Cited by 215Regulation of Appetite and ObesityHypothalamic control of reproductive hormonesPeroxisome Proliferator-Activated Receptors

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Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

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Gao, Su, Kinzig, Kimberly P., Aja, Susan, Scott, Karen A., Keung, Wendy, Kelly, Sandra, Strynadka, Ken, Chohnan, Shigeru, Smith, Wanli W., Tamashiro, Kellie L. K., Ladenheim, Ellen E., Ronnett, Gabriele V., Tu, Yajun, Birnbaum, Morris J., Lopaschuk, Gary D., Moran, Timothy H.·2007·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0708385104PMC PMC2077261

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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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Authors: Gao, S., Kinzig, K. P., Aja, S., Scott, K. A., Keung, W., Kelly, S., Strynadka, K., Chohnan, S., Smith, W. W., Tamashiro, K. L. K., Ladenheim, E. E., Ronnett, G. V., Tu, Y., Birnbaum, M. J., Lopaschuk, G. D., & Moran, T. H.
Affiliations: Departments of *Biological Chemistry,
Psychiatry and Behavioral Sciences, and
University of Alberta (CA)
Ibaraki University (JP)
Johns Hopkins University (US)
Howard Hughes Medical Institute (US)
Corresponding author: Gao, Su
ORCID: Scott, Karen A.
Keung, Wendy
Kelly, Sandra
Chohnan, Shigeru
Smith, Wanli W.
Tamashiro, Kellie L. K.
Birnbaum, Morris J.
Lopaschuk, Gary D.
Moran, Timothy H.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2007-10-30
Volume: 104
Issue: 44
Pages: 17358-17363
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0708385104
PMC: PMC2077261
OpenAlex: W2027922318
Cited by: 215
References: 33
Citations by year: 2026: 3 · 2025: 3 · 2024: 6 · 2023: 2 · 2022: 5 · 2021: 9 · 2020: 8 · 2019: 3 · 2018: 9 · 2017: 14 · 2016: 9 · 2015: 9 · 2014: 11 · 2013: 20 · 2012: 21
FWCI: 8.57
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
Locations: Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (DK068054, R56DK019302, DK 19302, K01DK068054, R01DK019302)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: leptin, acetyl-CoA carboxylase, AMPK, hypothalamus, arcuate nucleus, paraventricular nucleus, dietary intake, anorectic effect, malonyl-CoA, palmitoyl-CoA, fatty acid synthesis, neuropeptide Y, energy homeostasis
MeSH terms: Acetyl-CoA Carboxylase, Animals, Enzyme Activation, Enzyme Inhibitors, Feeding Behavior, Hypothalamus, Male, Multienzyme Complexes, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Leptin, Rats, AMP-Activated Protein Kinases

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Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

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