Wang 2023 Nature

Wang D, Townsend LK, DesOrmeaux GJ, Frangos SM, Batchuluun B, Dumont L, Kuhre RE, Ahmadi E, Hu S, Rebalka IA, Gautam J, Jabile MJT, Pileggi CA, Rehal S, Desjardins EM, Tsakiridis EE, Lally JSV, Juracic ES, Tupling AR, Gerstein HC, Paré G, Tsakiridis T, Harper ME, Hawke TJ, Speakman JR, Blondin DP, Holloway GP, Jørgensen SB, Steinberg GR (2023) GDF15 promotes weight loss by enhancing energy expenditure in muscle. https://doi.org/10.1038/s41586-023-06249-4

» Nature 619:143-50. PMID: 37380764 Open Access

Wang Dongdong, Townsend Logan K, DesOrmeaux Genevieve J, Frangos Sara M, Batchuluun Battsetseg, Dumont Lauralyne, Kuhre Rune Ehrenreich, Ahmadi Elham, Hu Sumei, Rebalka Irena A, Gautam Jaya, Jabile Maria Joy Therese, Pileggi Chantal A, Rehal Sonia, Desjardins Eric M, Tsakiridis Evangelia E, Lally James SV, Juracic Emma Sara, Tupling A Russell, Gerstein Hertzel C, Pare Guillaume, Tsakiridis Theodoros, Harper Mary-Ellen, Hawke Thomas J, Speakman John R, Blondin Denis P, Holloway Graham P, Joergensen Sebastian Beck, Steinberg Gregory R (2023) Nature

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 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 α-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-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.

• Bioblast editor: Plangger M • O2k-Network Lab: CA Ottawa Harper ME, UK Aberdeen Speakman JR, CA Sherbrooke Blondin DP, CA Guelph Holloway GP

Labels: MiParea: Respiration, Exercise physiology;nutrition;life style, Pharmacology;toxicology  Pathology: Obesity 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue, Isolated mitochondria, Intact cells 

Coupling state: LEAK, OXPHOS  Pathway: N, NS  HRR: Oxygraph-2k 

2023-07 

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