Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

Su Gao, Kimberly P. Kinzig, Susan M Aja, Karen A. Scott, Wendy Keung, Sandra Kelly, Ken Strynadka, Shigeru Chohnan, Wanli Smith, Kellie Tamashiro, Ellen Elizabeth Ladenheim, Gabriele V. Ronnett, Yajun Tu, Morris J. Birnbaum, Gary D. Lopaschuk, Timothy H Moran

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17358-17363
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number44
DOIs
StatePublished - Oct 30 2007

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Acetyl-CoA Carboxylase
Leptin
Eating
Malonyl Coenzyme A
AMP-Activated Protein Kinases
Paraventricular Hypothalamic Nucleus
Fatty Acids
Palmitoyl Coenzyme A
Appetite Depressants
Arcuate Nucleus of Hypothalamus
Neuropeptides
Hypothalamus
Homeostasis
Up-Regulation
Body Weight
Messenger RNA
Injections

Keywords

  • Carnitine palmitoyltransferase
  • Long-chain fatty acyl CoA
  • Malonyl CoA
  • Malonyl CoA decarboxylase
  • Oleic acid

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. / Gao, Su; Kinzig, Kimberly P.; Aja, Susan M; Scott, Karen A.; Keung, Wendy; Kelly, Sandra; Strynadka, Ken; Chohnan, Shigeru; Smith, Wanli; Tamashiro, Kellie; Ladenheim, Ellen Elizabeth; Ronnett, Gabriele V.; Tu, Yajun; Birnbaum, Morris J.; Lopaschuk, Gary D.; Moran, Timothy H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 44, 30.10.2007, p. 17358-17363.

Research output: Contribution to journalArticle

Gao, S, Kinzig, KP, Aja, SM, Scott, KA, Keung, W, Kelly, S, Strynadka, K, Chohnan, S, Smith, W, Tamashiro, K, Ladenheim, EE, Ronnett, GV, Tu, Y, Birnbaum, MJ, Lopaschuk, GD & Moran, TH 2007, 'Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 44, pp. 17358-17363. https://doi.org/10.1073/pnas.0708385104
Gao, Su ; Kinzig, Kimberly P. ; Aja, Susan M ; Scott, Karen A. ; Keung, Wendy ; Kelly, Sandra ; Strynadka, Ken ; Chohnan, Shigeru ; Smith, Wanli ; Tamashiro, Kellie ; Ladenheim, Ellen Elizabeth ; Ronnett, Gabriele V. ; Tu, Yajun ; Birnbaum, Morris J. ; Lopaschuk, Gary D. ; Moran, Timothy H. / Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 44. pp. 17358-17363.
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abstract = "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.",
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AU - Gao, Su

AU - Kinzig, Kimberly P.

AU - Aja, Susan M

AU - Scott, Karen A.

AU - Keung, Wendy

AU - Kelly, Sandra

AU - Strynadka, Ken

AU - Chohnan, Shigeru

AU - Smith, Wanli

AU - Tamashiro, Kellie

AU - Ladenheim, Ellen Elizabeth

AU - Ronnett, Gabriele V.

AU - Tu, Yajun

AU - Birnbaum, Morris J.

AU - Lopaschuk, Gary D.

AU - Moran, Timothy H

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N2 - 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.

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