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Central Pro-opiomelanocortin Gene Delivery Results in Hypophagia, Reduced Visceral Adiposity, and Improved Insulin Sensitivity in Genetically Obese Zucker Rats

  1. Gang Li1,
  2. Charles V. Mobbs2 and
  3. Philip J. Scarpace13
  1. 1Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida
  2. 2Neurobiology of Aging Laboratories, Fishberg Center for Neurobiology and Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York
  3. 3Geriatric Research, Education and Clinical Center, Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida
  1. Address correspondence and reprint requests to Philip J. Scarpace, Geriatric Research, Education and Clinical Center, Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida 32608-1197. E-mail: scarpace{at}ufl.edu

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.

Footnotes

    • Accepted May 1, 2003.
    • Received February 28, 2003.
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