GDF15 promotes weight loss by enhancing energy expenditure in muscle

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes(1). Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear(2,3). Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor alpha-like (GFRAL)-dependent suppression of food intake(4-7). Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-beta-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

Automated summary

Caloric restriction is effective in treating non-alcoholic fatty liver disease and improving insulin sensitivity, but weight loss is usually not maintained due to physiological adaptations that suppress energy expenditure. Treatment with recombinant GDF15 can reduce obesity and improve glycaemic control by suppressing food intake. Additionally, GDF15 counteracts compensatory reductions in energy expenditure, leading to greater weight loss and improvements in non-alcoholic fatty liver disease compared to caloric restriction alone. This effect of GDF15 on maintaining energy expenditure during calorie restriction requires a GFRAL-beta-adrenergic-dependent signaling axis.