Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure

Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically‐induced changes in energy expenditure. The sympathetic neurotransmitter Norepinephrine (NE) induced complete and rapid mitochondrial fragmentation in BA, characterized by Drp1 phosphorylation and Opa1 cleavage. Mechanistically, NE‐mediated Drp1 phosphorylation was dependent on Protein Kinase‐A (PKA) activity, whereas Opa1 cleavage required mitochondrial depolarization mediated by FFAs released as a result of lipolysis. This change in mitochondrial architecture was observed both in primary cultures and brown adipose tissue from cold‐exposed mice. Mitochondrial uncoupling induced by NE in brown adipocytes was reduced by inhibition of mitochondrial fission through transient Drp1 DN overexpression. Furthermore, forced mitochondrial fragmentation in BA through Mfn2 knock down increased the capacity of exogenous FFAs to increase energy expenditure. These results suggest that, in addition to its ability to stimulate lipolysis, NE induces energy expenditure in BA by promoting mitochondrial fragmentation. Together these data reveal that adrenergically‐induced changes to mitochondrial dynamics are required for BA thermogenic activation and for the control of energy expenditure. Synopsis In this study, norepinephrine‐mediated mitochondrial dynamics are shown to contribute to uncoupled respiration during thermogenesis in brown adipocytes. Norepinephrine induced complete and rapid mitochondrial fragmentation in brown adipocytes through PKA‐dependent Drp1 phosphorylation and Opa1 cleavage. Norepinephrine‐induced mitochondrial uncoupling was reduced by inhibition of mitochondrial fission and enhanced by Mfn2 knock down. Knockdown of Mfn2 enhanced the capacity of exogenous free fatty acids to increase energy expenditure. We conclude that in addition to its ability to stimulate lipolysis, norepinephrine induces energy expenditure in brown adipocytes by promoting mitochondrial fragmentation. Graphical Abstract In this study, norepinephrine‐mediated mitochondrial dynamics are shown to contribute to uncoupled respiration during thermogenesis in brown adipocytes.