Skeletal muscle and thermogenic adipose tissue are both critical for the maintenance of body temperature in mammals. However, whether these two tissues are interconnected to modulate thermogenesis and metabolic homeostasis in response to thermal stress remains inconclusive. Here, we report that human and mouse obesity is associated with elevated Musclin levels in both muscle and circulation. Intriguingly, muscle expression of Musclin is markedly increased or decreased when the male mice are housed in thermoneutral or chronic cool conditions, respectively. Beige fat is then identified as the primary site of Musclin action. Muscle-transgenic or AAV-mediated overexpression of Musclin attenuates beige fat thermogenesis, thereby exacerbating diet-induced obesity and metabolic disorders in male mice. Conversely, Musclin inactivation by muscle-specific ablation or neutralizing antibody treatment promotes beige fat thermogenesis and improves metabolic homeostasis in male mice. Mechanistically, Musclin binds to transferrin receptor 1 (Tfr1) and antagonizes Tfr1-mediated cAMP/PKA-dependent thermogenic induction in beige adipocytes. This work defines the temperature-sensitive myokine Musclin as a negative regulator of adipose thermogenesis that exacerbates the deterioration of metabolic health in obese male mice and thus provides a framework for the therapeutic targeting of this endocrine pathway.

骨骼肌和产热脂肪组织对于维持哺乳动物的体温都至关重要。然而，这两种组织是否相互关联以调节产热和代谢稳态以应对热应激仍无定论。在这里，我们报告人类和小鼠肥胖与肌肉和循环中肌肉蛋白水平升高有关。有趣的是，当雄性小鼠被饲养在中性或长期凉爽的条件下时，Musclin 的肌肉表达分别显着增加或减少。米色脂肪被确定为肌肉蛋白作用的主要部位。肌肉转基因或 AAV 介导的 Musclin 过度表达会减弱米色脂肪的生热作用，从而加剧雄性小鼠饮食诱导的肥胖和代谢紊乱。相反，通过肌肉特异性消融或中和抗体治疗使肌肉蛋白失活可促进米色脂肪产热并改善雄性小鼠的代谢稳态。从机制上讲，Musclin 与转铁蛋白受体 1 (Tfr1) 结合，并拮抗米色脂肪细胞中 Tfr1 介导的 cAMP/PKA 依赖性产热诱导。这项工作将温度敏感肌因子 Musclin 定义为脂肪产热的负调节因子，会加剧肥胖雄性小鼠代谢健康的恶化，从而为该内分泌途径的治疗靶向提供了框架。