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Simultaneous POMC gene transfer to hypothalamus and brainstem increases physical activity, lipolysis and reduces adult-onset obesity

Authors

  • Yi Zhang,

    1. Research Service, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL 32608, USA
    2. Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, FL, USA
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  • Enda Rodrigues,

    1. Research Service, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL 32608, USA
    2. Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, FL, USA
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  • Gang Li,

    1. Research Service, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL 32608, USA
    2. Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, FL, USA
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  • Yongxin Gao,

    1. Research Service, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL 32608, USA
    2. Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, FL, USA
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  • Michael King,

    1. Research Service, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL 32608, USA
    2. Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, FL, USA
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  • Christy S. Carter,

    1. Department of Aging and Geriatric Research, University of Florida, College of Medicine, Gainesville, FL, USA
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  • Nihal Tumer,

    1. Research Service, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL 32608, USA
    2. Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, FL, USA
    3. Department of Aging and Geriatric Research, University of Florida, College of Medicine, Gainesville, FL, USA
    4. Geriatric Research, Education and Clinical Center, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL, USA
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  • Kit-Yan Cheng,

    1. Research Service, Malcom Randall Veterans Affairs Medical Center, Gainesville, FL 32608, USA
    2. Department of Aging and Geriatric Research, University of Florida, College of Medicine, Gainesville, FL, USA
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  • Philip J. Scarpace

    1. Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, FL, USA
    2. Department of Aging and Geriatric Research, University of Florida, College of Medicine, Gainesville, FL, USA
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Dr Y. Zhang, 1Research Service, as above.
E-mail: yizhang@ufl.edu

Abstract

Pro-opiomelanocortin (POMC) neurons are identified in two brain sites, the arcuate nucleus of the hypothalamus and nucleus of the solitary tract (NTS) in brainstem. Earlier pharmacological and POMC gene transfer studies demonstrate that melanocortin activation in either site alone improves insulin sensitivity and reduces obesity. The present study, for the first time, investigated the long-term efficacy of POMC gene transfer concurrently into both sites in the regulation of energy metabolism in aged F344xBN rats bearing adult-onset obesity. Pair feeding was included to reveal food-independent POMC impact on energy expenditure. We introduced adeno-associated virus encoding either POMC or green fluorescence protein to the two brain areas in 22-month-old rats, then recorded food intake and body weight, assessed oxygen consumption, serum leptin, insulin and glucose, tested voluntary wheel running, analysed POMC expression, and examined fat metabolism in brown and white adipose tissues. POMC mRNA was significantly increased in both the hypothalamus and NTS region at termination. Relative to pair feeding, POMC caused sustained weight reduction and additional fat loss, lowered fasting insulin and glucose, and augmented white fat hormone-sensitive lipase activity and brown fat uncoupling protein 1 level. By wheel running assessment, the POMC animals ran twice the distance as the Control or pair-fed rats. Thus, the dual-site POMC treatment ameliorated adult-onset obesity effectively, involving a moderate hypophagia lasting ∼60 days, enhanced lipolysis and thermogenesis, and increased physical activity in the form of voluntary wheel running. The latter finding provides a clue for countering age-related decline in physical activity.

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