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.

Figure 1:. Proposed mechanisms whereby adipose tissue controls systemic insulin sensitivity.

Depicted are pathways in white adipocytes (left semicircle) and beige/brown adipocytes (right semicircle) that have been proposed to affect whole body insulin sensitivity and systemic metabolism. At room temperature (22°C) and above, most of WAT is composed of white adipocytes (left), while at low temperature (6°C) brown/beige adipocytes appear in WAT (right). (A) White adipocytes promote fatty acid esterification into triglycerides for storage, sequestering fat away from liver and skeletal muscle to prevent “lipotoxicity”. (B) Sustained release of norepinephrine (NE) by adipose efferent nerves activates β3-adrenergic (β3AR) receptor and induces “beige” adipocyte formation within white adipose tissue. Beige adipocytes display increased mitochondrial density and high capacity for fatty acid (FA) oxidation into acetyl-CoA (AcCOA) which fuels heat production via mitochondrial uncoupling protein-1 (UCP1) within the electron transport chain. (C) White adipocytes upregulate resident immune cells in obesity, releasing cytokines into the circulation. (D) Secretion of white adipocyte-derived bioactive molecules (denoted WATokines) and beige or brown adipocyte-derived factors (denoted BATokines) may modulate (E) adipose vascularization and (F) activate local afferent nerve fibers. These factors can also be released into the circulation to affect distant tissues.

Figure 2:. Adipose Signaling to Local Nerve Fibers Regulates Systemic Metabolism.

(A) Sensory nerves relay information from the white adipose tissue (WAT) microenvironment to the central nervous system. (B) The central nervous system (CNS) integrates adipose tissue signals to orchestrate a response to the adipose tissue microenvironment. The CNS conveys its response via sympathetic outflow back into the periphery. (C) The sympathetic nerve innervating WAT releases signaling factors that influence the adipose tissue microenvironment. (D) The autonomic nervous system also affects other metabolic organs in order to promote whole-body homeostasis. Whether adipose metabolic cues are conveyed to CNS to control sympathetic outflow into liver, muscle and pancreas (represented in red lines) is still unknown. Thus, the adipose tissue microenvironment may have a role in regulating systemic metabolism through signaling to local nerve fibers. The depicted cartoon illustrates a general concept. The scale in which the diagrams were drawn is not anatomically accurate.

Figure 3:. Adipose Tissue-Sensory Nerve Crosstalk.

(A) Adipose tissue resident cells release molecular mediators that can act on the afferent neuronal pathway and invoke a central response to the tissue microenvironment. The principle component of adipose tissue, the adipocyte, can release various neuro-active and neurotrophic peptides, such as leptin, neuregulin-4 (NRG4), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), free fatty acids (FFA), arachidonic acid (AA) and eicosanoids, such as eicosapentaenoic acid (EPA) and prostaglandin-E2 (PGE2), that act on surrounding cells, including sensory nerve fibers. Endothelial cells, comprising the vasculature of adipose tissue, secrete vascular endothelial growth factor (VEGF) that can promote nerve sprouting and sensory hypersensitization upon interaction with the VEGF receptor family (VEGFR). Cytokines secreted from macrophages, such as tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), may act directly on the sensory nerve itself, or indirectly through their pro-inflammatory effects within the adipose tissue microenvironment. Anti-inflammatory cytokines, such as interleukin-17A (IL-17A) and adenosine, originating from alternatively-activated macrophages and various lymphocytes, including regulatory T-cells (Tregs), can act similarly. (B) Conversely, signaling from the sensory nerve terminals to cells within adipose tissue has the potential to modulate adipocyte functions. Upon stimulation, the sensory nerve can release calcitonin gene-related peptide (CGRP) and substance P (SP) into the innervated tissue that modulates the microenvironment surrounding the sensory nerve.

Figure 4:. Central Integration of Adipose Signals and Obesity-mediated Dysregulation.

(A) Afferent sensory nerve fibers innervating white adipose tissue depots arise from dorsal root ganglia (DRG) proximal to the spinal cord. The DRG also projects to the brain via the dorsal horn of the spinal cord, relaying sensory information from the periphery to the central nervous system for integration. (B) The hypothalamus is a primary area for metabolic regulation in the central nervous system, influencing thermogenesis and food intake, as well as other critical homeostatic functions throughout the body. Projections into the preoptic area (POA), as well as resident temperature-sensitive neurons, relay critical thermoregulatory information to the dorsomedial hypothalamic nucleus (DMH), a core component of the orexinergic system and thermoregulatory function of the hypothalamus. The paraventricular hypothalamus (PVN), which is proximal to the third ventricle (3V), is involved food intake, thermoregulation and neuroendocrine functions through projections to the pituitary. The arcuate nucleus (ARC), along with the ventromedial nucleus of the hypothalamus (VMH) and lateral hypothalamus (LH), are also involved in appetitive behavior and food reward. The suprachiasmatic nucleus (SCN) is a critical area for regulating circadian rhythm. All of these centers play direct or indirect roles in influencing hypothalamic thermogenic regulation. Hypothalamic inflammation has been linked to metabolic dysregulation and obesity-related insulin resistance through excessive gliosis, leading to neuronal damage, particularly noted within arcuate nucleus. The hypothalamus sends sympathetic projections to periphery either directly through the intermediolateral nucleus of the spinal cord (IML), or via relay through the raphe pallidus nucleus (RPa) or the rostral ventrolateral medulla (RVLM) to the IML. The IML houses the preganglionic neurons responsible for synapsing onto the catecholaminergic postganglionic sympathetic fibers innervating the target tissues.

Figure 5:. Adipose Tissue-Sympathetic Nerve Crosstalk.

(A) Efferent nerve fibers are known to regulate adipose tissue functions through secretion of bioactive factors. Among them are catecholamine (norepinephrine), neuropeptide Y (NPY) and adenosine triphosphate (ATP). The central nervous system stimulates sympathetic outflow to adipose tissue, triggering the secretion of norepinephrine, NPY or ATP (represented by blue dots). These sympathetic-derived secreted factors, through the activation of their respective receptors, affect not only adipocytes, but also other adipose resident cells, such as endothelial cells, macrophages and lymphocytes. (B) In turn, the stimulated adipose cells also produce a number of secreted bioactive factors that communicate with adipose sympathetic fibers. For instance, multilocular beige adipocytes - induced via sympathetic norepinephrine and/or adenosine molecules - produce the neurotrophic factor neuregulin-4 (NRG4), which is known to promote neurite outgrowth. Additionally, white adipocytes have been shown to synthesize several factors with neurotrophic activity that may enhance sympathetic innervation of adipose tissue. Among these factors are the neuronal growth regulator 1 (NEGR1), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), free fatty acids (FFA) and endocannabinoids (EC). The vascular endothelial growth factor (VEGF) secreted by endothelial cells and adipocytes elicits sympathetic innervation in adipose tissue. Adipose resident immune cells, such as macrophage and lymphocytes, secrete cytokines, tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β), and factors demonstrated to affect neurite outgrowth and possibly adipose sympathetic innervation. Among them are interleukin-6 (IL6), interleukin-10 (IL10) and growth/differentiation factor 15 (GDF15).

Figure 6:. Integrating peripheral signals in adipose tissue.

(A) Much like the integration of adipose signals within the brain, neuro-adipose signal integration also occurs within the periphery. Examples include modulation of the adipose tissue microenvironment via interaction with immune cell populations, endothelial cells, and adipose stem cells (ASCs). Responses of adipose tissue to sympathetic nervous system (SNS) cues allows for the rapid adaptation and remodeling that is required to maintain systemic metabolic homeostasis. (B) Sympathetic nerve fibers engage in unique interactions with adipose tissue cell populations. (1) Norepinephrine (NE) release from sympathetic terminals leads to adipose macrophage polarization from a proinflammatory (M1) to an anti-inflammatory, alternatively-activated (M2) profile. Sympathetic neuron-associated macrophages (SAMs) localize around sympathetic synapses and take up secreted NE through the solute carrier family 6 member 2 (Slc6a2) NE transporter. Monoamine oxidase A (MAOA) catalyzes the degradation of NE within the SAMs. (2) NE release from sympathetic nerve endings stimulates the β2 adrenergic receptor (β2AR) of the endothelial cells of the vasculature, leading to vascular endothelial growth factor (VEGF) secretion from the endothelium. VEGF stimulates angiogenesis and neurite outgrowth, driving increased irrigation and innervation of the adipose tissue. (3) Adipose-derived stem cell (ASCs) β1 adrenergic receptor (β1AR) activation by sympathetic NE drives beige adipocyte differentiation. These beige adipocytes have an enhanced thermogenic capacity relative to white adipocytes and a brown-like adipokine expression profile, which may include neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neuregulin-4 (NRG4). These factors can drive increased sympathetic innervation and arborization. (4) The sympathetic cotransmitter adenosine triphosphate (ATP) is cleaved by regulatory T-cells (Tregs) into adenosine via CD73 and CD39-mediated degradation to create the anti-inflammatory “purinergic halo” surrounding the Tregs. The adenosine interacts with the adenosine A2A receptor to drive beige adipocyte thermogenesis through mitochondrial uncoupling protein 1 (UCP1) upregulation. Sympathetic-derived ATP can also directly interact with the purinergic P2 receptor family (P2R) to drive beige adipocyte thermogenesis.