GDF15 promotes weight loss by enhancing energy expenditure in muscle

Dongdong Wang, Logan K. Townsend, Geneviève J. DesOrmeaux, Sara M. Frangos, Battsetseg Batchuluun, Lauralyne Dumont, Rune Ehrenreich Kuhre, Elham Ahmadi, Sumei Hu, Irena A. Rebalka, Jaya Gautam, Maria Joy Therese Jabile, Chantal A. Pileggi, Sonia Rehal, Eric M. Desjardins, Evangelia E. Tsakiridis, James S. V. Lally, Emma Sara Juracic, A. Russell Tupling, Hertzel C. Gerstein, Guillaume Paré, Theodoros Tsakiridis, Mary-Ellen Harper, Thomas J. Hawke, John R. Speakman, Denis P. Blondin, Graham P. Holloway, Sebastian Beck Jørgensen and Gregory R. Steinberg ()
Additional contact information
Dongdong Wang: McMaster University
Logan K. Townsend: McMaster University
Geneviève J. DesOrmeaux: University of Guelph
Sara M. Frangos: University of Guelph
Battsetseg Batchuluun: McMaster University
Lauralyne Dumont: Université de Sherbrooke
Rune Ehrenreich Kuhre: Novo Nordisk
Elham Ahmadi: McMaster University
Sumei Hu: Beijing Technology and Business University
Irena A. Rebalka: McMaster University
Jaya Gautam: McMaster University
Maria Joy Therese Jabile: McMaster University
Chantal A. Pileggi: University of Ottawa
Sonia Rehal: McMaster University
Eric M. Desjardins: McMaster University
Evangelia E. Tsakiridis: McMaster University
James S. V. Lally: McMaster University
Emma Sara Juracic: University of Waterloo
A. Russell Tupling: University of Waterloo
Hertzel C. Gerstein: McMaster University
Guillaume Paré: McMaster University
Theodoros Tsakiridis: McMaster University
Mary-Ellen Harper: University of Ottawa
Thomas J. Hawke: McMaster University
John R. Speakman: Chinese Academy of Sciences
Denis P. Blondin: Université de Sherbrooke
Graham P. Holloway: University of Guelph
Sebastian Beck Jørgensen: Novo Nordisk
Gregory R. Steinberg: McMaster University

Nature, 2023, vol. 619, issue 7968, 143-150

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-06249-4

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