GDF15 promotes weight loss by enhancing energy expenditure in muscle

Nature. 2023 Jul;619(7968):143-150. doi: 10.1038/s41586-023-06249-4. Epub 2023 Jun 28.


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 diabetes1. 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 unclear2,3. 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 α-like (GFRAL)-dependent suppression of food intake4-7. 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-β-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.

MeSH terms

  • Animals
  • Appetite Depressants / metabolism
  • Appetite Depressants / pharmacology
  • Appetite Depressants / therapeutic use
  • Caloric Restriction
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / metabolism
  • Diet, High-Fat
  • Eating / drug effects
  • Energy Metabolism* / drug effects
  • Growth Differentiation Factor 15* / metabolism
  • Growth Differentiation Factor 15* / pharmacology
  • Growth Differentiation Factor 15* / therapeutic use
  • Humans
  • Mice
  • Muscle, Skeletal* / drug effects
  • Muscle, Skeletal* / metabolism
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / therapy
  • Receptors, Adrenergic, beta / metabolism
  • Weight Loss* / drug effects


  • Appetite Depressants
  • GDF15 protein, human
  • GFRAL protein, mouse
  • Growth Differentiation Factor 15
  • Receptors, Adrenergic, beta