Beige adipose tissues (BeAT) can metabolize lipids and carbohydrates to dissipate heat via non-shivering thermogenesis, making these tissues attractive targets for combating obesity. Whereas canonical activation of BeAT involves β-adrenergic (β-AR) stimulation of uncoupling protein 1 (UCP1), we discovered an additional actomyosin-dependent biomechanical pathway that was essential for efficient activation of beige adipocyte mitochondrial respiration. β-AR stimulation induced rapid contraction of beige adipocytes and stiffening of BeAT in vivo. This mechanical response was driven predominantly by myosin 9 (Myh9), which localized to both the cell periphery and lipid droplets. In parallel, β-AR stimulation of beige adipocyte also triggered formation of cage-like actin structures around lipid droplets, with targeted laser ablation of these cages altering lipid droplet fusion dynamics. Transcriptomic profiling of Myh9-deficient beige adipocytes reveals marked suppression of the key thermogenic effector UCP1 and the lipid droplet-mitochondria tethering protein PLIN5, resulting in blunted uncoupled respiration, decreased lipolysis, and reduced lipid droplet-mitochondria contact sites. Overexpression of PLIN5 restored lipolysis through those contact sites and enhanced respiration in Myh9-deficient cells. Surprisingly, β-AR-induced PKA pathway activation remained intact in the absence of actomyosin-dependent tension, suggesting that myosin-dependent thermogenesis operates independently of canonical thermogenesis pathways. We further identify focal adhesion kinase (FAK) as a novel downstream mediator of β-AR-signaling in beige adipocytes, with pharmacological and genetic antagonism of FAK phenocopying Myh9 depletion by suppressing PLIN5 expression and β-AR-induced UCP1 upregulation, thereby positioning FAK as a key mediator of this pathway. Collectively, our results support the existence of a non-canonical and previously unappreciated mechanism in which actomyosin contractility supports beige adipocyte bioenergetic function through FAK activation and PLIN5-dependent promotion of LD and mitochondrial organization and function.
Ling et al. (Sun,) studied this question.