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A β3-Adrenergic-Leptin-Melanocortin Circuit Regulates Behavioral and Metabolic Changes Induced by Chronic Stress

  • Jen-Chieh Chuang
    Affiliations
    Department of Internal Medicine (Division of Hypothalamic Research), The University of Texas Southwestern Medical Center, Dallas, Texas
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  • Vaishnav Krishnan
    Affiliations
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas
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  • Hana G. Yu
    Affiliations
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas
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  • Brittany Mason
    Affiliations
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas
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  • Huixing Cui
    Affiliations
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas

    Department of Internal Medicine (Division of Hypothalamic Research), The University of Texas Southwestern Medical Center, Dallas, Texas
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  • Matthew B. Wilkinson
    Affiliations
    Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York
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  • Jeffrey M. Zigman
    Affiliations
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas

    Department of Internal Medicine (Division of Hypothalamic Research), The University of Texas Southwestern Medical Center, Dallas, Texas
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  • Joel K. Elmquist
    Affiliations
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas

    Department of Internal Medicine (Division of Hypothalamic Research), The University of Texas Southwestern Medical Center, Dallas, Texas

    Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas
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  • Eric J. Nestler
    Affiliations
    Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York
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  • Michael Lutter
    Correspondence
    Address correspondence to Michael Lutter, M.D., Ph.D., The University of Texas Southwestern Medical Center, Department of Psychiatry, 2201 Inwood Road, Dallas, TX 75390-9070
    Affiliations
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas

    Department of Internal Medicine (Division of Hypothalamic Research), The University of Texas Southwestern Medical Center, Dallas, Texas
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      Background

      Obesity has been associated with an increased risk of developing several psychiatric illnesses, including major depression and posttraumatic stress disorder. Likewise, these stress-related disturbances are associated with a higher rate of obesity; yet, the neurobiological mechanisms linking obesity and stress remain incompletely understood.

      Methods

      Following exposure to chronic social defeat stress (CSDS), mice were given free access to either regular chow or a Western-style diet high in triglycerides and cholesterol. Comprehensive metabolic and behavioral testing was then conducted.

      Results

      Mice subjected to CSDS and then fed a high-fat diet for 30 days display severe behavioral deficits accompanied by redistribution of body fat. Stressed mice have decreased adipose tissue as well as decreased serum leptin levels compared with control mice. Pharmacological inhibition of β3-adrenergic signaling during CSDS normalizes these metabolic abnormalities but worsens behavioral symptoms. Furthermore, mice subjected to CSDS display central leptin resistance including reduced expression of pro-opiomelanocortin in hypothalamus. Administration of a central melanocortin agonist worsens stress-induced behavioral deficits, while mice lacking the melanocortin-4 receptor display attenuated symptoms.

      Conclusions

      These results indicate that chronic signaling through β3-adrenergic receptors during social stress is an adaptive response that improves behavioral function. However, these responses come at the expense of central leptin resistance and melanocortin signaling alterations that contribute to significant and long-lasting metabolic abnormalities.

      Key Words

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      • Erratum
        Biological PsychiatryVol. 68Issue 1
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          An error has been discovered in “A β3-Adrenergic-Leptin-Melanocortin Circuit Regulates Behavioral and Metabolic Changes Induced by Chronic Stress” by Chuang et al., which appeared in Biological Psychiatry (2010;67:1075–1082). The proper spelling of the fifth author's name is Huxing Cui.
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