Adipose Tissue in Obesity—An Inflammatory Issue
http://www.100md.com
内分泌学杂志 2005年第3期
Neuroendocrinology & Obesity Biology Unit, Liverpool Centre for Nutritional Genomics, Division of Metabolic and Cellular Medicine, School of Clinical Sciences, University of Liverpool, Liverpool L69 3GA, United Kingdom
Address all correspondence and requests for reprints to: Paul Trayhurn, Neuroendocrinology & Obesity Biology Unit, Liverpool Centre for Nutritional Genomics, Division of Metabolic and Cellular Medicine, School of Clinical Sciences, University of Liverpool, Third floor UCD Building, Liverpool L69 3GA, United Kingdom. E-mail: p.trayhurn@liverpool.ac.uk.
White adipose tissue (WAT), long regarded as a "Cinderella organ," has truly emerged into the limelight, and much of the stimulus for this relates to the current concern with obesity. This disease now affects over one in five adults in the United Kingdom, for example, with even more in the United States, and is associated with a reduced life expectancy and an increased incidence of several major diseases, particularly type II diabetes, coronary heart disease, and cancer. An important recent development is the emergence of the concept that obesity, like diabetes, is characterized by chronic low-grade inflammation (1, 2). WAT is itself recognized as an important site of the production of inflammation-related proteins, the production of which is (generally) increased in the obese (3, 4). Considerable interest was aroused just over a year ago by two reports that demonstrated that, in obesity, adipose tissue is infiltrated by macrophages (5, 6). One important factor produced by adipocytes underlying this infiltration is monocyte chemoattractant protein-1 (MCP-1) (7, 8); another may be macrophage migration inhibitory factor (MIF), and a key paper by Skurk et al. (9), in this issue of Endocrinology, demonstrates that MIF is secreted from human adipocytes and that the rate of secretion (in culture) is positively correlated with the body mass index of the subjects.
MIF, which was originally identified in activated T lymphocytes as a cytokine that inhibited the migration of macrophages from capillaries, is part of the accelerating list of protein factors and signals secreted from white adipocytes—the adipokines (3, 4, 10). The recognition that protein signals are secreted from adipocytes began in effect with adipsin in the late 1980s (11) and was followed by the proinflammatory cytokine TFN a few years later (12). The pivotal event in our evolving perspective on WAT as a secretory organ was the discovery in 1994 of leptin (13); this resulted in the characterization of the tissue as a critical endocrine system. Currently, more than 50 different adipokines are recognized, and these are highly heterogeneous both in terms of protein structure and of function (3, 4, 10). The adipokines are implicated in a wide range of physiological processes, including appetite and energy balance, glucose homeostasis, lipid metabolism, blood pressure regulation, hemostasis, and angiogenesis (3, 4, 10). An increasing number of adipokines are directly linked to inflammation and the inflammatory response (Fig. 1), and these encompass classical cytokines (e.g. TNF, IL-1?, IL-6, IL-10) and acute-phase proteins (e.g. haptoglobin, plasminogen activator inhibitor-1, serum amyloid A), as well as other inflammation-related signals such as MCP-1, nerve growth factor, and adiponectin (3, 4). Adiponectin, a major adipocyte-derived hormone with a role in insulin sensitivity, has a distinct antiinflammatory action (14).
FIG. 1. Inflammation-related adipokines and signals for macrophage infiltration into WAT. Only factors for which secretion from adipocytes has been clearly demonstrated are shown. NGF, Nerve growth factor; PAI-1, plasminogen activator inhibitor-1; VEGF, vascular endothelial growth factor.
The expression and secretion of MIF by adipose tissue was first described in mice and was found to be strongly up-regulated in 3T3-L1 adipocytes by TNF (15). Whether TNF also stimulates the synthesis and release of MIF in human adipocytes is not yet known, but, interestingly, Skurk et al. (9) indicate that neither lipopolysaccharide, IFN-, nor IL-4 have any effect on MIF secretion in human fat cells differentiated in culture. Stimulation of MIF in human adipocytes by TNF would be expected not only because of the data from the murine cell line (15), but also because this cytokine has pleiotropic effects on the production of inflammation-related adipokines in humans, including the stimulation of IL-6, MCP-1, and nerve growth factor expression (16). The capacity of human adipocytes to secrete MIF appears to be substantial, with similar levels of secretion from cells from the sc and omental depots (within the same individual). Some depot differences are evident, however; much lower rates of release are apparent with mammary fat cells (9).
Although, with human adipocytes, high concentrations of insulin do not affect the expression and release of MIF (9), in 3T3-L1 cells, a role for insulin in regulating the production of the factor is suggested (17). Recent studies on human subjects have indicated that MIF mRNA levels are increased in circulating mononuclear cells in obesity and the plasma levels of the protein are also increased (18, 19). Indeed, this up-regulation of MIF is related to body mass index, with the plasma levels being suppressed by treatment with metformin (19). Thus, MIF is one of the growing number of inflammation-related proteins whose circulating levels are increased in obesity. These proteins include IL-6, C-reactive protein, TNF and its soluble receptors, IL-18, plasminogen activator inhibitor-1, and haptoglobin, and are the basis for the view that the obese are characterized by chronic low-grade inflammation (20, 21, 22, 23, 24, 25). Importantly, the circulating level of adiponectin with its antiinflammatory effect falls in obesity (26). With the exception of IL-18, there is strong evidence that the expanded adipose tissue mass of the obese contributes either directly or indirectly to these increased circulating levels.
There is growing evidence of a causal link between what happens in adipose tissue in obesity and the development of type 2 diabetes and the metabolic syndrome (27, 28). Indeed, because expansion of the size and number of adipocytes is the key characteristic of obesity, it is unsurprising that there is a link between such events and the pathologies associated with the disorder. Although adipose tissue is clearly a source of at least some of the inflammation-related proteins whose circulating levels rise in obesity, the quantitative importance of the contribution from fat has not been established. A key issue, which has received little attention, is precisely why there should be a major increase in the production and release of inflammation-related adipokines in the obese. The parsimonious explanation, as advanced recently, is that it relates to specific events within WAT itself, raised plasma levels reflecting spillover from an "inflamed" tissue (4). The trigger may be hypoxia, through the recruitment of the transcription factor hypoxia-inducible factor-1, in clusters of adipocytes distant from the vasculature in the expanding adipose tissue mass in advance of angiogenesis (4).
The new work on MIF demonstrates that at least two major signals involved in the infiltration of WAT by macrophages are released in substantial quantities by human adipocytes, and MIF, like MCP-1, may be a key "obesity-dependent mediator of macrophage infiltration of adipose tissue" (9). The arrival of macrophages en masse is likely to result in a major amplification of the inflammatory state within adipose tissue, involving extensive cross-talk with mature adipocytes and also preadipocytes. Inflammation and its consequences, and the role of macrophages in particular, are destined to be hot topics in adipose tissue biology and obesity research over the next few years. One intriguing question is whether inflammation and macrophage infiltration are peculiar to obesity, or whether they are common to all situations in which there is a substantial expansion of adipose mass—such as in the pronounced prehibernatory fattening of ground squirrel species during which body weight can double over a matter of weeks.
References
Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW 1999 C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 19:972–978
Festa A, D’Agostino Jr R, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, Haffner SM 2001 The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord 25:1407–1415
Rajala MW, Scherer PE 2003 Minireview: the adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144:3765–3773
Trayhurn P, Wood IS 2004 Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92:347–355
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW 2003 Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H 2003 Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830
Gerhardt CC, Romero IA, Cancello R, Camoin L, Strosberg AD 2001 Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol 175:81–92
Sartipy P, Loskutoff DJ 2003 Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 100:7265–7270
Skurk T, Herder C, Kr?ft I, Müller-Scholze S, Hauner H, Kolb H 2005 Production and release of macrophage migration inhibitory factor from human adipocytes. Endocrinology 146:1006–1011
Trayhurn P, Beattie JH 2001 Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 60:329–339
Flier JS, Cook KS, Usher P, Spiegelman BM 1987 Severely impaired adipsin expression in genetic and acquired obesity. Science 237:405–408
Hotamisligil GS, Shargill NS, Spiegelman BM 1993 Adipose expression of tumor necrosis factor-—direct role in obesity-linked insulin resistance. Science 259:87–91
Zhang YY, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homolog. Nature 372:425–432
Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y 1999 Novel modulator for endothelial adhesion molecules—adipocyte-derived plasma protein adiponectin. Circulation 100:2473–2476
Hirokawa J, Sakaue S, Tagami S, Kawakami Y, Sakai M, Nishi S, Nishihira J 1997 Identification of macrophage migration inhibitory factor in adipose tissue and its induction by tumor necrosis factor-. Biochem Biophys Res Commun 235:94–98
Wang B, Jenkins JR, Trayhurn P 23 Nov 2004 Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-. Am J Physiol Endocrinol Metab 10.1152/ajpeno.00475.2004
Sakaue S, Nishihira J, Hirokawa J, Yoshimura H, Honda T, Aoki K, Tagami S, Kawakami Y 1999 Regulation of macrophage migration inhibitory factor (MIF) expression by glucose and insulin in adipocytes in vitro. Mol Med 5:361–371
Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P 2004 Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 110:1564–1571
Dandona P, Aljada A, Ghanim H, Mohanty P, Tripathy C, Hofmeyer D, Chaudhuri A 2004 Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin. J Clin Endocrinol Metab 89:5043–5047
Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW 1997 Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-, in vivo. J Clin Endocrinol Metab 82: 4196–4200
Alessi MC, Bastelica D, Morange P, Berthet B, Leduc I, Verdier M, Geel O, Juhan-Vague I 2000 Plasminogen activator inhibitor 1, transforming growth factor-?1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 49:1374–1380
Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H, Hainque B 2000 Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab 85:3338–3342
Esposito K, Pontillo A, Ciotola M, Di Palo C, Grella E, Nicoletti G, Giugliano D 2002 Weight loss reduces interleukin-18 levels in obese women. J Clin Endocrinol Metab 87:3864–3866
Bullo M, Garcia-Lorda P, Megias I, Salas-Salvado J 2003 Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obesity Res 11:525–531
Chiellini C, Santini F, Marsili A, Berti P, Bertacca A, Pelosini C, Scartabelli G, Pardini E, Lopez-Soriano J, Centoni R, Ciccarone AM, Benzi L, Vitti P, Del Prato S, Pinchera A, Maffei M 2004 Serum Haptoglobin: a novel marker of adiposity in humans. J Clin Endocrinol Metab 89:2678–2683
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83
Hotamisligil GS 2003 Inflammatory pathways and insulin action. Int J Obesity 27(Suppl 3):S53–S55
Yudkin JS 2003 Adipose tissue, insulin action and vascular disease: inflammatory signals. Int J Obesity 27(Suppl 3):S25–S28(Paul Trayhurn)
Address all correspondence and requests for reprints to: Paul Trayhurn, Neuroendocrinology & Obesity Biology Unit, Liverpool Centre for Nutritional Genomics, Division of Metabolic and Cellular Medicine, School of Clinical Sciences, University of Liverpool, Third floor UCD Building, Liverpool L69 3GA, United Kingdom. E-mail: p.trayhurn@liverpool.ac.uk.
White adipose tissue (WAT), long regarded as a "Cinderella organ," has truly emerged into the limelight, and much of the stimulus for this relates to the current concern with obesity. This disease now affects over one in five adults in the United Kingdom, for example, with even more in the United States, and is associated with a reduced life expectancy and an increased incidence of several major diseases, particularly type II diabetes, coronary heart disease, and cancer. An important recent development is the emergence of the concept that obesity, like diabetes, is characterized by chronic low-grade inflammation (1, 2). WAT is itself recognized as an important site of the production of inflammation-related proteins, the production of which is (generally) increased in the obese (3, 4). Considerable interest was aroused just over a year ago by two reports that demonstrated that, in obesity, adipose tissue is infiltrated by macrophages (5, 6). One important factor produced by adipocytes underlying this infiltration is monocyte chemoattractant protein-1 (MCP-1) (7, 8); another may be macrophage migration inhibitory factor (MIF), and a key paper by Skurk et al. (9), in this issue of Endocrinology, demonstrates that MIF is secreted from human adipocytes and that the rate of secretion (in culture) is positively correlated with the body mass index of the subjects.
MIF, which was originally identified in activated T lymphocytes as a cytokine that inhibited the migration of macrophages from capillaries, is part of the accelerating list of protein factors and signals secreted from white adipocytes—the adipokines (3, 4, 10). The recognition that protein signals are secreted from adipocytes began in effect with adipsin in the late 1980s (11) and was followed by the proinflammatory cytokine TFN a few years later (12). The pivotal event in our evolving perspective on WAT as a secretory organ was the discovery in 1994 of leptin (13); this resulted in the characterization of the tissue as a critical endocrine system. Currently, more than 50 different adipokines are recognized, and these are highly heterogeneous both in terms of protein structure and of function (3, 4, 10). The adipokines are implicated in a wide range of physiological processes, including appetite and energy balance, glucose homeostasis, lipid metabolism, blood pressure regulation, hemostasis, and angiogenesis (3, 4, 10). An increasing number of adipokines are directly linked to inflammation and the inflammatory response (Fig. 1), and these encompass classical cytokines (e.g. TNF, IL-1?, IL-6, IL-10) and acute-phase proteins (e.g. haptoglobin, plasminogen activator inhibitor-1, serum amyloid A), as well as other inflammation-related signals such as MCP-1, nerve growth factor, and adiponectin (3, 4). Adiponectin, a major adipocyte-derived hormone with a role in insulin sensitivity, has a distinct antiinflammatory action (14).
FIG. 1. Inflammation-related adipokines and signals for macrophage infiltration into WAT. Only factors for which secretion from adipocytes has been clearly demonstrated are shown. NGF, Nerve growth factor; PAI-1, plasminogen activator inhibitor-1; VEGF, vascular endothelial growth factor.
The expression and secretion of MIF by adipose tissue was first described in mice and was found to be strongly up-regulated in 3T3-L1 adipocytes by TNF (15). Whether TNF also stimulates the synthesis and release of MIF in human adipocytes is not yet known, but, interestingly, Skurk et al. (9) indicate that neither lipopolysaccharide, IFN-, nor IL-4 have any effect on MIF secretion in human fat cells differentiated in culture. Stimulation of MIF in human adipocytes by TNF would be expected not only because of the data from the murine cell line (15), but also because this cytokine has pleiotropic effects on the production of inflammation-related adipokines in humans, including the stimulation of IL-6, MCP-1, and nerve growth factor expression (16). The capacity of human adipocytes to secrete MIF appears to be substantial, with similar levels of secretion from cells from the sc and omental depots (within the same individual). Some depot differences are evident, however; much lower rates of release are apparent with mammary fat cells (9).
Although, with human adipocytes, high concentrations of insulin do not affect the expression and release of MIF (9), in 3T3-L1 cells, a role for insulin in regulating the production of the factor is suggested (17). Recent studies on human subjects have indicated that MIF mRNA levels are increased in circulating mononuclear cells in obesity and the plasma levels of the protein are also increased (18, 19). Indeed, this up-regulation of MIF is related to body mass index, with the plasma levels being suppressed by treatment with metformin (19). Thus, MIF is one of the growing number of inflammation-related proteins whose circulating levels are increased in obesity. These proteins include IL-6, C-reactive protein, TNF and its soluble receptors, IL-18, plasminogen activator inhibitor-1, and haptoglobin, and are the basis for the view that the obese are characterized by chronic low-grade inflammation (20, 21, 22, 23, 24, 25). Importantly, the circulating level of adiponectin with its antiinflammatory effect falls in obesity (26). With the exception of IL-18, there is strong evidence that the expanded adipose tissue mass of the obese contributes either directly or indirectly to these increased circulating levels.
There is growing evidence of a causal link between what happens in adipose tissue in obesity and the development of type 2 diabetes and the metabolic syndrome (27, 28). Indeed, because expansion of the size and number of adipocytes is the key characteristic of obesity, it is unsurprising that there is a link between such events and the pathologies associated with the disorder. Although adipose tissue is clearly a source of at least some of the inflammation-related proteins whose circulating levels rise in obesity, the quantitative importance of the contribution from fat has not been established. A key issue, which has received little attention, is precisely why there should be a major increase in the production and release of inflammation-related adipokines in the obese. The parsimonious explanation, as advanced recently, is that it relates to specific events within WAT itself, raised plasma levels reflecting spillover from an "inflamed" tissue (4). The trigger may be hypoxia, through the recruitment of the transcription factor hypoxia-inducible factor-1, in clusters of adipocytes distant from the vasculature in the expanding adipose tissue mass in advance of angiogenesis (4).
The new work on MIF demonstrates that at least two major signals involved in the infiltration of WAT by macrophages are released in substantial quantities by human adipocytes, and MIF, like MCP-1, may be a key "obesity-dependent mediator of macrophage infiltration of adipose tissue" (9). The arrival of macrophages en masse is likely to result in a major amplification of the inflammatory state within adipose tissue, involving extensive cross-talk with mature adipocytes and also preadipocytes. Inflammation and its consequences, and the role of macrophages in particular, are destined to be hot topics in adipose tissue biology and obesity research over the next few years. One intriguing question is whether inflammation and macrophage infiltration are peculiar to obesity, or whether they are common to all situations in which there is a substantial expansion of adipose mass—such as in the pronounced prehibernatory fattening of ground squirrel species during which body weight can double over a matter of weeks.
References
Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW 1999 C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 19:972–978
Festa A, D’Agostino Jr R, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, Haffner SM 2001 The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord 25:1407–1415
Rajala MW, Scherer PE 2003 Minireview: the adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144:3765–3773
Trayhurn P, Wood IS 2004 Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92:347–355
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW 2003 Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H 2003 Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830
Gerhardt CC, Romero IA, Cancello R, Camoin L, Strosberg AD 2001 Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol 175:81–92
Sartipy P, Loskutoff DJ 2003 Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 100:7265–7270
Skurk T, Herder C, Kr?ft I, Müller-Scholze S, Hauner H, Kolb H 2005 Production and release of macrophage migration inhibitory factor from human adipocytes. Endocrinology 146:1006–1011
Trayhurn P, Beattie JH 2001 Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 60:329–339
Flier JS, Cook KS, Usher P, Spiegelman BM 1987 Severely impaired adipsin expression in genetic and acquired obesity. Science 237:405–408
Hotamisligil GS, Shargill NS, Spiegelman BM 1993 Adipose expression of tumor necrosis factor-—direct role in obesity-linked insulin resistance. Science 259:87–91
Zhang YY, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homolog. Nature 372:425–432
Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y 1999 Novel modulator for endothelial adhesion molecules—adipocyte-derived plasma protein adiponectin. Circulation 100:2473–2476
Hirokawa J, Sakaue S, Tagami S, Kawakami Y, Sakai M, Nishi S, Nishihira J 1997 Identification of macrophage migration inhibitory factor in adipose tissue and its induction by tumor necrosis factor-. Biochem Biophys Res Commun 235:94–98
Wang B, Jenkins JR, Trayhurn P 23 Nov 2004 Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-. Am J Physiol Endocrinol Metab 10.1152/ajpeno.00475.2004
Sakaue S, Nishihira J, Hirokawa J, Yoshimura H, Honda T, Aoki K, Tagami S, Kawakami Y 1999 Regulation of macrophage migration inhibitory factor (MIF) expression by glucose and insulin in adipocytes in vitro. Mol Med 5:361–371
Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P 2004 Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 110:1564–1571
Dandona P, Aljada A, Ghanim H, Mohanty P, Tripathy C, Hofmeyer D, Chaudhuri A 2004 Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin. J Clin Endocrinol Metab 89:5043–5047
Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW 1997 Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-, in vivo. J Clin Endocrinol Metab 82: 4196–4200
Alessi MC, Bastelica D, Morange P, Berthet B, Leduc I, Verdier M, Geel O, Juhan-Vague I 2000 Plasminogen activator inhibitor 1, transforming growth factor-?1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 49:1374–1380
Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H, Hainque B 2000 Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab 85:3338–3342
Esposito K, Pontillo A, Ciotola M, Di Palo C, Grella E, Nicoletti G, Giugliano D 2002 Weight loss reduces interleukin-18 levels in obese women. J Clin Endocrinol Metab 87:3864–3866
Bullo M, Garcia-Lorda P, Megias I, Salas-Salvado J 2003 Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obesity Res 11:525–531
Chiellini C, Santini F, Marsili A, Berti P, Bertacca A, Pelosini C, Scartabelli G, Pardini E, Lopez-Soriano J, Centoni R, Ciccarone AM, Benzi L, Vitti P, Del Prato S, Pinchera A, Maffei M 2004 Serum Haptoglobin: a novel marker of adiposity in humans. J Clin Endocrinol Metab 89:2678–2683
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83
Hotamisligil GS 2003 Inflammatory pathways and insulin action. Int J Obesity 27(Suppl 3):S53–S55
Yudkin JS 2003 Adipose tissue, insulin action and vascular disease: inflammatory signals. Int J Obesity 27(Suppl 3):S25–S28(Paul Trayhurn)