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Increased Dietary Fat Attenuates the Anorexic Effects of Intracerebroventricular Injections of MTII

Departments of Psychiatry (D.J.C., S.C.B., E.L.A., S.C.W., R.J.S.), Biomedical Sciences and Cell Biology (E.L.A.), Pathology (P.T.), and Medicine (D.D’A.), University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0559; and Procter & Gamble Pharmaceuticals (A.J.), Cincinnati, Ohio 45040

Address all correspondence and requests for reprints to: Deborah J. Clegg, Ph.D., Department of Psychiatry, University of Cincinnati Medical Center, P.O. Box 670559, Cincinnati, Ohio 45267-0559. E-mail: debbie.clegg{at}uc.edu.

The hypothalamic melanocortin (MC) system provides a critical inhibitory control on food intake and body weight. Because access to high-fat (HF) diets is associated with the development of obesity, we hypothesized that increased dietary fat attenuates signaling through the MC system. To evaluate this hypothesis, we compared the efficacy of the MC3/4 receptor agonist, MTII, to reduce food intake in rats fed carefully matched HF or low-fat (LF) diets for 12 wk. Rats given the HF diet ad libitum were significantly more obese than rats given the LF diet, and had significantly higher plasma insulin and leptin levels. MTII given into the third cerebral ventricle in doses of 0.1, 0.3, and 1.0 nmol was less effective at reducing food intake in HF rats than in LF rats. Whole-hypothalamic expression of the MC agonist precursor gene, proopiomelanocortin, the MC antagonist agouti-related protein, and the MC4 receptor, were not different between the HF and LF groups. These results indicate that consumption of a HF diet decreases signaling through the melanocortin system, an abnormality that could contribute to diet-induced obesity.

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