The Importance of Peripheral Nerves in Adipose Tissue for the Regulation of Energy Balance

Abstract

Brown and white adipose tissues are essential for maintenance of proper energy balance and metabolic health. In order to function efficiently, these tissues require both endocrine and neural communication with the brain. Brown adipose tissue (BAT), as well as the inducible brown adipocytes that appear in white adipose tissue (WAT) after simulation, are thermogenic and energy expending. This uncoupling protein 1 (UCP1)-mediated process requires input from sympathetic nerves releasing norepinephrine. In addition to sympathetic noradrenergic signaling, adipose tissue contains sensory nerves that may be important for relaying fuel status to the brain. Chemical and surgical denervation studies of both WAT and BAT have clearly demonstrated the role of peripheral nerves in browning, thermogenesis, lipolysis, and adipogenesis. However, much is still unknown about which subtypes of nerves are present in BAT versus WAT, what nerve products are released from adipose nerves and how they act to mediate metabolic homeostasis, as well as which cell types in adipose are receiving synaptic input. Recent advances in whole-depot imaging and quantification of adipose nerve fibers, as well as other new research findings, have reinvigorated this field of research. This review summarizes the history of research into adipose innervation and brain–adipose communication, and also covers landmark and recent research on this topic to outline what we currently know and do not know about adipose tissue nerve supply and communication with the brain.

Neuropathy and neural plasticity in the subcutaneous white adipose depot

“…Nerves also rely on vasculature for sustained health, since they become damaged in a hypoxic state, while vasculature relies on innervation for constriction and vasodilation of blood vessels. Since nerves, such as those in the sympathetic nervous system, regulate vascular control (ie: vasoconstriction) and may also be involved in angiogenesis, adipose neuropathy may also have adverse effects on endocrine system communication with adipose tissue and may lead to adipose hypoxia due to lack of proper vascular supply [48]. The association here could also go in the other direction, with circulating factors affecting nerve supply (ie: glucose, lipids, hormones)–but these hypotheses require closer investigation.…”

Dietary Options for Rodents in the Study of Obesity

“…Importantly, it has been demonstrated that the levels of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter that suppresses neuron excitability, are increased in BAT of HFD-fed mice promoting BAT disfunction [118]. All these exiting results provide new insights into innervation patterns and nerve plasticity in adipose depots, suggesting that neuromodulation could become an essential strategy to explore new ways to treat obesity (reviewed in [119][120][121][122]). Additional research should be done to elucidate nerve subtypes and their tissue functions in order to understand the physiological crosstalk between brain and peripheral tissues and their contribution to maintain energy balance.…”

Single-Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

“…Norepinephrine (NE) released from SNFs activates the β-adrenergic receptor (βAR)-cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway to induce these morphological and thermogenic changes during cold stimulation ( Ceddia and Collins, 2020 ; Li et al, 2016 ). Accordingly, denervation of iWAT depots blocks cold-induced thermogenesis and the appearance of beige adipocytes ( Blaszkiewicz et al, 2019 ; Harris, 2018 ). Overall, activation of this β-adrenergic pathway to modulate adipose tissue composition and functions yields increased glucose tolerance and resistance to high-fat-diet (HFD)-induced insulin resistance ( Ceddia and Collins, 2020 ; Collins, 2012 ).…”