AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus
Abstract
Obesity is an epidemic in Western society, and causes rapidly accelerating rates of type 2 diabetes and cardiovascular disease. The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a 'fuel gauge' to monitor cellular energy status. We investigated the potential role of AMPK in the hypothalamus in the regulation of food intake. Here we report that AMPK activity is inhibited in arcuate and paraventricular hypothalamus (PVH) by the anorexigenic hormone leptin, and in multiple hypothalamic regions by insulin, high glucose and refeeding. A melanocortin receptor agonist, a potent anorexigen, decreases AMPK activity in PVH, whereas agouti-related protein, an orexigen, increases AMPK activity. Melanocortin receptor signalling is required for leptin and refeeding effects on AMPK in PVH. Dominant negative AMPK expression in the hypothalamus is sufficient to reduce food intake and body weight, whereas constitutively active AMPK increases both. Alterations of hypothalamic AMPK activity augment changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance.
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During starvation, ACC phosphorylation is mainly controlled by AMPK.
“During starvation, ACC phosphorylation is mainly controlled by the well-known energy sensor, AMPK ([115](#B115)), which acts also as an important hub, integrating in-cell energetic state sensing and its modulation due to different circulating hormones.”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [115]
Inhibition of hypothalamic AMPK lowers food intake and hepatic glucose production, while increasing hypothalamic AMPK has the opposite effect.
“inhibition of hypothalamic AMPK (using an adenovirus expressing the dominant negative form of AMPK) lowers food intake and HGP, while increasing hypothalamic AMPK has the opposite effect (113, 209)”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [113]
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“…be important for the ability of thehypothalamustoproperlyregulatefeedingbehaviorinresponseto changes in nutrient status, and inhibition of hypothalamic AMPK impairs the regulation of feeding behavior in response to fasting and refeeding or stimulation with hormones like ghrelin and leptin 26,45 .”
Background
- Authors
- Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y.-B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferré, P., Birnbaum, M. J., Stuck, B. J., & Kahn, B. B.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Howard Hughes Medical Institute (US)
- Inserm (FR)
- Corresponding author
- Kahn, Barbara B.
- ORCID
- Venue
- Nature
- Published
- 2004-03-17
- Volume
- 428
- Issue
- 6982
- Pages
- 569-574
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2074303577
- Cited by
- 1,637
- References
- 31
- Citations by year
- 2026: 23 · 2025: 22 · 2024: 48 · 2023: 32 · 2022: 52 · 2021: 72 · 2020: 48 · 2019: 44 · 2018: 60 · 2017: 60 · 2016: 72 · 2015: 74 · 2014: 87 · 2013: 93 · 2012: 129
- FWCI
- 33.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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 › Metabolism, Diabetes, and Cancer
- Keywords
- AMPK, food intake regulation, hypothalamus, leptin, insulin, melanocortin receptors, agouti-related protein, arcuate nucleus, paraventricular nucleus, energy balance, obesity, refeeding, fasting, neuropeptides, body weight
- MeSH terms
- Adenylate Kinase, Animals, Body Weight, Energy Metabolism, Feeding Behavior, Glucose, Hormones, Hypothalamus, Insulin, Male, Models, Biological, RNA, Messenger, Leptin, Receptors, Melanocortin, Mice
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