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Article: Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

TitleLeptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake
Authors
KeywordsCarnitine palmitoyltransferase
Long-chain fatty acyl CoA
Malonyl CoA
Malonyl CoA decarboxylase
Oleic acid
Issue Date2007
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2007, v. 104 n. 44, p. 17358-17363 How to Cite?
AbstractHypothalamic 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. © 2007 by The National Academy of Sciences of the USA.
Persistent Identifierhttp://hdl.handle.net/10722/195863
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorGao, S-
dc.contributor.authorKinzig, KP-
dc.contributor.authorAja, S-
dc.contributor.authorScott, KA-
dc.contributor.authorKeung, W-
dc.contributor.authorKelly, S-
dc.contributor.authorStrynadka, K-
dc.contributor.authorChohnan, S-
dc.contributor.authorSmith, WW-
dc.contributor.authorTamashiro, KLK-
dc.contributor.authorLadenheim, EE-
dc.contributor.authorRonnett, GV-
dc.contributor.authorTu, Y-
dc.contributor.authorBirnbaum, MJ-
dc.contributor.authorLopaschuk, GD-
dc.contributor.authorMoran, TH-
dc.date.accessioned2014-03-19T01:46:11Z-
dc.date.available2014-03-19T01:46:11Z-
dc.date.issued2007-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2007, v. 104 n. 44, p. 17358-17363-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/195863-
dc.description.abstractHypothalamic 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. © 2007 by The National Academy of Sciences of the USA.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectCarnitine palmitoyltransferase-
dc.subjectLong-chain fatty acyl CoA-
dc.subjectMalonyl CoA-
dc.subjectMalonyl CoA decarboxylase-
dc.subjectOleic acid-
dc.titleLeptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1073/pnas.0708385104-
dc.identifier.pmid17956983-
dc.identifier.scopuseid_2-s2.0-36849071229-
dc.identifier.volume104-
dc.identifier.issue44-
dc.identifier.spage17358-
dc.identifier.epage17363-
dc.identifier.isiWOS:000250638400025-
dc.identifier.f1000718529406-
dc.identifier.issnl0027-8424-

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