Peroxisome Proliferator-Activated Receptors and Insulin Secretion
http://www.100md.com
内分泌学杂志 2005年第8期
Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; and Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
Address all correspondence and requests for reprints to: Dr. Takashi Kadowaki, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan. E-mail: kadowaki-3im@h.u-tokyo.ac.jp.
Type 2 diabetes is considered to be a polygenic disease that is aggravated by environmental factors, such as low physical activity or a hypercaloric lipid-rich diet. If we take in more calories or fats than we can consume, obesity will develop, and along with it come the associated medical problems of glucose intolerance, hypertension, and dyslipidemia. This accumulation of risk factors for atherosclerosis collectively referred to as the metabolic syndrome now provides serious threats to public health. Like this, fat metabolism and glucose homeostasis are inherently related. Lipid abnormalities can cause profound effects on glucose homeostasis. This is often exemplified by the lipotoxicity hypothesis, which suggests that abnormal accumulation of triglycerides and fatty acyl-coenzyme A in muscle and liver can result in insulin resistance (1). Indeed, even short-term infusions of lipid emulsions can induce rapid and profound insulin resistance. Free fatty acids have also been shown to influence insulin secretion (2). According to the lipotoxicity hypothesis, chronic exposure to elevated free fatty acid levels impairs ?-cell function and is often accompanied by increased islet triglyceride content and fatty acyl-coenzyme A (3, 4).
Members of the nuclear hormone receptor superfamily have emerged as key coordinators in this metabolic axis. The first genetic sensor for fats was identified in the early 1990s and termed the peroxisome proliferator-activated receptor (PPAR)- because of its ability to bind chemicals known to induce peroxisome proliferation (5). Subsequent studies identified two additional, related receptors known as PPAR and PPAR (also called PPAR?) (6, 7). As members of the nuclear receptor superfamily, these three PPARs act by controlling networks of target genes. This subfamily of nuclear receptors can be activated by both dietary fatty acids and their metabolic derivatives in the body and serve as central regulators of lipid homeostasis and are involved in regulating insulin sensitivity (8). The three PPAR family members have distinct patterns of tissue distribution. Whereas PPAR and PPAR are predominantly present in liver and adipose tissue, respectively, PPAR is abundantly expressed throughout the body but at low levels in liver. PPARs each carry out unique functions in the regulation of energy metabolism. Thus, PPAR activates primarily genes encoding proteins involved in fatty acid oxidation during fasting (9), whereas PPAR activates genes directly involved in lipogenic pathways and insulin signaling (10). The different biological actions of PPAR subtypes may be due in part to the differential expression patterns of the PPAR subtypes.
All members of the PPAR family have been reported to be expressed in pancreatic ?-cells (11). Models positioning both PPAR and - as mediators of the diverse effects of fatty acids on ?-cell function have been suggested. It was previously shown that PPAR ectopically expressed in insulinoma (INS)-1 cells could induce lipid accumulation along with a modest increase in ?-oxidation (12). A significant reduction in glucose-induced insulin secretion by both ectopic PPAR expression and the PPAR agonist clofibrate led to the conclusion that PPAR activity could indeed cause ?-cell dysfunction, possibly through an induction of uncoupling protein-2 (12). However, these results are at odds with the generally protective and restorative roles of PPAR activation in islets under conditions of increased fatty acid challenge (13). Interestingly, it was very recently reported that isolated islets from PPAR null mice had a 44% reduction in ?-oxidation, normal glucose use and oxidation, and enhanced glucose-induced insulin secretion (14). PPAR was shown to have lipopenic potential promoting fatty acid disposal in pancreatic ?-cells (15). This result apparently disagrees with the conventional lipogenic role of PPAR but may be supported by reports indicating that PPAR ligands induce delipidation of pancreatic islets (16).
As discussed above, observations on PPAR and PPAR effects on lipid partitioning and ?-cell function are diverse (summarized in Table 1). Confusion on the direct function of PPAR subtypes in lipid partitioning into pancreatic ?-cells is remarkable. In this issue of Endocrinology, Ravnskj?r et al. (17) investigated and directly compared the roles of these PPAR subtypes in ?-cell function. In the present work, they showed that acute ectopic expression of PPAR and retinoid X receptor (RXR)- synergistically and in a PPAR subtype-specific manner increased fatty acid uptake and oxidation capacity in the INS-1E rat ?-cell line and improved glucose-stimulated insulin secretion (Fig. 1, black arrow). By contrast, acute ectopic expression of PPAR and RXR did not affect fatty acid oxidation but induced massive accumulation of triglycerides and impaired glucose-stimulated insulin secretion (Fig. 1, black arrow). These results were consistent with the roles of PPAR as a catabolic and PPAR as a lipogenic transcription factor also when ectopically expressed in pancreatic ?-cells. Importantly, acute activation of PPAR potentiated whereas acute activation of PPAR compromised glucose-stimulated insulin secretion under their experimental conditions. These results show a strong subtype specificity of the two PPAR subtypes ( and ) on lipid partitioning and insulin secretion when systematically compared in a ?-cell line. Moreover, Ravnskj?r et al. (17) compared the effects of acute ectopic expression of PPAR or /RXR on lipid metabolism in ?-cells and insulin secretion and those of PPAR agonist or PPAR agonist (WY14643 and BRL49653 on lipid metabolism in ?-cells and insulin secretion.
TABLE 1. A summary table of experimental data on the ?-cell function with different PPAR experimental systems
FIG. 1. Direct (?-cell-specific) and indirect (systemic) effects of three PPAR subtypes on ?-cell function. Regulation of metabolism and insulin secretion in pancreatic ?-cells can be affected by not only direct effect of PPARs (black arrows) but also lipid partitioning among adipose tissues, skeletal muscle, liver, and the islets modulated by PPARs (gray arrows).
It should be noted, however, that impact of acute ectopic expression of PPAR or /RXR on fatty acid metabolism and insulin secretion in INS-1E cells may be different under lipotoxic conditions in which INS-1 cells are surrounded by higher concentrations of lipids. The authors predict in this paper that PPAR expression under lipotoxic conditions would have a protective effect on the ?-cells. In the future, for example, the effect of palmitate on lipid metabolism and insulin secretion when PPAR or PPAR/RXR is overexpressed in INS-1E cells should be examined.
Ravnskj?r et al. (17) investigated the impact of acute ectopic expression of PPARs and PPAR agonists on insulin secretion and metabolism predominantly using INS-1E cells and isolated rat islets. In rodent models or human subjects, however, the regulation of metabolism and insulin secretion in pancreatic ?-cells can be affected by not only direct effect of PPARs but also lipid partitioning among adipose tissues, skeletal muscle, liver, and the islets (Fig. 1, gray arrows). It was recently reported that PPAR agonist pioglitazone restored impaired insulin secretion under conditions of islet fat accumulation (18). Lupi et al. (19) showed that rosiglitazone prevented the impairment of human islet function induced by fatty acids under conditions of islet fat accretion or increased fatty acid availability. These papers demonstrate that we must consider indirect effect via lipid partitioning among various tissues in addition to direct effect to assess the roles of PPARs and their agonists, such as thiazolidinedione and lipid-lowering fibrate drugs, in ?-cells.
References
Shulman GI 2000 Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176
Milburn JL, Hirose H, Lee YH, Nagasawa Y, Ogawa A, Ohneda M, BeltrandelRio H, Newgard CB, Johnson JH, Unger RH 1995 Pancreatic ?-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids. J Biol Chem 270:1295–1299
Zhou YP, Grill VE 1994 Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest 93:870–876
Briaud I, Harmon JS, Kelpe CL, Segu VB, Poitout V 2001 Lipotoxicity of the pancreatic ?-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 50:315–321
Issemann I, Green S 1990 Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347:645–650
Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W 1992 Control of the peroxisomal ?-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68:879–887
Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM 1994 Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91:7355–7359
Evans RM, Barish GD, Wang YX 2004 PPARs and the complex journey to obesity. Nat Med 10:355–361
Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W 1999 Peroxisome proliferator-activated receptor mediates the adaptive response to fasting. J Clin Invest 103:1489–1498
Mueller E, Drori S, Aiyer A, Yie J, Sarraf P, Chen H, Hauser S, Rosen ED, Ge K, Roeder RG, Spiegelman BM 2002 Genetic analysis of adipogenesis through peroxisome proliferator-activated receptor isoforms. J Biol Chem 277:41925–41930
Zhou YT, Shimabukuro M, Wang MY, Lee Y, Higa M, Milburn JL, Newgard CB, Unger RH 1998 Role of peroxisome proliferator-activated receptor in disease of pancreatic ? cells. Proc Natl Acad Sci USA 95:8898–8903
Tordjman K, Standley KN, Bernal-Mizrachi C, Leone TC, Coleman T, Kelly DP, Semenkovich CF 2002 PPAR suppresses insulin secretion and induces UCP2 in insulinoma cells. J Lipid Res 43:936–943
Koh EH, Kim MS, Park JY, Kim HS, Youn JY, Park HS, Youn JH, Lee KU 2003 Peroxisome proliferator-activated receptor (PPAR)- activation prevents diabetes in OLETF rats: comparison with PPAR- activation. Diabetes 52:2331–2337
Gremlich S, Nolan C, Roduit R, Burcelin R, Peyot ML, Delghingaro-Augusto V, Desvergne B, Michalik L, Prentki M, Wahli W 2005 Pancreatic islet adaptation to fasting is dependent on peroxisome proliferator-activated receptor transcriptional up-regulation of fatty acid oxidation. Endocrinology 146:375–382
Parton LE, Diraison F, Neill SE, Ghosh SK, Rubino MA, Bisi JE, Briscoe CP, Rutter GA 2004 Impact of PPAR overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays. Am J Physiol Endocrinol Metab 287:E390–E404
Shimabukuro M, Zhou YT, Lee Y, Unger RH 1998 Troglitazone lowers islet fat and restores ? cell function of Zucker diabetic fatty rats. J Biol Chem 273:3547–3550
Ravnskj?r K, B?rgesen M, Rubi B, Larsen JK, Nielsen T, Fridriksson J, Maechler P, Mandrup S2005 Peroxisome proliferator-activated receptor (PPAR) potentiates, whereas PPAR attenuates, glucose-stimulated insulin secretion in pancreatic ?-cells. Endocrinology 146:3266–3276
Matsui J, Terauchi Y, Kubota N, Takamoto I, Eto K, Yamashita T, Komeda K, Yamauchi T, Kamon J, Kita S, Noda M, Kadowaki T 2004 Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous PPAR-deficient mice on a high-fat diet. Diabetes 53:2844–2854
Lupi R, Del Guerra S, Marselli L, Bugliani M, Boggi U, Mosca F, Marchetti P, Del Prato S 2004 Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPAR2 in the modulation of insulin secretion. Am J Physiol Endocrinol Metab 286:E560–E567(Yasuo Terauchi and Takash)
Address all correspondence and requests for reprints to: Dr. Takashi Kadowaki, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan. E-mail: kadowaki-3im@h.u-tokyo.ac.jp.
Type 2 diabetes is considered to be a polygenic disease that is aggravated by environmental factors, such as low physical activity or a hypercaloric lipid-rich diet. If we take in more calories or fats than we can consume, obesity will develop, and along with it come the associated medical problems of glucose intolerance, hypertension, and dyslipidemia. This accumulation of risk factors for atherosclerosis collectively referred to as the metabolic syndrome now provides serious threats to public health. Like this, fat metabolism and glucose homeostasis are inherently related. Lipid abnormalities can cause profound effects on glucose homeostasis. This is often exemplified by the lipotoxicity hypothesis, which suggests that abnormal accumulation of triglycerides and fatty acyl-coenzyme A in muscle and liver can result in insulin resistance (1). Indeed, even short-term infusions of lipid emulsions can induce rapid and profound insulin resistance. Free fatty acids have also been shown to influence insulin secretion (2). According to the lipotoxicity hypothesis, chronic exposure to elevated free fatty acid levels impairs ?-cell function and is often accompanied by increased islet triglyceride content and fatty acyl-coenzyme A (3, 4).
Members of the nuclear hormone receptor superfamily have emerged as key coordinators in this metabolic axis. The first genetic sensor for fats was identified in the early 1990s and termed the peroxisome proliferator-activated receptor (PPAR)- because of its ability to bind chemicals known to induce peroxisome proliferation (5). Subsequent studies identified two additional, related receptors known as PPAR and PPAR (also called PPAR?) (6, 7). As members of the nuclear receptor superfamily, these three PPARs act by controlling networks of target genes. This subfamily of nuclear receptors can be activated by both dietary fatty acids and their metabolic derivatives in the body and serve as central regulators of lipid homeostasis and are involved in regulating insulin sensitivity (8). The three PPAR family members have distinct patterns of tissue distribution. Whereas PPAR and PPAR are predominantly present in liver and adipose tissue, respectively, PPAR is abundantly expressed throughout the body but at low levels in liver. PPARs each carry out unique functions in the regulation of energy metabolism. Thus, PPAR activates primarily genes encoding proteins involved in fatty acid oxidation during fasting (9), whereas PPAR activates genes directly involved in lipogenic pathways and insulin signaling (10). The different biological actions of PPAR subtypes may be due in part to the differential expression patterns of the PPAR subtypes.
All members of the PPAR family have been reported to be expressed in pancreatic ?-cells (11). Models positioning both PPAR and - as mediators of the diverse effects of fatty acids on ?-cell function have been suggested. It was previously shown that PPAR ectopically expressed in insulinoma (INS)-1 cells could induce lipid accumulation along with a modest increase in ?-oxidation (12). A significant reduction in glucose-induced insulin secretion by both ectopic PPAR expression and the PPAR agonist clofibrate led to the conclusion that PPAR activity could indeed cause ?-cell dysfunction, possibly through an induction of uncoupling protein-2 (12). However, these results are at odds with the generally protective and restorative roles of PPAR activation in islets under conditions of increased fatty acid challenge (13). Interestingly, it was very recently reported that isolated islets from PPAR null mice had a 44% reduction in ?-oxidation, normal glucose use and oxidation, and enhanced glucose-induced insulin secretion (14). PPAR was shown to have lipopenic potential promoting fatty acid disposal in pancreatic ?-cells (15). This result apparently disagrees with the conventional lipogenic role of PPAR but may be supported by reports indicating that PPAR ligands induce delipidation of pancreatic islets (16).
As discussed above, observations on PPAR and PPAR effects on lipid partitioning and ?-cell function are diverse (summarized in Table 1). Confusion on the direct function of PPAR subtypes in lipid partitioning into pancreatic ?-cells is remarkable. In this issue of Endocrinology, Ravnskj?r et al. (17) investigated and directly compared the roles of these PPAR subtypes in ?-cell function. In the present work, they showed that acute ectopic expression of PPAR and retinoid X receptor (RXR)- synergistically and in a PPAR subtype-specific manner increased fatty acid uptake and oxidation capacity in the INS-1E rat ?-cell line and improved glucose-stimulated insulin secretion (Fig. 1, black arrow). By contrast, acute ectopic expression of PPAR and RXR did not affect fatty acid oxidation but induced massive accumulation of triglycerides and impaired glucose-stimulated insulin secretion (Fig. 1, black arrow). These results were consistent with the roles of PPAR as a catabolic and PPAR as a lipogenic transcription factor also when ectopically expressed in pancreatic ?-cells. Importantly, acute activation of PPAR potentiated whereas acute activation of PPAR compromised glucose-stimulated insulin secretion under their experimental conditions. These results show a strong subtype specificity of the two PPAR subtypes ( and ) on lipid partitioning and insulin secretion when systematically compared in a ?-cell line. Moreover, Ravnskj?r et al. (17) compared the effects of acute ectopic expression of PPAR or /RXR on lipid metabolism in ?-cells and insulin secretion and those of PPAR agonist or PPAR agonist (WY14643 and BRL49653 on lipid metabolism in ?-cells and insulin secretion.
TABLE 1. A summary table of experimental data on the ?-cell function with different PPAR experimental systems
FIG. 1. Direct (?-cell-specific) and indirect (systemic) effects of three PPAR subtypes on ?-cell function. Regulation of metabolism and insulin secretion in pancreatic ?-cells can be affected by not only direct effect of PPARs (black arrows) but also lipid partitioning among adipose tissues, skeletal muscle, liver, and the islets modulated by PPARs (gray arrows).
It should be noted, however, that impact of acute ectopic expression of PPAR or /RXR on fatty acid metabolism and insulin secretion in INS-1E cells may be different under lipotoxic conditions in which INS-1 cells are surrounded by higher concentrations of lipids. The authors predict in this paper that PPAR expression under lipotoxic conditions would have a protective effect on the ?-cells. In the future, for example, the effect of palmitate on lipid metabolism and insulin secretion when PPAR or PPAR/RXR is overexpressed in INS-1E cells should be examined.
Ravnskj?r et al. (17) investigated the impact of acute ectopic expression of PPARs and PPAR agonists on insulin secretion and metabolism predominantly using INS-1E cells and isolated rat islets. In rodent models or human subjects, however, the regulation of metabolism and insulin secretion in pancreatic ?-cells can be affected by not only direct effect of PPARs but also lipid partitioning among adipose tissues, skeletal muscle, liver, and the islets (Fig. 1, gray arrows). It was recently reported that PPAR agonist pioglitazone restored impaired insulin secretion under conditions of islet fat accumulation (18). Lupi et al. (19) showed that rosiglitazone prevented the impairment of human islet function induced by fatty acids under conditions of islet fat accretion or increased fatty acid availability. These papers demonstrate that we must consider indirect effect via lipid partitioning among various tissues in addition to direct effect to assess the roles of PPARs and their agonists, such as thiazolidinedione and lipid-lowering fibrate drugs, in ?-cells.
References
Shulman GI 2000 Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176
Milburn JL, Hirose H, Lee YH, Nagasawa Y, Ogawa A, Ohneda M, BeltrandelRio H, Newgard CB, Johnson JH, Unger RH 1995 Pancreatic ?-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids. J Biol Chem 270:1295–1299
Zhou YP, Grill VE 1994 Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest 93:870–876
Briaud I, Harmon JS, Kelpe CL, Segu VB, Poitout V 2001 Lipotoxicity of the pancreatic ?-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 50:315–321
Issemann I, Green S 1990 Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347:645–650
Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W 1992 Control of the peroxisomal ?-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68:879–887
Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM 1994 Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91:7355–7359
Evans RM, Barish GD, Wang YX 2004 PPARs and the complex journey to obesity. Nat Med 10:355–361
Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W 1999 Peroxisome proliferator-activated receptor mediates the adaptive response to fasting. J Clin Invest 103:1489–1498
Mueller E, Drori S, Aiyer A, Yie J, Sarraf P, Chen H, Hauser S, Rosen ED, Ge K, Roeder RG, Spiegelman BM 2002 Genetic analysis of adipogenesis through peroxisome proliferator-activated receptor isoforms. J Biol Chem 277:41925–41930
Zhou YT, Shimabukuro M, Wang MY, Lee Y, Higa M, Milburn JL, Newgard CB, Unger RH 1998 Role of peroxisome proliferator-activated receptor in disease of pancreatic ? cells. Proc Natl Acad Sci USA 95:8898–8903
Tordjman K, Standley KN, Bernal-Mizrachi C, Leone TC, Coleman T, Kelly DP, Semenkovich CF 2002 PPAR suppresses insulin secretion and induces UCP2 in insulinoma cells. J Lipid Res 43:936–943
Koh EH, Kim MS, Park JY, Kim HS, Youn JY, Park HS, Youn JH, Lee KU 2003 Peroxisome proliferator-activated receptor (PPAR)- activation prevents diabetes in OLETF rats: comparison with PPAR- activation. Diabetes 52:2331–2337
Gremlich S, Nolan C, Roduit R, Burcelin R, Peyot ML, Delghingaro-Augusto V, Desvergne B, Michalik L, Prentki M, Wahli W 2005 Pancreatic islet adaptation to fasting is dependent on peroxisome proliferator-activated receptor transcriptional up-regulation of fatty acid oxidation. Endocrinology 146:375–382
Parton LE, Diraison F, Neill SE, Ghosh SK, Rubino MA, Bisi JE, Briscoe CP, Rutter GA 2004 Impact of PPAR overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays. Am J Physiol Endocrinol Metab 287:E390–E404
Shimabukuro M, Zhou YT, Lee Y, Unger RH 1998 Troglitazone lowers islet fat and restores ? cell function of Zucker diabetic fatty rats. J Biol Chem 273:3547–3550
Ravnskj?r K, B?rgesen M, Rubi B, Larsen JK, Nielsen T, Fridriksson J, Maechler P, Mandrup S2005 Peroxisome proliferator-activated receptor (PPAR) potentiates, whereas PPAR attenuates, glucose-stimulated insulin secretion in pancreatic ?-cells. Endocrinology 146:3266–3276
Matsui J, Terauchi Y, Kubota N, Takamoto I, Eto K, Yamashita T, Komeda K, Yamauchi T, Kamon J, Kita S, Noda M, Kadowaki T 2004 Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous PPAR-deficient mice on a high-fat diet. Diabetes 53:2844–2854
Lupi R, Del Guerra S, Marselli L, Bugliani M, Boggi U, Mosca F, Marchetti P, Del Prato S 2004 Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPAR2 in the modulation of insulin secretion. Am J Physiol Endocrinol Metab 286:E560–E567(Yasuo Terauchi and Takash)