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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{at}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 ß-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 PPARß) (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 ß-cells (11). Models positioning both PPAR and - as mediators of the diverse effects of fatty acids on ß-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 ß-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 ß-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 ß-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 ß-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 ß-cell function are diverse (summarized in Table 1
). Confusion on the direct function of PPAR subtypes in lipid partitioning into pancreatic ß-cells is remarkable. In this issue of Endocrinology, Ravnskjær et al. (17) investigated and directly compared the roles of these PPAR subtypes in ß-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 ß-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 ß-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 ß-cell line. Moreover, Ravnskjær et al. (17) compared the effects of acute ectopic expression of PPAR or /RXR on lipid metabolism in ß-cells and insulin secretion and those of PPAR agonist or PPAR agonist (WY14643 and BRL49653 on lipid metabolism in ß-cells and insulin secretion.
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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 ß-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.
Ravnskjær 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 ß-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 ß-cells.
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Footnotes |
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Received May 2, 2005.
Accepted for publication May 11, 2005.
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mediates the adaptive response to fasting. J Clin Invest 103:1489–1498[Medline]
isoforms. J Biol Chem 277:41925–41930 in disease of pancreatic ß cells. Proc Natl Acad Sci USA 95:8898–8903 suppresses insulin secretion and induces UCP2 in insulinoma cells. J Lipid Res 43:936–943 activation prevents diabetes in OLETF rats: comparison with PPAR- activation. Diabetes 52:2331–2337 transcriptional up-regulation of fatty acid oxidation. Endocrinology 146:375–382 overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays. Am J Physiol Endocrinol Metab 287:E390–E404
(PPAR) potentiates, whereas PPAR attenuates, glucose-stimulated insulin secretion in pancreatic ß-cells. Endocrinology 146:3266–3276
-deficient mice on a high-fat diet. Diabetes 53:2844–28542 in the modulation of insulin secretion. Am J Physiol Endocrinol Metab 286:E560–E567This article has been cited by other articles:
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  R. C. Reddy, Y. Hao, S.-H. Lee, S. R. Gangireddy, C. Owyang, and M. J. DiMagno Pioglitazone reverses insulin resistance and impaired CCK-stimulated pancreatic secretion in eNOS(-/-) mice: therapy for exocrine pancreatic disorders? Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G112 - G120. [Abstract] [Full Text] [PDF]
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 R. Bergeron, J. Yao, J. W. Woods, E. I. Zycband, C. Liu, Z. Li, A. Adams, J. P. Berger, B. B. Zhang, D. E. Moller, et al. Peroxisome Proliferator-Activated Receptor (PPAR)-{alpha} Agonism Prevents the Onset of Type 2 Diabetes in Zucker Diabetic Fatty Rats: A Comparison with PPAR{gamma} Agonism Endocrinology, September 1, 2006; 147(9): 4252 - 4262. [Abstract] [Full Text] [PDF]
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