Mansuy-Aubert, V. | bioRxiv Science

bioRxiv2020

Neuronal LXR Regulates Neuregulin-1 Expression and Sciatic Nerve-Associated Cell signaling

Neuropathic pain caused by peripheral nerve injury significantly affects sensory perception and quality of life. Accumulating evidence strongly link cholesterol and inflammation with development and progression of Obesity and Diabetes associated-neuropathies. However, the exact mechanisms of how lipid metabolism in peripheral nervous system (PNS) contributes to the pathogenesis of neuropathy remains poorly understood. Dysregulation of LXR pathways have been identified in many transcriptomic analyses in neuropathy models. LXR /{beta} expressed in sensory neurons are necessary for proper peripheral nerve function. Deletion of LXR /{beta} from sensory neurons lead to pain-like behaviors. In this study, we identified that LXR /{beta} expressed in sensory neurons regulates neuronal neuregulin-1 (Nrg1). Using in vivo cell-specific approaches, we observed that loss of LXR from sensory neurons altered genes regulating lipid metabolism in non-neuronal cells potentially representing Schwann cells (SC). Our data suggest that neuronal LXR may regulates SC function via a Nrg1-dependent mechanism. The decrease in Nrg1 expression in DRG neurons of WD-fed mice may suggest an altered Nrg1-dependent neuron-SC communication in Obesity. The communication between neurons and non-neuronal cell such as SC could be a new biological pathway to study and to treat Obesity-associated neuropathy and PNS dysfunction.

neuroscience↗

bioRxiv2019

Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance

ObjectiveRates of overweight and obesity epidemic have risen significantly in the past few decades, and 34% of adults and 15-20% of children and adolescents in the United States are now obese. Melanocortin receptor 4 (MC4R), contributes to appetite control in hypothalamic neurons and is a target for future anti-obesity treatments (such as setmelanotide) or novel drug development effort. Proper MC4R trafficking regulation in hypothalamic neurons is crucial for normal neural control of homeostasis and is altered in obesity and in presence of lipids. The mechanisms underlying altered MC4R trafficking in the context of obesity is still unclear. Here, we discovered that C2CD5 expressed in the hypothalamus is involved in the regulation of MC4R endocytosis. This study unmasked a novel trafficking protein nutritionally regulated in the hypothalamus providing a novel target for MC4R dependent pathways involved in bodyweight homeostasis and Obesity.\n\nMethodsTo evaluate the expression of C2cd5, we first used in situ hybridization and RNAscope technology in combination with electronic microscopy. For in vivo, we characterized the energy balance of wild type (WT) and C2CD5 whole-body knockout (C2CD5KO) mice fed normal chow (NC) and/or western-diet (high-fat/high-sucrose/cholesterol) (WD). To this end, we performed comprehensive longitudinal assessment of bodyweight, energy balance (food intake, energy expenditure, locomotor activity using TSE metabolic cages), and glucose homeostasis. In addition, we evaluated the consequence of loss of C2CD5 on feeding behavior changes normally induced by MC4R agonist (Melanotan, MTII) injection in the paraventricular hypothalamus (PVH). For in vitro approach, we tease out the role of C2CD5 and its calcium sensing domain C2 in MC4R trafficking. We focused on endocytosis of MC4R using an antibody feeding experiment (in a neuronal cell line - Neuro2A (N2A) stably expressing HA-MC4R-GFP; against HA-tag and analyzed by flux cytometry).\n\nResultsWe found that 1) the expression of hypothalamic C2CD5 is decreased in diet-induced obesity models compared to controls, 2) mice lacking C2CD5 exhibit an increase in food intake compared to WT mice, 3) C2CD5 interacts with endocytosis machinery in hypothalamus, 4) loss of functional C2CD5 (lacking C2 domain) blunts MC4R endocytosis in vitro and increases MC4R at the surface that fails to respond to MC4R ligand, and, 5) C2CD5KO mice exhibit decreased acute responses to MTII injection into the PVH.\n\nConclusionsBased on these, we conclude that hypothalamic C2CD5 is involved in MC4R endocytosis and regulate bodyweight homeostasis. These studies suggest that C2CD5 represents a new protein regulated by metabolic cues and involved in metabolic receptor endocytosis. C2CD5 represent a new target and pathway that could be targeted in Obesity.

physiology↗