Elsevier

Biological Psychiatry

Volume 67, Issue 11, 1 June 2010, Pages 1075-1082
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2009.12.003Get rights and content

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.

Section snippets

Animals and Housing

Male c57BL6/J mice (Jackson Laboratories, Bar Harbor, Maine) (8–10 weeks old) and CD1 retired breeder mice (Charles River, Wilmington, Massachusetts) were housed in the The University of Texas Southwestern Medical Center (UTSW) vivarium in a temperature-controlled environment (lights on: 04:00-16:00) with ad lib access to water and standard chow (4% fat diet #7001, Harlan-Teklad, Madison, Wisconsin) or high-fat diet (HFD) (42% kcal from fat, TD.88137, Harlan-Teklad) as noted. Melanocortin 4

Metabolic Effects of Chronic Social Defeat Stress

Following 10 days of CSDS, wild-type C57BL/6 male mice were tested for social interaction and randomized into two groups with equivalent interaction scores. The mice received either regular chow or a Western-style diet that is high in fat and cholesterol (high-fat diet). In the first set of experiments, we characterized the effect of CSDS on food intake and body weight regulation in chow-fed animals. Mice initially lost weight during the first days of the CSDS paradigm; however, beginning at

Discussion

Determining the effects of chronic stress on the regulation of feeding and body weight is of critical importance because of the well-known association between psychiatric disorders and metabolic diseases, as outlined above. The current findings provide a molecular and neurobiologic model that explains, in part, the link between altered mood and metabolic status. This model, and the extensive characterization provided here, can now be used in future studies to further investigate the underlying

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