Hypothalamic responses to long-chain fatty acids are nutritionally regulated.

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.