Central pro-opiomelanocortin gene delivery results in hypophagia, reduced visceral adiposity, and improved insulin sensitivity in genetically obese Zucker rats.
Zucker (fa/fa) rats with defective leptin receptors are obese, hyperphagic, and hyperinsulinemic. For testing whether chronic activation of the central melanocortin pathway can bypass the defective leptin signaling and normalize altered energy homeostasis in these rats, recombinant adeno-associated virus encoding pro-opiomelanocortin (rAAV-POMC) or control vector was delivered bilaterally into the basal hypothalamus with coordinates targeting the arcuate nucleus. Thirty-eight days after POMC gene delivery, hypothalamic POMC expression increased fourfold and melanocortin signaling (indicated by phosphorylation of CREB) increased by 62% with respect to controls. There was a sustained reduction in food intake, a moderate but significant attenuation of weight gain, and a 24% decrease in visceral adiposity in rAAV-POMC rats. POMC gene delivery enhanced uncoupling protein 1 in brown adipose tissue (BAT) by more than fourfold. Fasting serum leptin, insulin, and cholesterol levels were also significantly reduced by rAAV-POMC treatment. This study demonstrates that targeted POMC gene delivery in the hypothalamus suppresses food intake and weight gain and reduces visceral adiposity and hyperinsulinemia in leptin-resistant obese Zucker rats. The mechanisms may involve the sustained hypophagia and the augmentation of thermogenesis in BAT.
Li
Gang
G
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida, USA.
Mobbs
Charles V
CV
Scarpace
Philip J
PJ
D002001:Adipose Tissue, Brown / Q000502:physiology*; D054369:Agouti-Related Protein; D000818:Animals; D001786:Blood Glucose; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003920:Diabetes Mellitus / Q000503:physiopathology* / Q000628:therapy; D004435:Eating / Q000502:physiology; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005247:Feeding Behavior / Q000502:physiology*; D015316:Genetic Therapy; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels; D007668:Kidney / Q000166:cytology; D020738:Leptin / Q000097:blood; D008565:Membrane Proteins / Q000235:genetics; D024101:Mitochondrial Proteins; D009765:Obesity; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D015398:Signal Transduction / Q000502:physiology; D000071256:Uncoupling Protein 1; D014781:Viscera
D054369:Agouti-Related Protein; D001786:Blood Glucose; D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C000604371:UCP1 protein, human; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D011333:Pro-Opiomelanocortin; D002784:Cholesterol