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.


Sample-size estimation
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Replicates
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Statistical reporting
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Group allocation
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The statistical analyses comply with the Journal requirements. Statistical analysis methods are described in the methods section and in the figure legends. For all graph bars, the raw data for biological replicates is represented as individual dots. P-values are reported in the figure legends.
Several cohorts of animals were used for the different experiments. Littermate control mice from the different genotypes were randomly assigned to the different experiments and treatments. Whenever possible, investigators were blinded to animals' genotype and treatment.