Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake
Open accessAbstract
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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The mechanism of leptin action also appears to be related to increases in physiological malonyl-CoA in the arcuate nucleus, which promotes a reduction in food intake and body weight, using different mechanisms from those previously reported for ghrelin action, during energetically wealthy states.
“The mechanism of leptin action also appears to be related to increases in physiological malonyl-CoA in the arcuate nucleus, which promotes a reduction in food intake and body weight, using different mechanisms to those previously reported for ghrelin action, during energetically wealthy states ([49](#B49), [141](#B141)).”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [49]
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Self-citation
- 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
- 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
- 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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