they become resistant to leptin and insulin’s ability to regulate food intake and body weight. The epidemiological data that increasing dietary fat accelerates the development of obesity are quite compelling and have been summarized in several reviews (138–140). Animal studies provide strong corroborative evidence, i.e., across numerous experiments, diets, and species, and the conclusion that increased consumption of high-fat diets leads to increased body fat is inescapable (141–148). Importantly, there are strong genetic influences that dictate whether or not a given individual will be prone or resistant to becoming obese when exposed to a high-fat diet (141,146,149–153). As Bray and Popkin (138) point out, a high-fat diet can be viewed as the environmental agent that acts on a susceptible host animal to produce the noninfectious disease obesity. Importantly, the consequences of obesity, including dietary-induced obesity, are well documented and include type 2 diabetes and insulin insensitivity. Further, some detrimental effects of dietary fat are not limited to obese individuals. For example, we have recently demonstrated that while high-fat diet–induced obesity decreases central sensitivity to the anorexic effects of central insulin administration, increased dietary fat, in the absence of frank obesity, also attenuates the potency of central insulin to reduce food intake and body weight (148; K. Gotoh, M.D. Wortman, S.C.B., D.J.C., D. D’Alessio, P. Tso, R.J. Seeley, S.C.W., unpublished data).
HIPPOCAMPAL INSULIN RESISTANCE
Consistent with the concept that insulin acts in multiple regions of the brain to influence multiple processes, dietary-induced insulin resistance has recently been linked to impaired cognitive function in both humans and animals. Specifically, high levels of dietary saturated fats and simple carbohydrates (which promote insulin resistance and obesity) have been demonstrated to reduce hippocampal-dependent memory processes. For example, Gomez-Pinilla and colleagues (154) have shown that long-term access to obesigenic diets impairs rats’ performance in the Morris water maze task, a classic measure of spatial memory. These deficits are associated with reductions in hippocampal expression of brain-derived neurotrophic factor mRNA (155). We and others have found that increased body weight and peripheral metabolic disruptions are also associated with reduced insulin receptor gene expression in the hippocampus. Several important questions remain unanswered, however, including the specific molecular mechanisms by which central insulin resistance might lead to decreased expression of such factors as brain-derived neurotrophic factor.
SUMMARY
To summarize, increased insulin in the mediobasal hypothalamus provides a signal that ample or excess energy is available in the body, and one consequence is a reduction of food intake. It has recently been reported that the increased hypothalamic insulin signal also elicits a vagal reflex to the liver that reduces glucose secretion. Increased insulin (and probably leptin) locally within the hypothalamus therefore can be considered to be analogous to other signals that indicate a surfeit of energy in the body. In addition to satiety and adiposity signals, this includes certain lipids and glucose, and there is compelling evidence that overlapping intracellular signaling pathways within the mediobasal hypothalamus mediate the overall catabolic response to these diverse metabolic signals. Insulin receptors are also densely expressed in the hippocampus, and there is evidence that insulin acts there to facilitate certain cognitive functions. The function of insulin receptors in other brain areas is poorly understood. Obesity and/or the consumption of diets high in fat render the brain as well as the body insulin resistant. In the hypothalamus, this is manifest as a reduced ability of insulin to reduce food intake and body weight, and in the hippocampus, it is manifest as a reduced ability of insulin to improve learning and/or memory. Figure 2 is a model depicting some of the feedback loops involving insulin in the brain.
FOOTNOTES
This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
REFERENCES
Strubbe JH, Woods SC: The timing of meals. Psychol Rev 111:128–141, 2004
Woods SC: The eating paradox: how we tolerate food. Psychol Rev 98:488–505, 1991
Woods SC, Strubbe JH: The psychobiology of meals. Psychol Bull Rev 1:141–155, 1994
Kaplan JM, Moran TH: Gastrointestinal signaling in the control of food intake. In Handbook of Behavioral Neurobiology: Neurobiology of Food and Fluid Intake. Vol. 4, no. 2. Stricker EM, Woods SC, Eds. New York, Kluwer Academic/Plenum, 2004, p.273–303
Moran TH, Kinzig KP: Gastrointestinal satiety signals II. Cholecystokinin. Am J Physiol Gastrointest Liver Physiol 286:G183–G188, 2004
Strader AD, Woods SC: Gastrointestinal hormones and food intake. Gastroenterology 128:175–191, 2005
Woods SC: Gastrointestinal satiety signals I. An overview of gastrointestinal signals that influence food intake. Am J Physiol Gastrointest Liver Physiol 286:G7–G13, 2004
Smith GP, Gibbs J: The development and proof of the cholecystokinin hypothesis of satiety. In Multiple Cholecystokinin Receptors in the CNS. Dourish CT, Cooper SJ, Iversen SD, Iversen LL, Eds. Oxford, U.K., Oxford University Press, 1992, p.166–182
Porte D Jr, Baskin DG, Schwartz MW: Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes 54:1264–1276, 2005
Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG: Central nervous system control of food intake. Nature 404:661–671, 2000
Schwartz MW, Porte D Jr: Diabetes, obesity, and the brain. Science 307:375–379, 2005
Woods SC, Seeley RJ, Porte D Jr, Schwartz MW: Signals that regulate food intake and energy homeostasis. Science 280:1378–1383, 1998
Woods SC, Seeley RJ: Insulin as an adiposity signal. Int J Obes Relat Metab Disord 25:S35–S38, 2001
Friedman JM: The function of leptin in nutrition, weight, and physiology. Nutr Rev 60:S1–S14, 2002
Woods SC, Seeley RJ: Adiposity signals and the control of energy homeostasis. Nutrition 16:894–902, 2000
Figlewicz DP, Sipols AJ, Seeley RJ, Chavez M, Woods SC, Porte DJ: Intraventricular insulin enhances the meal-suppressive efficacy of intraventricular cholecystokinin octapeptide in the baboon. Behav Neurosci 109:567–569, 1995
Riedy CA, Chavez M, Figlewicz DP, Woods SC: Central insulin enhances sensitivity to cholecystokinin. Physiol Behav 58:755–760, 1995
Emond M, Schwartz GJ, Ladenheim EE, Moran TH: Central leptin modulates behavioral and neural responsivity to CCK. Am J Physiol Regul Integr Comp Physiol 276:R1545–R1549, 1999
Matson CA, Wiater MF, Kuijper JL, Weigle DS: Synergy between leptin and cholecystokinin (CCK) to control daily caloric intake. Peptides 18:1275–1278, 1997
Matson CA, Reid DF, Cannon TA, Ritter RC: Cholecystokinin and leptin act synergistically to reduce body weight. Am J Physiol Regul Integr Comp Physiol 278:R882–R890, 2000
Morton GJ, Blevins JE, Williams DL, Niswender KD, Gelling RW, Rhodes CJ, Baskin DG, Schwartz MW: Leptin action in the forebrain regulates the hindbrain response to satiety signals. J Clin Invest 115:703–710, 2005
Barrachina MD, Martinez V, Wang L, Wei JY, Tache Y: Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice. Proc Natl Acad Sci U S A 94:10455–10460, 1997
Ikeda H, West DB, Pustek JJ, Figlewicz DP, Greenwood MRC, Porte D Jr, Woods SC: Intraventricular insulin reduces food intake and body weight of lean but not obese Zucker rats. Appetite 7:381–386, 1986
McMinn JE, Sindelar DK, Havel PJ, Schwartz MW: Leptin deficiency induced by fasting impairs the satiety response to cholecystokinin. Endocrinology 141:4442–4448, 2000
Bagdade JD, Bierman EL, Porte D Jr: The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest 46:1549–1557, 1967
Polonsky KS, Given E, Carter V: Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest 81:442–448, 1988
Woods SC, Decke E, Vasselli JR: Metabolic hormones and regulation of body weight. Psychol Rev 81:26–43, 1974
Kennedy GC: The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond (Biol ) 140:579–592, 1953
Woods SC, Lotter EC, McKay LD, Porte D Jr: Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282:503–505, 1979
Chavez M, Seeley RJ, Woods SC: A comparison between the effects of intraventricular insulin and intraperitoneal LiCl on three measures sensitive to emetic agents. Behav Neurosci 109:547–550, 1995
Schwartz MW, Figlewicz DP, Baskin DG, Woods SC, Porte D Jr: Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev 13:387–414, 1992
Woods SC, Chavez M, Park CR, Riedy C, Kaiyala K, Richardson RD, Figlewicz DP, Schwartz MW, Porte D, Seeley RJ: The evaluation of insulin as a metabolic signal controlling behavior via the brain. Neurosci Biobehav Rev 20:139–144, 1995
Woods SC: Insulin and the brain: a mutual dependency. Prog Psychobiol Physiol Psychol 16:53–81, 1996
McGowan MK, Andrews KM, Grossman SP: Chronic intrahypothalamic infusions of insulin or insulin antibodies alter body weight and food intake in the rat. Physiol Behav 51:753–766, 1992
Strubbe JH, Mein CG: Increased feeding in response to bilateral injection of insulin antibodies in the VMH. Physiol Behav 19:309–313, 1977
Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Müller-Wieland D, Kahn CR: Role of brain insulin receptor in control of body weight and reproduction. Science 289:2122–2125, 2000
Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L: Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5:566–572, 2002
Hallschmid M, Benedict C, Schultes B, Fehm HL, Born J, Kern W: Intranasal insulin reduces body fat in men but not in women. Diabetes 53:3024–3029, 2004
Banks WA, Jaspan JB, Huang W, Kastin AJ: Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin. Peptides 18:1423–1429, 1997
Baura G, Foster D, Porte D Jr, Kahn SE, Bergman RN, Cobelli C, Schwartz MW: Saturable transport of insulin from plasma into the central nervous system of dogs in vivo: a mechanism for regulated insulin delivery to the brain. J Clin Invest 92:1824–1830, 1993
Schwartz MW, Bergman RN, Kahn SE, Taborsky GJ Jr, Fisher LD, Sipols AJ, Woods SC, Steil GM, Porte D Jr: Evidence for uptake of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. J Clin Invest 88:1272–1281, 1991
Woods SC, Seeley RJ, Baskin DG, Schwartz MW: Insulin and the blood-brain barrier. Curr Pharm Des 9:795–800, 2003
Strubbe JH, Porte DJ, Woods SC: Insulin responses and glucose levels in plasma and cerebrospinal fluid during fasting and refeeding in the rat. Physiol Behav 44:205–208, 1988
Kaiyala K, Prigeon RL, Kahn SE, Woods SC, Schwartz MW: Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes 49:1525–1533, 2000
Israel PA, Park CR, Schwartz MW, Green PK, Sipols AJ, Woods SC, Porte D Jr, Figewicz DP: Effect of diet-induced obesity and experimental hyperinsulinemia on insulin uptake into CSF of the rat. Brain Res Bull 30:571–575, 1993
Stein LJ, Dorsa DM, Baskin DG, Figlewicz DP, Ikeda H, Frankmann SP, Greenwood MR, Porte D Jr, Woods SC: Immunoreactive insulin levels are elevated in the cerebrospinal fluid of genetically obese Zucker rats. Endocrinology 113:2299–2301, 1983
Vanderweele DA, Haraczkiewicz E, Van Itallie TB: Elevated insulin and satiety in obese and normal weight rats. Appetite 3:99–109, 1982
Nicolaidis S, Rowland N: Metering of intravenous versus oral nutrients and regulation of energy balance. Am J Physiol 231:661–668, 1976
Baskin DG, Marks JL, Schwartz MW, Figewicz DP, Woods SC, Porte D Jr: Insulin and insulin receptors in the brain in relation to food intake and body weight. In Endocrine and Nutritional Control of Basic Biological Functions. Lehnert H, Murison R, Weiner H, Hellhammer D, Beyer J, Eds. Stuttgart, Hogrefe & Huber, 1990, p.202–222
Baskin DG, Woods SC, West DB, van HM, Posner BI, Dorsa DM, Porte D Jr: Immunocytochemical detection of insulin in rat hypothalamus and its possible uptake from cerebrospinal fluid. Endocrinology 113:1818–1825, 1983
Corp ES, Woods SC, Porte D Jr, Dorsa DM, Figlewicz DP, Baskin DG: Localization of 125I-insulin binding sites in the rat hypothalamus by quantitative autoradiography. Neurosci Lett 70:17–22, 1986
Havrankova J, Brownstein M, Roth J: Insulin and insulin receptors in the rodent brain. Diabetologia 20:268–273, 1981
Unger J, McNeil TH, Moxley RTI, White M, Moss A, Livingston JN: Distribution of insulin receptor-like immunoreactivity in the rat forebrain. Neuroscience 31:143–157, 1989
Unger JW, Moss AM, Livingston JN: Immunohistochemical localization of insulin receptors and phosphotyrosine in the brainstem of the adult rat. Neuroscience 42:853–861, 1991
Unger JW, Livingston JN, Moss AM: Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Neurobiol 36:343–362, 1991
Obici S, Zhang BB, Karkanias G, Rossetti L: Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376–1382, 2002
Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L: Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 11:320–327, 2005
Lin X, Taguchi A, Park S, Kushner JA, Li F, Li Y, White MF: Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes. J Clin Invest 114:886–888, 2004
Levin BE, Routh VH, Kang L, Sanders NM, Dunn-Meynell AA: Neuronal glucosensing: what do we know after 50 years Diabetes 53:2521–2528, 2004
Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L: Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51:271–275, 2002
Obici S, Feng Z, Arduini A, Conti R, Rossetti L: Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 9:756–761, 2003
Obici S, Rossetti L: Minireview: nutrient sensing and the regulation of insulin action and energy balance. Endocrinology 144:5172–5178, 2003
Pocai A, Morgan K, Buettner C, Gutierrez-Juarez R, Obici S, Rossetti L: Central leptin acutely reverses diet-induced hepatic insulin resistance. Diabetes 54:3182–3189, 2005
He W, Lam TK, Obici S, Rossetti L: Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat Neurosci 9:227–233, 2006
Pocai A, Obici S, Schwartz GJ, Rossetti L: A brain-liver circuit regulates glucose homeostasis. Cell Metab 1:53–61, 2005
Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L: Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434:1026–1031, 2005
Lam TK, Gutierrez-Juarez R, Pocai A, Rossetti L: Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309:943–947, 2005
Wajchenberg BL, Giannella-Neto D, da Silva ME, Santos RF: Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Horm Metab Res 34:616–621, 2002
Woods SC, Gotoh K, Clegg DJ: Gender differences in the control of energy homeostasis. Exp Biol Med 228:1175–1180, 2003
Bjorntorp P: Body fat distribution, insulin resistance, and metabolic diseases. Nutrition 13:795–803, 1997
Wajchenberg BL: Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 21:697–738, 2000
Clegg DJ, Brown LM, Woods SC, Benoit SC: Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes 55:978–987, 2006
Clegg DJ, Riedy CA, Smith KA, Benoit SC, Woods SC: Differential sensitivity to central leptin and insulin in male and female rats. Diabetes 52:682–687, 2003
Geary N: Estradiol, CCK and satiation. Peptides 22:1251–1263, 2001
Geary N: Is the control of fat ingestion sexually differentiated Physiol Behav 83:659–671, 2004
Yanovsky S: Sugar and fat: Cravings and aversions. J Nutr 133:835S–837S, 2003
Valle A, Catala-Niell A, Colom B, Garcia-Palmer FJ, Oliver J, Roca P: Sex related differences in energy balance in response to caloric restriction. Am J Physiol Endocrinol Metab 289:E15–E22, 2005
Bulik CM, Reba L, Siega-Riz AM, Reichborn-Kjennerud T: Anorexia nervosa: definition, epidemiology, and cycle of risk. Int J Eat Dis 37 (Suppl. 1):S2–S9, 2005
Xu AW, Kaelin CB, Takeda K, Akira S, Schwartz MW, Barsh GS: PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115:951–958, 2005
Guitterez-Juarez R, Obici S, Rossetti L: Melanocortin-independent effects of leptin on hepatic glucose fluxes. J Biol Chem 279:49704–49715, 2004
Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS: Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252, 1996
Ahima RS: Central actions of adipocyte hormones. Trends Endocrinol Metab 16:307–313, 2005
Kishi T, Elmquist JK: Body weight is regulated by the brain: a link between feeding and emotion. Mol Psychiatry 10:132–146, 2005
Porte DJ, Baskin DG, Schwartz MW: Leptin and insulin action in the central nervous system. Nutr Rev 60:S20–S29, 2002
Considine RV, Sinha MK, Heiman ML, Kriaucinas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF: Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295, 1996
Havel PJ: Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. Diabetes 53 (Suppl. 1):S143–S151, 2004
Wisse BE, Campfield LA, Marliss EB, Morais JA, Tenenbaum R, Gougeon R: Effect of prolonged moderate and severe energy restriction and refeeding on plasma leptin concentrations in obese women. Am J Clin Nutr 70:321–330, 1999
Ahren B, Mansson S, Gingerich RL, Havel PJ: Regulation of plasma leptin in mice: influence of age, high-fat diet and fasting. Am J Physiol Regul Integr Comp Physiol 273:R113–R120, 1997
Zhao AZ, Shinohara MM, Huang D, Shimizu H, Eldar-Finkelman H, Krebs EG, Beavo JA, Bornfeldt KE: Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes. J Biol Chem 275:11348–11354, 2000
Niswender KD, Schwartz MW: Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Front Neuroendocrinol 24:1–10, 2003
Niswender KD, Baskin DG, Schwartz MW: Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol Metab 15:362–369, 2004
Hikita M, Bujo H, Hirayama S, Takahashi K, Morisaki N, Saito Y: Differential regulation of leptin receptor expression by insulin and leptin in neuroblastoma cells. Biochem Biophys Res Commun 271:703–709, 2000
Carvalheira JB, Siloto RM, Ignacchitti I, Brenelli SL, Carvalho CR, Leite A, Velloso LA, Gontijo JA, Saad MJ: Insulin modulates insulin-induced STAT3 activation in rat hypothalamus. FEBS Lett 500:119–124, 2001
Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr, Schwartz MW: Intracellular signaling: key enzyme in leptin-induced anorexia. Nature 413:794–795, 2001
Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers MG Jr, Seeley RJ, Schwartz MW: Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52:227–231, 2003
Akabayashi A, Wahlestedt C, Alexander JT, Leibowitz SF: Specific inhibition of endogenous neuropeptide Y synthesis in arcuate nucleus by antisense oligonucleotides suppresses feeding behavior and insulin secretion. Brain Res 21:55–61, 1994
Flier JS: Obesity wars: molecular progress confronts an expanding epidemic. Cell 116:337–350, 2004
Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ: Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:480–484, 2001
Seeley RJ, Drazen DL, Clegg DJ: The critical role of the melanocortin system in the control of energy balance. Ann Rev Nutr 24:133–149, 2004
Benoit SC, Tracy AL, Air EL, Kinzig K, Seeley RJ, Davidson TL: The role of the hypothalamic melanocortin system in behavioral appetitive processes. Pharmacol Biochem Behav 69:603–609, 2001
Baskin DG, Hahn TM, Schwartz MW: Leptin sensitive neurons in the hypothalamus. Horm Metab Res 31:345–350, 1999
Baskin DG, Porte DJ, Guest K, Dorsa DM: Regional concentrations of insulin in the rat brain. Endocrinology 112:898–903, 1983
Baskin DG, Sipols AJ, Schwartz MW, White MF: Insulin receptor substrate-1 (IRS-1) expression in rat brain. Endocrinology 134:1952–1955, 1994
Baskin DG, Sipols AJ, Schwartz MW, White MF: Immunocytochemical detection of insulin receptor substrate-1 (IRS- 1) in rat brain: colocalization with phosphotyrosine. Reg Peptides 48:257–266, 1993
Henneberg N, Hoyer S: Short-term or long-term intracerebroventricular (i.c.v.) infusion of insulin exhibits a discrete anabolic effect on cerebral energy metabolism in the rat. Neurosci Letters 175:153–156, 1994
Palovcik R, Phillips M, Kappy M, Raizada M: Insulin inhibits pyramidal neurons in hippocampal slices. Brain Res 309:187–191, 1984
Phillips M, Palovcik R: Dose-response testing of peptides by hippocampal brain slice recording. Meth Enzymol 168:129–144, 1989
Beal MF: Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci 23:298–304, 2000
Biessels G: Cerebral complications of diabetes: clinical findings and pathogenetic mechanisms. Neth J Med 54:35–45, 1999
Podolsky S, Leopold N: Abnormal glucose tolerance and arginine tolerance tests in Huntington’s disease. Gerontology 23:55–63, 1977
Mattson M, Pedersen W, Duan W, Culmsee C, Camandola S: Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer’s and Parkinson’s diseases. Ann N Y Acad Sci 893:154–175, 1999
Nolan JH, Wright CE: Evidence of impaired glucose tolerance and insulin resistance in patients with Alzheimer’s disease. Curr Dir Psychol Sci 10:102–105, 2001
Craft S, Newcomer J, Kanne S, Dagogo-Jack S, Cryer P, Sheline Y, Luby J, Dagogo-Jack A, Alderson A: Memory improvement following induced hyperinsulinemia in Alzheimer’s disease. Neurobiol Aging 17:123–130, 1996
Kumari M, Brunner E, Fuhrer R: Minireview: mechanisms by which the metabolic syndrome and diabetes impair memory. J Gerontol Series A Biol Sci Med 55:B228–B232, 2000
Strachan M, Deary I, Ewing F, Frier B: Is type II diabetes associated with an increased risk of cognitive dysfunction A critical review of published studies. Diabetes Care 20:438–445, 1997
Stewart R, Liolitsa D: Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med 16:93–112, 1999
Richardson J: Cognitive function in diabetes mellitus. Neurosci Biobehav Rev 14:385–388, 1990
Park CR: Cognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev 25:311–323, 2001
Flood J, Mooradian A, Morley J: Characteristics of learning and memory in streptozocin-induced diabetic mice. Diabetes 39:1391–1398, 1990
Kamal A, Biessels G, Urban I, Gispen W: Hippocampal synaptic plasticity in streptozotocin-diabetic rats: impairment of long-term potentiation and facilitation of long-term depression. Neuroscience 90:737–745, 1999
Kamal A, Biessels G, Duis S, Gispen W: Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing. Diabetologia 43:500–506, 2000
Biessels G, Kamal A, Ramakers G, Urban I, Spruijt B, Erkelens D, Gispen W: Place learning and hippocampal synaptic plasticity in streptozotocin-induced diabetic rats. Diabetes 45:1259–1266, 1996
Biessels G, Kamal A, Urban I, Spruijt B, Erkelens D, Gispen W: Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res 800:125–135, 1998
Lannert H, Hoyer S: Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 112:1199–1208, 1998
Di Luca M, Ruts L, Gardoni F, Cattabeni F, Biessels G, Gispen W: NMDA receptor subunits are modified transcriptionally and post-translationally in the brain of streptozotocin-diabetic rats. Diabetologia 42:693–701, 1999
Chabot C, Massicotte G, Milot M, Trudeau F, Gagne J: Impaired modulation of AMPA receptors by calcium-dependent processes in streptozotocin-induced diabetic rats. Brain Res 768:249–256, 1997
Collingridge G: Synaptic plasticity: the role of NMDA receptors in learning and memory. Nature 330:604–605, 1987
Park C, Seeley R, Craft S, Woods S: Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav 68:509–514, 2000
Parkes M, White K: Glucose attenuation of memory impairments. Behav Neurosci 114:307–319, 2000
Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon M, Alkon D: Brain insulin receptors and spatial memory: correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 274:34893–34902, 1999
Blanchard J, Duncan P: Effect of combinations of insulin, glucose and scopolamine on radial arm maze performance. Pharmacol Biochem Behav 58:209–214, 1997
Kopf S, Baratti C: The impairment of retention induced by insulin in mice may be mediated by a reduction in central cholinergic activity. Neurobiol Learn Mem 63:220–228, 1995
Kopf S, Baratti C: Effects of posttraining administration of insulin on retention of a habituation response in mice: participation of a central cholinergic mechanism. Neurobiol Learn Mem 71:50–61, 1999
Schwarzberg H, Bernstein H, Reiser M, Gunther O: Intracerebroventricular administration of insulin attenuates retrieval of a passive avoidance response in rats. Neuropeptides 13:79–81, 1989
Chen G, Koyama K, Yuan X, Lee Y, Zhou YT, O’Doherty R, Newgard CB, Unger RH: Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proc Natl Acad Sci U S A 93:14795–14799, 1996
Park C, Chavez M, Woods SC: IVT insulin decreases respiratory quotient in rats. Soc Neurosci Abstr 22:939, 1992
Chavez M, Riedy CA, van Dijk G, Woods SC: Central insulin and macronutrient intake in the rat. Am J Physiol Regul Integr Comp Physiol 271:R727–R731, 1996
Bray GA, Popkin BM: Dietary fat does affect obesity. Am J Clin Nutr 68:1157–1173, 1998
Gibney MJ: Epidemiology of obesity in relation to nutrient intake. Int J Obes 19 (Suppl. 5):S1–S3, 1995
Samaras K, Kelly PJ, Chiano MN, Arden N, Spector TD, Campbell LV: Genes versus environment. Diabetes Care 21:2069–2076, 1998
Bray GA, Fisler J, York DA: Neuroendocrine control of the development of obesity: understanding gained from studies of experimental animal models. Front Neuroendocrinol 11:128–181, 1990
Golay A, Bobbioni E: The role of dietary fat in obesity. Int J Obes Rel Metab Dis 21 (Suppl. 3):S2–S11, 1997
Hill JO, Lin D, Yakubu F, Peters JC: Development of dietary obesity in rats: influence of amount and composition of dietary fat. Int J Obes 16:321–333, 1992
Warwick ZS, Schiffman SS: Role of dietary fat in calorie intake and weight gain. Neurosci Biobehav Rev 16:585–596, 1992
Warwick ZS: Probing the causes of high-fat diet hyperphagia: a mechanistic and behavioral dissection. Neurosci Biobehav Rev 20:155–161, 1996
West DB, York B: Dietary fat, genetic predisposition, and obesity: lessons from animal models. Am J Clin Nutr 67 (Suppl. 3):505S–512S, 1998
Woods SC, Seeley RJ, Rushing PA, D’Alessio DA, Tso P: A controlled high-fat diet induces an obese syndrome in rats. J Nutr 133:1081–1087, 2003
Woods SC, D’Alessio DA, Tso P, Rushing PA, Clegg DJ, Benoit SC, Gotoh K, Liu M, Seeley RJ: Consumption of a high-fat diet alters the homeostatic regulation of energy balance. Physiol Behav 83:573–578, 2004
Leibel RL, Chung WK, Chua SC Jr: The molecular genetics of rodent single gene obesities. J Biol Chem 272:31937–31940, 1997
Levin BE, Brown KL, Dunn-Meynell AA: Differential effects of diet and obesity on high and low affinity sulfonylurea binding sites in the rat brain. Brain Res 739:293–300, 1996
Levin BE, Dunn-Meynell AA, Balkan B, Keesey RE: Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am J Physiol Regul Integr Comp Physiol 273:R725–R730, 1997
Reed DR, Bachmanov AA, Beauchamp GK, Tordoff MG, Price RA: Heritable variation in food preferences and their contribution to obesity. Behav Genet 27:373–387, 1997
West DB: Genetics of obesity in humans and animal models. Endocrinol Metab Clin N Am 25:801–813, 1996
Molteni R, Barnard RJ, Ying Z, Roberts CK, Gomez-Pinilla F: A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 112:803–814, 2002
Wu A, Molteni R, Ying Z, Gomez-Pinilla F: A saturated-fat diet aggravates the outcome of traumatic brain injury on hippocampal plasticity and cognitive function by reducing brain-derived neurotrophic factor. Neuroscience 119:365–375, 2003(Stephen C. Woods, Stephen C. Benoit, and)