Objective: To investigate the differential effects of acute central administration of distinct fatty acids (FA) on food intake, body weight and energy metabolism. Design: Male Sprague-Dawley rats were treated with bolus intracerebroventricular injections of control hydroxypropylb-cyclodextrin (HPB) or HPB complexed with 30 nmol of saturated palmitic acid (PA), monounsaturated oleic acid (OA) or polyunsaturated o-3 docosahexaenoic acid (DHA). Food intake, body weight, neuropeptide expression and various serum parameters were assessed. Results: When compared with controls, rats injected with either OA or DHA had significantly reduced food intake and body weight for 48 h following injections. No significant changes in food intake or body weight were observed in the PA group. In conjunction with reduced food intake, hypothalamic anorexigenic pro-opiomelanocortin (POMC) gene expression was significantly augmented in the OA and DHA groups, with essentially no changes observed in the PA group. Changes in serum measures of energy metabolism also changed coinciding with the observed differences in food intake. Moreover, central administration of SHU9119, a melanocortin-4-rececptor (MC4R) antagonist, completely abolished the anorexigenic actions of OA, suggesting a role for OA-induced augmentation of hypothalamic POMC expression in mediating its central inhibition of food intake. Conclusions: The hypothalamus differentially senses FA and, specifically, that OA and DHA, but not PA, reduce food intake and body weight, which may be mediated through POMC/MC4R signaling.

Nutrient sensing within the hypothalamus plays a critical role in the complex network of signals controlling energy metabolism. We used intracerebroventricular (ICV) injections of the saturated palmitic acid (PA), monounsaturated oleic acid (OA), and polyunsaturated omega‐3 docosahexaenoic acid (DHA) to investigate the effects of various fatty acids on food intake, body weight, and the hypothalamic melanocortin system in rats. Both the OA and DHA groups experienced significant decreases in food intake and body weight when compared to controls. PA injections produced no changes in either food intake or body weight. Expression of POMC, a prominent anorectic neuropeptide, was found to be significantly increased in the OA and DHA groups, whereas POMC expression was essentially unaltered in the PA group. Central administration of a melanocortin receptor antagonist, SHU9119, blocked the effects of OA on food intake and body weight, thus implicating a central role for POMC in mediating the effects of fatty acids. Delineating the mechanisms and signaling pathways through which different fatty acids alter central control of energy metabolism may provide future opportunities for the prevention and treatment of metabolic diseases such as obesity and diabetes. This work was supported by the Minnesota Obesity Center.