Growing evidence implicates the brain in the regulation of both immediate fuel availability (for example, circulating glucose) and long-term energy stores (that is, adipose tissue mass). Rather than viewing the adipose tissue and glucose control systems separately, we suggest that the brain systems that control them are components of a larger, highly integrated, ‘fuel homeostasis’ control system. This conceptual framework, along with new insights into the organization and function of distinct neuronal systems, provides a context within which to understand how metabolic homeostasis is achieved in both basal and postprandial states. We also review evidence that dysfunction of the central fuel homeostasis system contributes to the close association between obesity and type 2 diabetes, with the goal of identifying more effective treatment options for these common metabolic disorders.
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M.G.M. is supported by grants from the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; DK056731, DK104999 and DK020572) and the Marilyn H. Vincent Foundation. A.H.A. is supported by NIH NIDDK (F32 DK122660). N.R. is supported by the NIDDK-funded University of Washington Diabetes, Obesity and Metabolism Fellowship Training Grant (T32 DK007247). M.W.S. is supported by NIDDK grants DK083042 and DK089056.
M.G.M. receives research funding from AstraZeneca, Novo Nordisk and Ionis, and consults for LG Chem. M.W.S. receives research funding from Novo Nordisk. The authors declare no other competing interests.
Peer review information Nature Metabolism thanks Young-Hwan Jo, Miguel López and Giles Yeo for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt.
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Myers, M.G., Affinati, A.H., Richardson, N. et al. Central nervous system regulation of organismal energy and glucose homeostasis. Nat Metab 3, 737–750 (2021). https://doi.org/10.1038/s42255-021-00408-5
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