Sympathetic Transmitters Controlling Thermogenic Efficacy of Brown Adipocytes by Modulating Mitochondrial Complex V

Obesity is epidemic worldwide as the results of excessive energy intake or inefficient energy expenditure. It is promising to utilize the thermogenic function of brown adipose tissue for obesity intervention. However, the mechanisms controlling the efficacy of norepinephrine-induced thermogenesis in brown adipocytes remain elusive. Here, we demonstrate that the proton ATPase activity of mitochondrial complex V is a key factor, which antagonizes proton leak by UCP1 and determines the efficacy of norepinephrine-induced thermogenesis in brown adipocytes. Furthermore, to avoid unnecessary and undesired heat production, we reveal that ATP as a sympathetic cotransmitter is necessary for the high efficacy and specificity of norepinephrine-induced thermogenesis in brown adipocytes by upregulating the ATP synthase activity of complex V. Thus, we demonstrate the modulation mechanism of thermogenic efficacy in brown adipocytes. These findings imply new strategies for efficiently utilizing brown adipocytes thermogenic capacity, and therapeutic targets for the treatments of obesity and diabetes.\n\nHighlights1. Norepinephrine (NE) induces heterogeneous responses in brown adipocytes\n\n2. NE activates the H+-ATPase activity of mitochondrial complex V\n\n3. Mitochondrial complex V is a key factor in NE-induced thermogenic efficacy\n\n4. ATP as a sympathetic cotransmitter enhances the NE-induced thermogenic efficacy