Melanin Concentrating Hormone Is a Novel Regulator of Islet Function and Growth

Abstract

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 ...

Pmchexpression during early development is critical for normal energy homeostasis

“…Plasma leptin levels were lower in pmch Ϫ/Ϫ rats, correlating with the lower adipose amounts. Two independent studies (48,65) showed that MCH is a positive regulator of insulin release; thus loss of Pmch expression could explain the decreased basal plasma insulin levels and the delayed glucose clearance in the IVGTT studies. Basal insulin levels were lower especially at the end of the dark phase, suggesting a combinatorial effect of decreased caloric intake and loss of MCH-stimulated insulin release.…”

Melanin-concentrating hormone as a mediator of intestinal inflammation

“…More recent studies extended the physiological functions of MCH as a broad regulator of cognitive and autonomic aspects related to rewarding behaviors (6,7). Outside the brain, MCH is localized in the pancreas (8), skin (9), and gastrointestinal tract (10). It has been also found in tissular and circulating immune cells (11)(12)(13)(14).…”

“…In the rodent brain, MCHR1 is expressed in areas important for feeding, learning and motivated behavior, integration of sensory and gustatory inputs, autonomic control, and arousal (22,23). MCHR1 mRNA is also expressed in the thyroid, kidney, adipose tissue, lung, testes, and tongue (23), whereas functional MCHR1 is also present in lymphocytes (12,14), insulin-producing cell lines (24), and mouse and human pancreatic islets (8).…”

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

“…Moreover, MCH has been detected in the periphery in testis and enteric neural system. In the peripheral tissue it is known to induce insulin hypersecretion and enhanced levels of the hepatocyte nuclear factor [190]. The absence of the peptide results in hypophagia and leaness [191].…”