Key Points
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Cells sense ratios of adenine nucleotides (AMP and ADP) to monitor energy levels
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AMP-activated protein kinase (AMPK) is the main cellular energy sensor; by monitoring changes in the ratios between AMP and ATP, and ADP and ATP, AMPK is activated by conditions that increase ATP utilization
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AMPK mediates a global counter-regulatory response by reducing ATP-consuming processes, while upregulating ATP-producing processes to maintain energy homeostasis
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In the hypothalamus and the hindbrain, AMPK acts to regulate whole-body energy status
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By sensing central and peripheral nutritional and hormonal signals, hypothalamic AMPK modulates all aspects of energy balance, including food intake, energy expenditure/thermogenesis and glucose homeostasis
Abstract
AMP-activated protein kinase (AMPK) has a major role in the modulation of energy balance. AMPK is activated in conditions of low energy, increasing energy production and reducing energy consumption. The AMPK pathway is a canonical route regulating energy homeostasis by integrating peripheral signals, such as hormones and metabolites, with neuronal networks. Current evidence has implicated AMPK in the hypothalamus and hindbrain with feeding, brown adipose tissue thermogenesis and browning of white adipose tissue, through modulation of the sympathetic nervous system, as well as glucose homeostasis. Interestingly, several potential antiobesity and/or antidiabetic agents, some of which are currently in clinical use such as metformin and liraglutide, exert some of their actions by acting on AMPK. Furthermore, the orexigenic and weight-gain effects of commonly used antipsychotic drugs are also mediated by hypothalamic AMPK. Overall, this evidence suggests that hypothalamic AMPK signalling is an interesting target for drug development, but is this approach feasible? In this Review we discuss the current understanding of hypothalamic AMPK and its role in the central regulation of energy balance and metabolism.
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Acknowledgements
The authors would like to acknowledge funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 281854: the ObERStress project (awarded to M.L.). Xunta de Galicia awarded to M.L. (2015-CP079) and R.N. (2015-CP080 and PIE13/00024), Ministry of Economy and Competitiveness (MINECO) Instituto de Salud Carlos III (PI12/01814 and PIE13/00024 awarded to M.L.), MINECO co-funded by the FEDER Program of EU (awarded to M.L. (SAF2015-71026-R); R.N. (BFU2015-70664-R); M.T.S. (BFU2014-2502157581-P); and C.D. (BFU2014-55871-P)). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of Instituto de Salud Carlos III, Spain.
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M.L. researched data for the article and wrote the manuscript. All authors made substantial contributions to discussion of the content and reviewed/edited the manuscript before submission.
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López, M., Nogueiras, R., Tena-Sempere, M. et al. Hypothalamic AMPK: a canonical regulator of whole-body energy balance. Nat Rev Endocrinol 12, 421–432 (2016). https://doi.org/10.1038/nrendo.2016.67
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DOI: https://doi.org/10.1038/nrendo.2016.67
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