FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes

ABSTRACT Objective Our previous studies showed that mice lacking the mitochondrial fusion protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) have high metabolic rates and are resistant to diet‐induced obesity (DIO) via effects partially mediated by independent actions of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) secretion from BAT. We examined whether FGF21 and GDF15 act synergistically, contributing to the systemic metabolic adaptations reported in OPA1 BKO mice. Methods We generated mice simultaneously lacking the Opa1 , Fgf21 , and Gdf15 genes in thermogenic adipocytes (TKO) and assessed energy homeostasis and glucose metabolism after regular chow or high‐fat diet feeding. Results Young TKO mice fed regular chow had impaired glucose tolerance, while insulin sensitivity was unchanged. Notably, combined Fgf21 and Gdf15 deletion in OPA1 BKO significantly blunted the resistance to DIO and insulin resistance observed in OPA1 BKO mice. Conclusions FGF21 and GDF15 act synergistically to maintain glucose homeostasis and promote resistance to DIO in mice lacking OPA1 in BAT, highlighting the potential of combined therapies using FGF21 and GDF15 for the treatment of metabolic disorders.