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Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus

Abstract

Adipose tissue comprises adipocytes and many other cell types that engage in dynamic crosstalk in a highly innervated and vascularized tissue matrix. Although adipose tissue has been studied for decades, it has been appreciated only in the past 5 years that extensive arborization of nerve fibres has a dominant role in regulating the function of adipose tissue. This Review summarizes the latest literature, which suggests that adipocytes signal to local sensory nerve fibres in response to perturbations in lipolysis and lipogenesis. Such adipocyte signalling to the central nervous system causes sympathetic output to distant adipose depots and potentially other metabolic tissues to regulate systemic glucose homeostasis. Paracrine factors identified in the past few years that mediate such adipocyte–neuron crosstalk are also reviewed. Similarly, immune cells and endothelial cells within adipose tissue communicate with local nerve fibres to modulate neurotransmitter tone, blood flow, adipocyte differentiation and energy expenditure, including adipose browning to produce heat. This understudied field of neurometabolism related to adipose tissue biology has great potential to reveal new mechanistic insights and potential therapeutic strategies for obesity and type 2 diabetes mellitus.

Key points

  • Adipocytes modulate whole-body metabolism through secretion of endocrine and paracrine factors that modulate local immune cell cytokine secretion, endothelium blood flow and neuronal signalling to the brain.

  • Adipocytes, the endothelium and immune cells within adipose tissues secrete factors such as leptin, vascular endothelial growth factor (VEGF) and tumour necrosis factor (TNF) that regulate local sensory nerve fibre functions.

  • Adipocyte lipid metabolism communicates with local sensory nerve fibres, sending signals to the central nervous system; conversely, sensory nerve fibres secrete factors such as calcitonin-related gene peptide (CGRP) and substance P that might regulate the metabolism of adipocytes and other adipose-resident cells.

  • Increased lipolysis in white adipose tissue in response to sympathetic activation can cause sensory nerve fibres to regulate the metabolic activity of distant brown adipose tissue depots.

  • Extensive and dynamic signalling networks among the diverse cell types in adipose tissue integrate and mediate communication through bioactive lipids to local sensory nerve fibres and neurotrophic factors to sympathetic nerve fibres.

  • Identifying factors within adipose tissues that regulate the function of sensory and sympathetic nerve fibres might reveal therapeutic strategies for obesity and type 2 diabetes mellitus.

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Fig. 1: Proposed mechanisms whereby adipose tissue controls systemic insulin sensitivity.
Fig. 2: Adipose signalling to local nerve fibres regulates systemic metabolism.
Fig. 3: Adipose tissue–sensory nerve crosstalk.
Fig. 4: Central integration of adipose signals and obesity-mediated dysregulation.
Fig. 5: Adipose tissue–sympathetic nerve crosstalk.
Fig. 6: Integrating peripheral signals in adipose tissue.

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Acknowledgements

Work from the laboratory of M.P.C. discussed in this Review was supported by NIH grants DK30898 and DK103047 to M.P.C.

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Nature Reviews Endocrinology thanks K. Rahmouni, and other anonymous reviewers, for their contribution to the peer review of this work.

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A.G., F.H., A.H.B. and M.P.C. contributed equally to the discussion of content, researching data for the article, writing the article and reviewing and editing the manuscript before submission.

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Correspondence to Michael P. Czech.

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Guilherme, A., Henriques, F., Bedard, A.H. et al. Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus. Nat Rev Endocrinol 15, 207–225 (2019). https://doi.org/10.1038/s41574-019-0165-y

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