GFRAL is required to mediate changes in systemic metabolism in response to mitochondrial stress in brown adipose tissue.

Growth differentiation factor 15 (GDF15) is a cytokine induced in several tissues in response to stress. GDF15 suppresses food intake and increases energy expenditure via its actions on the glial-derived neurotrophic factor receptor α family-like specific receptor (GFRAL), located in the hindbrain. We recently showed that selective deletion of the mitochondrial fusion protein optic atrophy 1 (OPA1) in brown adipocytes (OPA1 BKO) leads to GDF15 secretion, partially mediating resistance to diet-induced obesity (DIO), and improving thermoregulation. To investigate whether GDF15 signaling through GFRAL is necessary to mediate these metabolic effects, we crossed OPA1 BKO mice with GFRAL global knockout mice (DKO). Under isocaloric conditions, DKO mice had similar body weight as control and OPA1 BKO mice. Upon high-fat diet feeding, DKO mice were partially resistant to DIO, but lacked the improvement in glucose homeostasis and insulin sensitivity observed in OPA1 BKO mice. Finally, DKO mice were susceptible to cold-induced hypothermia, suggesting a role for GFRAL in core body temperature regulation in the OPA1 BKO mice. Our data reveals a novel BAT-GDF15-GFRAL axis that modulates resistance to DIO and improves thermoregulation in mice in the context of mitochondrial stress. KEY MESSAGES: OPA1 deletion induces a BAT-GDF15-GFRAL axis to regulate systemic metabolic homeostasis. GDF15-signaling through GFRAL partially mediates resistance to DIO in mice lacking OPA1 in BAT. GFRAL mediates GDF15's effects on energy homeostasis in DIO OPA1 BKO mice. GDF15-GFRAL signaling is required to maintain core body temperature in cold-exposed OPA1 BKO mice.