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  • Perspective
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POMC neuronal heterogeneity in energy balance and beyond: an integrated view

Abstract

Hypothalamic AgRP and POMC neurons are conventionally viewed as the yin and yang of the body’s energy status, since they act in an opposite manner to modulate appetite and systemic energy metabolism. However, although AgRP neurons’ functions are comparatively well understood, a unifying theory of how POMC neuronal cells operate has remained elusive, probably due to their high level of heterogeneity, which suggests that their physiological roles might be more complex than initially thought. In this Perspective, we propose a conceptual framework that integrates POMC neuronal heterogeneity with appetite regulation, whole-body metabolic physiology and the development of obesity. We highlight emerging evidence indicating that POMC neurons respond to distinct combinations of interoceptive signals and food-related cues to fine-tune divergent metabolic pathways and behaviours necessary for survival. The new framework we propose reflects the high degree of developmental plasticity of this neuronal population and may enable progress towards understanding of both the aetiology and treatment of metabolic disorders.

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Fig. 1: Current classification methods used to identify POMC neuron subtypes.
Fig. 2: Mode(s) of action of different subsets of POMC neurons for the regulation of energy balance.
Fig. 3: Physiological roles of POMC neurons beyond energy balance.

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Acknowledgements

We acknowledge support by INSERM (D.C. and C.Q.), Nouvelle Aquitaine Region (D.C.) and Agence Nationale de la Recherche (LabEX BRAIN (ANR-10-LABX-43), OPTOPATH (ANR-10-EQX-008-1), BABrain (ANR-17-CE14-0007) and MitObesity (ANR-18-CE14-0029) to D.C. and neuroIDobese (ANR-20-CE14-0046) to C.Q.). C.Q. is also supported by the Société Française d’Endocrinologie (Pfizer–SFE Prix de Recherche en Endocrinologie), Société Française de Nutrition and Société Francophone du Diabète. M.C. is supported by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement 725004) and CERCA Programme/Generalitat de Catalunya. L.M.Z. is supported by the Russell Berrie and Klarman Family foundations, 1R01 DK125094, 1R01 MH113353 and 2P01 AG032959. K.W.W. is supported by NIH R01 DK119169 and DK119130–5830. S.D. is supported by NIH DK097566, DK105571, DK107293 and DK120321. G.S.H.Y. is supported by the Medical Research Council Metabolic Diseases Unit (MC_UU_00014/1). J.C.B. received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement number 266408 (SYNEME). We thank C. Padgett for artwork.

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D.C. conceived the idea. C.Q. and D.C. wrote the manuscript. M.C., L.M.Z., K.W.W., G.S.H.Y., M.H.T., S.D. and J.C.B. gave critical input to the different sections of the manuscript and selected content. All authors edited the final version of the manuscript.

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Correspondence to Daniela Cota.

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Peer review information Nature Metabolism thanks Michael Krashes and Qingchun Tong for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt.

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Quarta, C., Claret, M., Zeltser, L.M. et al. POMC neuronal heterogeneity in energy balance and beyond: an integrated view. Nat Metab 3, 299–308 (2021). https://doi.org/10.1038/s42255-021-00345-3

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