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

¹ Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
² Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts
³ Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
⁴ Department of Chemistry and Pharmacology, University of Michigan, Ann Arbor, Michigan
⁵ Department of Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota

Address correspondence and reprint requests to Rohit N. Kulkarni, MD, PhD, Room 602, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: rohit.kulkarni{at}joslin.harvard.edu

Abbreviations: ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal–related kinase; HNF, hepatocyte nuclear factor; MCH, melanin concentrating hormone; MCHR, MCH receptor; RIA, radioimmunoassay; TBS, Tris-buffered solution

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 ß-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 ß-cell mass and complemented our earlier observation of increased ß-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 ß-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 ß-cell mass dynamics and in islet secretory function and suggest that MCH is part of a hypothalamic-islet (pancreatic) axis.

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