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J. Biol. Chem., Vol. 279, Issue 30, 31139-31148, July 23, 2004

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Hypothalamic Responses to Long-chain Fatty Acids Are Nutritionally Regulated^*

Kimyata Morgan, Silvana Obici, and Luciano Rossetti

From the Departments of Medicine and Molecular Pharmacology, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461

Central administration of the long-chain fatty acid oleic acid inhibits food intake and glucose production in rats. Here we examined whether short term changes in nutrient availability can modulate these metabolic and behavioral effects of oleic acid. Rats were divided in three groups receiving a highly palatable energy-dense diet at increasing daily caloric levels (below, similar, or above the average of rats fed standard chow). Following 3 days on the assigned diet regimen, rats were tested for acute biological responses to the infusion of oleic acid in the third cerebral ventricle. Three days of overfeeding virtually obliterated the metabolic and anorectic effects of the central administration of oleic acid. Furthermore, the infusion of oleic acid in the third cerebral ventricle failed to decrease the expression of neuropeptide Y in the hypothalamus and of glucose-6-phosphatase in the liver following short term overfeeding. The lack of hypothalamic responses to oleic acid following short term overfeeding is likely to contribute to the rapid onset of weight gain and hepatic insulin resistance in this animal model.

Received for publication, January 15, 2004 , and in revised form, April 15, 2004.

^* This work was supported in part by National Institutes of Health Grants DK 48321 and DK 45024 (to L. R.) and AECOM Diabetes Research and Training Center Grant DK 20541 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Junior Faculty Award from the American Diabetes Association.

To whom correspondence should be addressed: Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-4118; Fax: 718-430-8557; E-mail: rossetti{at}aecom.yu.edu.

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