Central pro-opiomelanocortin gene delivery results in hypophagia, reduced visceral adiposity, and improved insulin sensitivity in genetically obese Zucker rats.

Abstract	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.
Authors	Gang Li, Charles V Mobbs, Philip J Scarpace
Journal	Diabetes (Diabetes) Vol. 52 Issue 8 Pg. 1951-7 (Aug 2003) ISSN: 0012-1797 [Print] United States
PMID	12882910 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References	Agouti-Related Protein Blood Glucose Carrier Proteins Cyclic AMP Response Element-Binding Protein Fatty Acids, Nonesterified Insulin Intercellular Signaling Peptides and Proteins Ion Channels Leptin Membrane Proteins Mitochondrial Proteins Proteins Receptors, Cell Surface Receptors, Leptin UCP1 protein, human Ucp1 protein, rat Uncoupling Protein 1 Pro-Opiomelanocortin Cholesterol
Topics	Adipose Tissue, Brown (physiology) Agouti-Related Protein Animals Blood Glucose Carrier Proteins (genetics) Cell Line Cholesterol (blood) Cyclic AMP Response Element-Binding Protein (metabolism) Diabetes Mellitus (physiopathology, therapy) Eating (physiology) Fasting Fatty Acids, Nonesterified (blood) Feeding Behavior (physiology) Genetic Therapy Humans Hypothalamus (metabolism) Insulin (blood) Insulin Resistance (physiology) Intercellular Signaling Peptides and Proteins Ion Channels Kidney (cytology) Leptin (blood) Membrane Proteins (genetics) Mitochondrial Proteins Obesity Phosphorylation Pro-Opiomelanocortin (genetics) Proteins (genetics) Rats Rats, Zucker Receptors, Cell Surface (genetics) Receptors, Leptin Signal Transduction (physiology) Uncoupling Protein 1 Viscera

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