Immunomodulatory Leptin Receptor⁺Sympathetic Perineurial Cells Protect Against Obesity by Facilitating Neuroendocrine-Mediated Brown Adipose Tissue Thermogenesis

Abstract

SummaryAdipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor (LepR)-expressing barrier cells which ensheath sympathetic axon bundles in adipose tissues. These LepR-expressing Sympathetic Perineurial Cells (SPCs) produce IL33, a factor for maintenance and recruitment of regulatory T cell (Treg) and eosinophils in AT. Brown adipose tissues (BAT) of mice lacking IL33 in SPCs (SPCIL33cKO) have fewer Treg and eosinophils, resulting in increased BAT inflammation. SPCIL33cKOmice are more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCIL33cKOmice have impaired adaptive thermogenesis, and are unresponsive to leptin-induced rescue of metabolic adaptation. We, therefore, identify LepR-expressing SPCs as a source of IL33 which orchestrate an anti-inflammatory environment in BAT, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+IL33+SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.Graphical AbstractHighlights-Sympathetic Perineurial Cells (SPCs) co-express LepR+and IL33-SPC-derived IL33 prevents BAT inflammation via Treg and eosinophil recruitment-Obesity is worsened in high fat diet-fed SPCIL33cKOmice, despite normal food intake-Adaptive thermogenesis is impaired in SPCIL33cKOmice-Rescue of metabolic adaptation to fasting by leptin is impaired in SPCIL33cKOmice-SPCs link leptin to immunometabolic regulation of body weight homeostasis

Stromal KITL/SCF promotes pancreas tissue homeostasis and restrains tumor progression

“…Interestingly, upon tissue damage such as irradiation or chemotherapy requiring regeneration of hematopoietic stem cells, LEPRpositive mesenchymal cells differentiate into adipocytes which in turn produce KITL to enable a functional niche and support hematopoietic regeneration (30). Complementary mesenchymal and signaling components were recently shown to support normal tissue homeostasis and suppress inflammation in brown adipose tissue (BAT): LEPR-positive mesenchyme supports adaptive thermogenesis and restrains inflammation in BAT (23), while endothelial cell-derived KITL/SCF signals to KIT on brown adipocytes to promote homeostatic lipid accumulation when thermogenesis is inhibited (31). As the stellate cells under investigation in our study are also lipidstoring cells, these studies raise the possibility that lipid-storing stromal cells engage KITL signaling to promote tissue homeostasis and limit inflammation more broadly across organs.…”

“…These experiments focused on pancreatic stellate cells (PSCs), tissue-resident mesenchymal cells which serve as cells of origin for PDAC CAFs. We found that this mesenchymal lineage in normal human and murine pancreas tissue expresses KITL-this lineage has lipid storage capacity and co-expresses the leptin receptor (LEPR), with parallels to LEPR-positive mesenchyme previously implicated in tissue homeostasis in the bone marrow (22) and brown adipose tissue (23). Mesenchymal KITL expression is lost during tumor evolution and acquisition of a cancer-associated fibroblast (CAF) stromal phenotype, with functional significance for tissue state and tumorigenic potential.…”