Adipose Tissue Myeloid-Lineage Neuroimmune Cells Express Genes Important for Neural Plasticity and Regulate Adipose Innervation

Abstract

Peripheral nerves allow a bidirectional communication between brain and adipose tissues, and many studies have clearly demonstrated that a loss of the adipose nerve supply results in tissue dysfunction and metabolic dysregulation. Neuroimmune cells closely associate with nerves in many tissues, including subcutaneous white adipose tissue (scWAT). However, in scWAT, their functions beyond degrading norepinephrine in an obese state remain largely unexplored. We previously reported that a myeloid-lineage knockout (KO) of brain-derived neurotrophic factor (BDNF) resulted in decreased innervation of scWAT, accompanied by an inability to brown scWAT after cold stimulation, and increased adiposity after a high-fat diet. These data underscored that adipose tissue neuroimmune cells support the peripheral nerve supply to adipose and impact the tissue’s metabolic functions. We also reported that a subset of myeloid-lineage monocyte/macrophages (Ly6c+CCR2+Cx3cr1+) is recruited to scWAT in response to cold, a process known to increase neurite density in adipose and promote metabolically healthy processes. These cold-induced neuroimmune cells (CINCs) also expressed BDNF. Here we performed RNAseq on CINCs from cold-exposed and room temperature-housed mice, which revealed a striking and coordinated differential expression of numerous genes involved in neuronal function, including neurotrophin signaling and axonal guidance, further supporting that CINCs fulfill a nerve-supporting role in adipose. The increased expression of leukocyte transendothelial migration genes in cold-stimulated CINCs also confirms prior evidence that they are recruited to scWAT and are not tissue resident. We now provide whole-depot imaging of scWAT from LysM-BDNF KO mice, revealing a striking reduction of innervation across the depot fitting with their reduced energy expenditure phenotype. By contrast, Cx3cr1-BDNF KO mice (a macrophage subset of LysM+ cells) exhibited increased thermogenesis and energy expenditure, with compensatory increased food intake and no change in adiposity or body weight. While these KO mice also exhibit a significantly reduced innervation of scWAT, especially around the subiliac lymph node, they displayed an increase in small fiber sympathetic neurite branching, which may underlie their increased thermogenesis. We propose a homeostatic role of scWAT myeloid-lineage neuroimmune cells together in nerve maintenance and neuro-adipose regulation of energy expenditure.

Reciprocal signaling between adipose tissue depots and the central nervous system

“…Frontiers in Cell and Developmental Biology frontiersin.org (CINCs), are recruited to the tissue in response to cold stimulation and have shown to coordinate gene expression involved in nerve survival and plasticity (Blaszkiewicz et al, 2022). These cells secrete neurotrophic factors such as brainderived neurotrophic factor (BDNF), which has been shown to exert an important role in WAT innervation (Blaszkiewicz et al, 2020;Wang et al, 2020) (Figure 2C).…”

“…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.…”

“…Slit3 promotes sympathetic nerve growth via the Slit-ROBO pathway, and additionally stimulates the synthesis and release of NE, which in turn promotes thermogenesis ( Figure 2B ) ( Wang et al, 2021 ). A subset of macrophages, cold-induced neuroimmune cells (CINCs), are recruited to the tissue in response to cold stimulation and have shown to coordinate gene expression involved in nerve survival and plasticity ( Blaszkiewicz et al, 2022 ). These cells secrete neurotrophic factors such as brain-derived neurotrophic factor (BDNF), which has been shown to exert an important role in WAT innervation ( Blaszkiewicz et al, 2020 ; Wang et al, 2020 ) ( Figure 2C ).…”

“…For instance, the knockout of BNDF in myeloid lineage cells in mice leads to decreased innervation of inguinal subcutaneous WAT depots ( Blaszkiewicz et al, 2020 ). In addition, the TrkB receptor (a receptor with high binding affinity for BDNF) was shown to be expressed on sensory and sympathetic nerve fibers in subcutaneous WAT ( Blaszkiewicz et al, 2022 ). Moreover, hypothalamic BDNF overexpression in DIO and lean mice lead to an up-regulation of β-ARs and UCP-1 in the WAT ( Cao et al, 2009 ; Cao et al, 2011 ).…”

Schwann cells contribute to demyelinating diabetic neuropathy and nerve terminal structures in white adipose tissue

“… 4 , 5 , 6 We previously demonstrated that aging leads to peripheral neuropathy in subcutaneous white adipose tissue (scWAT), 7 and that in obese and diabetic mice homozygous for the spontaneous Lep ob mutation (BTBR ob/ob ), 8 the peripheral neuropathy also extended to metabolically relevant tissues like adipose and muscle. 7 Deletion of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in human obesity, from myeloid-lineage immune cells also caused a “genetic denervation” of adipose tissue 9 , 10 that was accompanied by an altered metabolic phenotype. From these prior studies, it was clear that peripheral neuropathy negatively impacts adipose tissue, and that adipose neuropathy has implications for whole-body metabolic health.…”