Wireless optogenetics protects against obesity via stimulation of non-canonical fat thermogenesis

Cold stimuli and the subsequent activation of β-adrenergic receptor (β-AR) potently stimulate adipose tissue thermogenesis and increase whole-body energy expenditure. However, systemic activation of the β3-AR pathway inevitably increases blood pressure, a significant risk factor for cardiovascular disease, and, thus, limits its application for the treatment of obesity. To activate fat thermogenesis under tight spatiotemporal control without external stimuli, here, we report an implantable wireless optogenetic device that bypasses the β-AR pathway and triggers Ca 2+ cycling selectively in adipocytes. The wireless optogenetics stimulation in the subcutaneous adipose tissue potently activates Ca 2+ cycling fat thermogenesis and increases whole-body energy expenditure without cold stimuli. Significantly, the light-induced fat thermogenesis was sufficient to protect mice from diet-induced body-weight gain. The present study provides the first proof-of-concept that fat-specific cold mimetics via activating non-canonical thermogenesis protect against obesity. Cardiovascular risks of cold exposure and the subsequent activation of the β3-AR pathway limit the application of beige fat thermogenesis for the treatment of obesity. Here, the authors show that optogenetics light-activated Ca2+ cycling in adipocytes triggers a fat-specific “cold-mimetic” thermogenesis response protecting mice against diet-induced obesity.