Brown adipose tissue (BAT) undergoes mitochondrial uncoupling and expends energy in response to adrenergic stimulation. Mechanistically, norepinephrine promotes the release of free fatty acids (FFAs), which activate Ucp1 to mediate thermogenesis. Shirihai and colleagues report that norepinephrine also induces mitochondrial fragmentation in BAT to promote thermogenesis (EMBO J. 33, 418–436; 2014).

Norephinephrine and FFA treatment in mouse primary brown adipocytes synergistically induced energy expenditure, indicating that adrenergic signalling promotes thermogenesis through FFA-independent pathways. Indeed, norephinephrine, but not FFA alone, induced mitochondrial fragmentation. Norepinephrine promoted protein kinase A (PKA)-mediated phosphorylation of the pro-fission protein Drp1, and its localization with the mitochondria. Intriguingly, inhibiting FFA release by treating cells with Orlistat blocked depolarization but did not affect mitochondrial fragmentation, suggesting that Drp1-mediated fragmentation is stimulated by norephinephrine but not FFA.

Overexpressing a dominant-negative Drp1 mutant blocked norephinephrine-stimulated energy expenditure and mitochondrial depolarization, revealing the importance of mitochondrial fission in thermogenesis. Consistent with this observation, knocking down the pro-fusion protein Mitofusin 2 (Mfn2) caused mitochondrial fragmentation and depolarization, and increased oxygen respiration. Mfn2 knockdown also synergized with FFAs to promote energy expenditure in brown adipocytes. Thus, adrenergic signalling promotes thermogenesis by promoting FFA release and mitochondrial uncoupling, and by activating Drp1 and stimulating mitochondrial fission.