UCSF Diabetes Center, San Francisco, CA, 94143, USA.
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, 94143, USA.
Nat Commun. 2020 Apr 7;11(1):1730. doi: 10.1038/s41467-020-15589-y.
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 cycling selectively in adipocytes. The wireless optogenetics stimulation in the subcutaneous adipose tissue potently activates Ca 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.
冷刺激和随后的β-肾上腺素能受体（β-AR）激活强烈刺激脂肪组织产热并增加全身能量消耗。然而，β3-AR 途径的全身激活不可避免地会升高血压，这是心血管疾病的一个重要危险因素，因此限制了其在肥胖治疗中的应用。为了在没有外部刺激的情况下进行紧密的时空控制下激活脂肪产热，我们在这里报告了一种可植入的无线光遗传学装置，该装置绕过β-AR 途径并选择性地在脂肪细胞中触发 Ca 循环。在皮下脂肪组织中的无线光遗传学刺激强烈激活 Ca 循环脂肪产热并增加全身能量消耗，而无需冷刺激。重要的是，光诱导的脂肪产热足以保护小鼠免受饮食诱导的体重增加。本研究首次证明了通过激活非经典产热的脂肪特异性冷模拟物可以预防肥胖。
