Reciprocal signaling between adipose tissue depots and the central nervous system

Abstract

In humans, various dietary and social factors led to the development of increased brain sizes alongside large adipose tissue stores. Complex reciprocal signaling mechanisms allow for a fine-tuned interaction between the two organs to regulate energy homeostasis of the organism. As an endocrine organ, adipose tissue secretes various hormones, cytokines, and metabolites that signal energy availability to the central nervous system (CNS). Vice versa, the CNS is a critical regulator of adipose tissue function through neural networks that integrate information from the periphery and regulate sympathetic nerve outflow. This review discusses the various reciprocal signaling mechanisms in the CNS and adipose tissue to maintain organismal energy homeostasis. We are focusing on the integration of afferent signals from the periphery in neuronal populations of the mediobasal hypothalamus as well as the efferent signals from the CNS to adipose tissue and its implications for adipose tissue function. Furthermore, we are discussing central mechanisms that fine-tune the immune system in adipose tissue depots and contribute to organ homeostasis. Elucidating this complex signaling network that integrates peripheral signals to generate physiological outputs to maintain the optimal energy balance of the organism is crucial for understanding the pathophysiology of obesity and metabolic diseases such as type 2 diabetes.

Keywords: adipogenesis; adipose tissue; adipose tissue macrophage; central nervous system; hypothalamus; lipolysis; resident immune cells; sympathetic regulation.

FIGURE 1

Sympathetic regulation of adipose tissue lipolysis. Sympathetic and sensory innervation of human adipose tissue. Sympathetic nerve fibres that travel from the CNS to innervate adipose tissue (purple) and sensory nerve fibres that relay information from adipose tissue to the CNS (green) are shown. Release of noradrenaline (NE) from efferent sympathetic fibres leads to the activation of β-adrenergic receptors and the subsequent dissociation of the receptor-coupled Gs protein leads to activation of adenylate cyclase (AC), which increases intracellular cAMP levels. High cAMP levels activate protein kinase A (PKA), phosphorylating hormone-sensitive lipase (HSL) and perilipin-A (PLIN1). This initiates the activation of a set of lipases, such as adipose triglyceride lipase (ATGL) and monoglyceride lipase (MGL) or α/β hydrolase-domain 6 (ABHD6), allowing for consecutive hydrolysis of TGs into fatty acids (FA) and glycerol. Increased lipolysis in turn activates WAT afferent sensory nerve endings, which are able to sense local FA and leptin concentrations (Garretson et al., 2016). Created with BioRender.com.

FIGURE 2

Sympathetic regulation of adipose tissue macrophages. (A) Beta-2 adrenergic receptor (β2-AR) stimulation in macrophages promotes the production and secretion of acetylcholine, which acts on adipocytes via acetylcholine receptors, stimulating thermogenesis through the PKA pathway and consequently inducing thermogenic gene expression (Knights et al., 2021; Meng et al., 2021). Additionally, β2-AR stimulation is essential for maintaining low tumor necrosis factor -alpha (TNFα) levels (Wang et al., 2003). (B) After cold stimulation M2 macrophages secrete cytokine Slit3, which promotes sympathetic nerve growth pathway, and stimulates the synthesis and release of norepinephrine (NE), subsequently inducing thermogenesis (Wang et al., 2021). Specialized sympathetic neuron-associated macrophages (SAMs) scavenge noradrenaline through the transporter Slc6a2 and degrade it using the enzyme monoamine oxidase A (MAOa). Thereby regulating local adipose tissue availability of NE (Camell et al., 2017; Pirzgalska et al., 2017). (C) A subset of macrophages belonging to the cold-induced neuroimmune cells (CINCs) and M2 macrophages secrete neurotrophic factors such as brain-derived neurotrophic factor (BDNF) upon cold exposure, promoting adipocyte nerve growth (Blaszkiewicz et al., 2022; Xie et al., 2022). (D) Neuropeptide Y (NPY) modulates inflammatory response in macrophages. NPY supplementation in lean mice leads to a decreased number of M1 adipose tissue macrophages (ATMs) (Singer et al., 2013). Deficiency of NPY1 receptor increases the secretion of TNFα and monocyte chemoattractant protein-1 (MCP-1) under inflammatory conditions (Macia et al., 2012). Neuropeptide FF receptor 2 (NPFFR2) is predominantly expressed in ATMs compared to other macrophage populations. In ATMs neuropeptide FF (NPFF) increases arginase 1, interleukin (Il-) 10, and Il-4 receptor expression (Waqas et al., 2017). Created with BioRender.com.

FIGURE 3

Sympathetic regulation of immune cells in adipose tissue. (A) Sympathetic outflow acts on β2-AR of mesenchymal cells (MSC), which release glial-derived neurotrophic factor (GDNF). GDNF in turn activates group 2 innate lymphoid cells (ILC2) cells via the receptor RET. Activated ILC2 cells secrete interleukin (IL-)5, IL-13 cytokines and Met-enkephalin (Met-enk) and subsequently regulate adipocyte function and energy expenditure (Cardoso et al., 2021). (B) B cells and T cells release acetylcholine upon acute cold exposure in inguinal white adipose tissue (Jun et al., 2018). Furthermore, Gamma delta (yδ) T cells maintain sympathetic innervation of adipose tissue by driving the expression of transforming growth factor beta-1 (TGFβ1) in adipocytes via the IL-17F effector cytokine (Hu et al., 2020). Created with BioRender.com.