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.

Keywords: BAT; WAT; adipose innervation; adipose neuropathy; adipose peripheral nerves; brain–adipose communication; neural plasticity; sympathetic; thermogenesis.

Figure 1

Architecture and neuroimmune cell types in white (WAT) and brown adipose tissue (BAT) in the basal state. Both WAT and BAT are comprised of lipid-laden mature adipocytes, where white adipocytes have one large (or unilocular) lipid droplet and brown adipocytes have many small (or multilocular) lipid droplets. The stromal vascular fraction (SVF) is the non-adipocyte cell fraction of the tissue, and contains preadipocytes (and stem/progenitor cells that will undergo white or brown adipogenesis) and a milieu of immune cells. Immune cell populations include innate immune cells, such as several subtypes of monocyte-macrophages, dendritic cells, mast cells, neutrophils, eosinophils, and innate lymphatic cells (ILCs); as well as adaptive immune cells, such as several subsets of T cells, natural killer cells, and B cells. Neurovasculature of WAT and BAT includes blood vessels, lymphatic vessels, and a dense nerve supply of both sensory and sympathetic fiber types, although it is currently unclear if one tissue has a greater extent of innervation than another, or if their nerve plasticity (such as with cold or exercise) differs between tissues or depots. Some nerves innervate the vasculature itself, while other nerves innervate the parenchyma of the tissue. It is currently unclear which cell types are directly innervated and receive synaptic input. Some nerve fibers are myelinated and others are unmyelinated (it has been suggested that the majority of TH⁺ nerve fibers in BAT are thin and unmyelinated [155]), and sensory nerve products such as calcitonin gene-related peptide (CGRP), Substance P, and neuropeptide Y (NPY) [26,50,155,156] have been detected in both tissues. Although, NPY may also be released from vasculature-associated sympathetic nerves as well [157], and should not be considered, by itself, a marker of sensory innervation. Sympathetic nerves release NE. Additional neurotransmitters and neuropeptides may also be active in WAT and BAT. The presence of Schwann cells, in both BAT and WAT, further underscores the presence of myelinated nerves [158]. Interestingly, Schwann cells, as a myelinated glial cell type, can behave similarly to an immune cell. Other immune cells, that are also present in adipose tissue, are well documented for neuroimmune functions, including monocyte/macrophage subtypes, as reviewed previously [159,160]. Monocytes, as well as T and B cells can produce BDNF in human peripheral blood and in human inflammatory brain lesions [154]. Human CD4⁺ T cell clones (from peripheral blood) were shown to produce and release NGF in vitro [153]. In addition, eosinophils from human peripheral blood can produce nerve growth factor (NGF), neurotrophin-3 (NT3), and brain derived neurotrophic factor (BDNF) neurotrophic factors upon immunologic stimulus [161,162], and mast cells contain mRNA for NGF and may be another source of neurotrophic factor [163]. It is currently unclear if these immune cell types play similar roles in adipose tissue, or if other tissue-resident immune cells have neuroimmune roles. Differences between BAT and WAT immune cells include more SAMs in white than brown [145], the presence of BAT specific Cx3cr1⁺ macrophages that play a role in regulating axonal outgrowth [147], and the presence of a subset of T_regs (CD4⁺) that exhibited a differential gene expression in BAT versus visceral adipose tissue [164]. There is very little knowledge about the lymphatic system in BAT compared to WAT, and changes with obesity or cold likely differs between BAT and WAT as well, but this warrants further exploration. In total, cellular cross-talk in the adipose organ is clearly important for immunometabolic function and brain adipose communication, but our understanding is still at a very primitive stage.