Wang 2023 Nature

From Bioblast
Publications in the MiPMap
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, ParΓ© G, Tsakiridis T, Harper ME, Hawke TJ, Speakman JR, Blondin DP, Holloway GP, JΓΈrgensen SB, Steinberg GR (2023) GDF15 promotes weight loss by enhancing energy expenditure in muscle. https://doi.org/10.1038/s41586-023-06249-4

Β» 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 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 Ξ±-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-Ξ²-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.

β€’ Bioblast editor: Plangger M β€’ 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 

References

  1. Petersen, K. F. et al. (2005) Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54, 603–608.
  2. Tremblay, A., Royer, M. M., Chaput, J. P. & Doucet, E. (2013) Adaptive thermogenesis can make a difference in the ability of obese individuals to lose body weight. Int J Obes 37, 759–764.
  3. Johannsen, D. L. et al. (2012) Metabolic slowing with massive weight loss despite preservation of fat-free mass. J Clin Endocrinol Metab 97, 2489–2496.
  4. Yang, L. et al. (2017) GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med 23, 1158–1166.
  5. Emmerson, P. J. et al. (2017) The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med 23, 1215–1219.
  6. Mullican, S. E. et al. (2017) GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med 23, 1150–1157.
  7. Hsu, J. Y. et al. (2017) Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 550, 255–259.
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