Hypothalamic fatty acid metabolism has recently been implicated in the controls of food intake and energy homeostasis. We report that intracerebroventricular (ICV) injection of leptin, concomitant with inhibiting AMP-activated kinase (AMPK), activates acetyl-CoA carboxylase (ACC), the key regulatory enzyme in fatty acid biosynthesis, in the arcuate nucleus (Arc) and paraventricular nucleus (PVN) in the hypothalamus. Arc overexpression of constitutively active AMPK prevents the Arc ACC activation in response to ICV leptin, supporting the hypothesis that AMPK lies upstream of ACC in leptin's Arc intracellular signaling pathway. Inhibiting hypothalamic ACC with 5-tetradecyloxy-2-furoic acid, a specific ACC inhibitor, blocks leptin-mediated decreases in food intake, body weight, and mRNA level of the orexigenic neuropeptide NPY. These results show that hypothalamic ACC activation makes an important contribution to leptin's anorectic effects. Furthermore, we find that ICV leptin up-regulates the level of malonyl-CoA (the intermediate of fatty acid biosynthesis) specifically in the Arc and increases the level of palmitoyl-CoA (a major product of fatty acid biosynthesis) specifically in the PVN. The rises of both levels are blocked by 5-tetradecyloxy-2-furoic acid along with the blockade of leptinmediated hypophagia. These data suggest malonyl-CoA as a downstream mediator of ACC in leptin's signaling pathway in the Arc and imply that palmitoyl-CoA, instead of malonyl-CoA, could be an effector in relaying ACC signaling in the PVN. Together, these findings highlight site-specific impacts of hypothalamic ACC activation in leptin's anorectic signaling cascade.carnitine palmitoyltransferase ͉ long-chain fatty acyl CoA ͉ malonyl CoA ͉ oleic acid ͉ malonyl CoA decarboxylase E nergy balance is maintained by hypothalamic systems responding to hormonal and neural signals that sense body energy status (1). Leptin is an anorexigenic hormone secreted mainly from adipocytes that controls food intake and energy homeostasis primarily by acting at hypothalamic nuclei such as the arcuate nucleus (Arc) (1, 2). The Arc, the primary nucleus in the hypothalamus in mediating leptin's control of energy balance, contains first-order neurons that express leptin receptors and a variety of feeding-related neuropeptides such as neuropeptide Y (NPY), agouti-related peptide (AgRP), and ␣-melanocyte stimulating hormone (␣-MSH) (1). Leptin exerts its anorectic effects by modulating the levels of these neuropeptides. Activation of signal transducer and activator of transcription 3 (STAT3) and activation of phosphatidylinositol 3-kinase have been shown to play critical roles in leptin's hypothalamic intracellular signaling pathways (3, 4).Further aspects of leptin's hypothalamic intracellular signaling have been identified. Minokoshi et al. (5) have demonstrated that exogenous administration of leptin inhibits AMP-activated kinase (AMPK) in the Arc, and, based on the finding that constitutive activity of AMPK in the Arc prevents leptin's anorectic acti...

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