The transcriptional coactivator PPARγ coactivator 1α (PGC-1α) is a strong activator of mitochondrial biogenesis and oxidative metabolism. While expression of PGC-1α and many of its mitochondrial target genes are decreased in the skeletal muscle of patients with type 2 diabetes, no causal relationship between decreased PGC-1α expression and abnormal glucose metabolism has been established. To address this question, we generated skeletal muscle-specific PGC-1α knockout mice (MKOs), which developed significantly impaired glucose tolerance but showed normal peripheral insulin sensitivity. Surprisingly, MKOs had expanded pancreatic β cell mass, but markedly reduced plasma insulin levels, in both fed and fasted conditions. Muscle tissue from MKOs showed increased expression of several proinflammatory genes, and these mice also had elevated levels of the circulating IL-6. We further demonstrated that IL-6 treatment of isolated mouse islets suppressed glucose-stimulated insulin secretion. These data clearly illustrate a causal role for muscle PGC-1α in maintenance of glucose homeostasis and highlight an unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets.

Summary Glucagon plays an important role in glucose homeostasis by regulating hepatic glucose output in both normo- and hypo-glycemic conditions. In this study, we created and characterized α-cell specific insulin receptor knockout (αIRKO) mice to directly explore the role of insulin signaling in the regulation of glucagon secretion in vivo. Adult male αIRKO mice exhibited mild glucose intolerance, hyperglycemia and hyperglucagonemia in the fed state, and enhanced glucagon secretion in response to L-Arginine stimulation. Hyperinsulinemic-hypoglycemic clamp studies revealed an enhanced glucagon secretory response and an abnormal norepinephrine response to hypoglycemia in αIRKO mice. The mutants also exhibited an age-dependent increase in β-cell mass. Furthermore, siRNA-mediated knockdown of insulin receptor in glucagon-secreting InR1G cells promoted enhanced glucagon secretion and complemented our in vivo findings. Together, these data indicate a significant role for intra-islet insulin signaling in the regulation of α-cell function in both normo- and hypo-glycemic conditions.

Obesity is characterized by hyperinsulinemia, hyperleptinemia, and an increase in islet volume. While the mechanisms that hasten the onset of diabetes in obese individuals are not known, it is possible that the adipose-derived hormone leptin plays a role. In addition to its central actions, leptin exerts biological effects by acting in peripheral tissues including the endocrine pancreas. To explore the impact of disrupting leptin signaling in the pancreas on β cell growth and/or function, we created pancreas-specific leptin receptor (ObR) KOs using mice expressing Cre recombinase under the control of the pancreatic and duodenal homeobox 1 (Pdx1) promoter. The KOs exhibited improved glucose tolerance due to enhanced early-phase insulin secretion, and a greater β cell mass secondary to increased β cell size and enhanced expression and phosphorylation of p70S6K. Similar effects on p70S6K were observed in MIN6 β cells with knockdown of the ObR gene, suggesting crosstalk between leptin and insulin signaling pathways. Surprisingly, challenging the KOs with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Together, these data provide direct genetic evidence, from a unique mouse model lacking ObRs only in the pancreas, for a critical role for leptin signaling in islet biology and suggest that altered leptin action in islets is one factor that contributes to obesity-associated diabetes. IntroductionThe factors that promote β cell failure and increase the incidence of diabetes in obese individuals are not fully understood. The presence of hyperglycemia and hyperphagia in obese individuals, despite the presence of high levels of circulating insulin and leptin, suggests these individuals are resistant to the actions of both hormones (1). The hypothalamic actions of leptin are relatively well characterized; however, the expression of the long form of the leptin receptor (ObRb) in peripheral tissues, including the endocrine pancreas, indicates that leptin can also exert peripheral actions independent of its effects in the hypothalamus (2). For example, in vitro studies have reported inhibitory effects of leptin on insulin gene expression and insulin secretion in β cell lines and isolated murine and human islets (2-4). Furthermore, leptin treatment of ob/ob mice reversed hyperinsulinemia (5). Although the db/db mouse, which carries a mutation in the ObR gene (6), manifests hyperinsulinemia and hyperplastic islets (7), it is unclear whether the alterations in islet growth and function in db/db mice are due to a lack of direct leptin action in β cells or secondary to the effects of insulin resistance in peripheral tissues.To directly assess the role of leptin signaling in the pancreas, we used the Cre-loxP technique to create a mouse model that is

Melanin concentrating hormone (MCH) is a hypothalamic neuropeptide known to play a critical role in energy balance. We have previously reported that overexpression of MCH is associated with mild obesity. In addition, mice have substantial hyperinsulinemia and islet hyperplasia that is out of proportion with their degree of obesity. In this study, we further explored the role of MCH in the endocrine pancreas. Both MCH and MCHR1 are expressed in mouse and human islets and in clonal ␤-cell lines as assessed using quantitative real-time PCR and immunohistochemistry. Mice lacking MCH (MCH-KO) on either a C57Bl/6 or 129Sv genetic background showed a significant reduction in ␤-cell mass and complemented our earlier observation of increased ␤-cell mass in MCH-overexpressing mice. Furthermore, the compensatory islet hyperplasia secondary to a high-fat diet, which was evident in wild-type controls, was attenuated in MCH-KO. Interestingly, MCH enhanced insulin secretion in human and mouse islets and rodent ␤-cell lines in a dose-dependent manner. Real-time PCR analyses of islet RNA derived from MCH-KO revealed altered expression of islet-enriched genes such as glucagon, forkhead homeobox A2, hepatocyte nuclear factor (HNF)4␣, and HNF1␣. Together, these data provide novel evidence for an autocrine role for MCH in the regulation of ␤-cell mass dynamics and in islet secretory function and suggest that MCH is part of a hypothalamic-islet (pancreatic) axis. Diabetes 56:311-319, 2007 S everal neuropeptides that act in the central nervous system to regulate feeding behavior and energy homeostasis are also expressed in the enteric system as part of a potential hypothalamic-pancreatic axis (1). While some of these neuropeptides have an effect on exocrine pancreatic function, their effects on endocrine secretion are not fully understood. Thus, ghrelin, neuropeptide Y, galanin, orexins A and B, leptin, and the agouti gene product are neuropeptides that act in the hypothalamus to regulate feeding behavior and have also been reported to modulate islet function and/or growth (2-11). Melanin concentrating hormone (MCH) is another hypothalamic peptide that is known to regulate energy balance. A previous study reported that mice overexpressing MCH have islet hyperplasia, suggesting that MCH may also play a role in islet growth. However, the potential role of MCH and its receptors in the endocrine pancreas and a potential role of MCH in islet biology have not been explored.MCH is expressed in the lateral hypothalamus and zona incerta and has been shown to be important for feeding and energy homeostasis in rodents (12,13). MCH expression in the hypothalamus is upregulated by fasting and suppressed by leptin injection (13-15). Intracerebroventricular injections of MCH acutely stimulate feeding behavior (16). Mice lacking the prohormone are lean and hypophagic, whereas mice overexpressing MCH are obese (17,18). In rodents, MCH acts via a high-affinity G-proteincoupled receptor, designated MCH receptor (MCHR)1. In humans and primates, a second ...