Sensory Neurons Expressing Calcitonin Gene-Related Peptide Regulate Adaptive Thermogenesis and Diet-Induced Obesity

Sensory neurons arising from the dorsal root ganglia play a pivotal role in thermoregulation through the detection of cutaneous temperature and transmission of sensory signals to the brain. However, the functional significance of sensory perception in thermogenesis and weight loss has remained elusive. Here, we show that genetic ablation of heat sensing neurons containing Calcitonin Gene-Related Peptide (CGRPα) promotes resistance to weight gain upon high fat diet (HFD) feeding and drives a thermogenic program in brown and white adipose tissues. Remarkably, mice lacking CGRPα-expressing sensory neurons feel colder when challenged with cooling stimuli and their brown fat displays increased energy utilization during cold and HFD challenges. As these neurons are peptidergic, we also investigated the role of the CGRPα secreted peptide in this process. Depletion of CGRPα with a monoclonal antibody leads to a lesser weight loss than full neural depletion on HFD and partially recapitulates the increased energy expenditure and brown fat thermogenic profile observed with sensory ablation. Mechanistically, recombinant CGRPα impaired glycolysis and reduced fatty acid oxidation in cultured cells. Collectively, our results suggest that CGRPα-expressing sensory neurons are the first step to regulate adaptive thermogenesis in brown adipose tissue by detecting alterations in environmental temperatures. These neural processes have the dual ability to both influence central regulation of adrenergic stimulation of thermogenesis and to release peptidergic signals inhibiting fuel consumption in adipocytes.