Adaptive thermogenesis is mediated by GDF15 via the GFRAL neuronal axis in mice

Adaptive thermogenesis is a key homeostatic mechanism that primarily occurs in brown adipocytes and enables the maintenance of body temperature. Although this process involves coordinated responses in multiple tissues, the precise inter-organ crosstalk underlying adaptive thermogenesis is unclear. Here, we investigate the pivotal role of the GDNF family receptor alpha-like (GFRAL) neuronal axis in modulating compensatory thermogenic responses in brown and white adipose depots under stress conditions, specifically the mitochondrial unfolded protein response resulting from genetic modification and cold exposure. We found that Crif1 deletion driven by UCP1-Cre model resulted in browning of inguinal white adipose depots, increased energy expenditure, reduced food intake, and resistance to weight gain. Retrograde neuronal tracing established that GFRAL-positive neurons and sympathetic preganglionic neurons mediated the GDF15-associated browning of inguinal white adipose tissue. Antisense oligonucleotides that inhibit Gfral expression blunted the effect of Crif1 deletion on energy expenditure and food intake. Our findings suggest that the GFRAL neuronal axis is key in coordinating the adaptive thermogenic response across multiple tissues and adipose depots, thereby ensuring metabolic homeostasis during mitochondrial stress. ### Competing Interest Statement The authors have declared no competing interest.