OPA1 Regulates Lipid Metabolism and Cold-Induced Browning of White Adipose Tissue in Mice.

Mitochondria play a vital role in white adipose tissue (WAT) homeostasis including adipogenesis, fatty acid synthesis, and lipolysis. We recently reported that the mitochondrial fusion protein optic atrophy 1 (OPA1) is required for induction of fatty acid oxidation and thermogenic activation in brown adipocytes. In the current study we investigated the role of OPA1 in WAT function in vivo. We generated mice with constitutive or inducible knockout of OPA1 selectively in adipocytes. Studies were conducted under baseline conditions, at thermoneutrality, following high-fat feeding or during cold exposure. OPA1 deficiency reduced mitochondrial respiratory capacity in white adipocytes, impaired lipolytic signaling, repressed expression of de novo lipogenesis and triglyceride synthesis pathways, and promoted adipose tissue senescence and inflammation. Reduced WAT mass was associated with hepatic triglycerides accumulation and glucose intolerance. Moreover, mice deficient for OPA1 in adipocytes had impaired adaptive thermogenesis and reduced cold-induced browning of subcutaneous WAT and were completely resistant to diet-induced obesity. In conclusion, OPA1 expression and function in adipocytes are essential for adipose tissue expansion, lipid biosynthesis, and fatty acid mobilization of WAT and brown adipocytes and for thermogenic activation of brown and beige adipocytes.

OPA1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via FGF21.

Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, which is activated independently of BAT thermogenic function.