Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake
| Autor: | Wendy Keung, Timothy H. Moran, Ken Strynadka, Ellen E. Ladenheim, Yajun Tu, Kellie L.K. Tamashiro, Shigeru Chohnan, Morris J. Birnbaum, Gabriele V. Ronnett, Susan Aja, Kimberly P. Kinzig, Su Gao, Gary D. Lopaschuk, Karen A. Scott, Sandra E. Kelly, Wanli W. Smith |
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| Rok vydání: | 2007 |
| Předmět: |
Leptin
Male medicine.medical_specialty Hypothalamus AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Energy homeostasis Rats Sprague-Dawley chemistry.chemical_compound AMP-activated protein kinase Multienzyme Complexes Internal medicine medicine Animals Enzyme Inhibitors Multidisciplinary Arc (protein) biology digestive oral and skin physiology Acetyl-CoA carboxylase AMPK Feeding Behavior Malonyl-CoA decarboxylase Biological Sciences Rats Enzyme Activation Endocrinology Malonyl-CoA nervous system chemistry biology.protein hormones hormone substitutes and hormone antagonists Acetyl-CoA Carboxylase |
| Zdroj: | Proceedings of the National Academy of Sciences. 104:17358-17363 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0708385104 |
| Popis: | 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 leptin-mediated 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. |
| Databáze: | OpenAIRE |
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