Hypothalamic POMC Deficiency Improves Glucose Tolerance Despite Insulin Resistance by Increasing Glycosuria.

KAVALJIT H. CHHABRA, JESSICA M. ADAMS,1,2 BRIAN FAGEL,1 DANIEL D. LAM,1 NATHAN QI, MARCELO RUBINSTEIN AND MALCOLM J. LOW

DIABETES

AMER DIABETES ASSOC

Año: 2016 vol. 65 p. 660 - 672

0012-1797

Hypothalamic proopiomelanocortin (POMC) is essentialfor the physiological regulation of energy balance;however, its role in glucose homeostasis remains lessclear. We show that hypothalamic arcuate nucleus(Arc)POMC-deficient mice, which develop severe obesityand insulin resistance, unexpectedly exhibit improvedglucose tolerance and remain protected fromhyperglycemia. To explain these paradoxical phenotypes,we hypothesized that an insulin-independentpathway is responsible for the enhanced glucose tolerance.Indeed, the mutant mice demonstrated increasedglucose effectiveness and exaggerated glycosuria relativeto wild-type littermate controls at comparable bloodglucose concentrations. Central administration of themelanocortin receptor agonist melanotan II in mutantmice reversed alterations in glucose tolerance andglycosuria, whereas, conversely, administration of theantagonist Agouti-related peptide (Agrp) to wild-typemice enhanced glucose tolerance. The glycosuria ofArcPOMC-deficient mice was due to decreased levels ofrenal GLUT 2 (rGLUT2) but not sodium?glucose cotransporter2 and was associated with reduced renal catecholaminecontent. Epinephrine treatment abolished thegenotype differences in glucose tolerance and rGLUT2levels, suggesting that reduced renal sympathetic nervoussystem (SNS) activity is the underlying mechanismfor the observed glycosuria and improved glucose tolerancein ArcPOMC-deficient mice. Therefore, theArcPOMC-SNS-rGLUT2 axis is potentially an insulinindependenttherapeutic target to control diabetes.