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 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 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.
| Original language | English |
|---|---|
| Pages (from-to) | 143-150 |
| Number of pages | 8 |
| Journal | Nature |
| Volume | 619 |
| Issue number | 7968 |
| Early online date | 28 Jun 2023 |
| DOIs | |
| Publication status | Published - 6 Jul 2023 |
Bibliographical note
Funding Information:We thank R. Seeley for sharing GFRAL-null mice; B. Lowell for sharing β-less mice; and J. Wu for shipping β-less mice to us. G.R.S. was supported by a Diabetes Canada Investigator Award (DI-5-17-5302-GS), a Canadian Institutes of Health Research Foundation Grant (201709FDN-CEBA-116200), a Tier 1 Canada Research Chair in Metabolic Diseases and a J. Bruce Duncan Endowed Chair in Metabolic Diseases; D.W. by Fellowship Grants from the McMaster Institute for Research on Aging (MIRA) at McMaster University; S.R. by a postdoctoral fellowship supported by MITACS and Novo Nordisk; L.K.T. by a CIHR Post-Doctoral Fellowship Award and Michael DeGroote Fellowship Award in Basic Biomedical Science; E.M.D. by a Vanier Canada Graduate Scholarship; G.P.H. by the Natural Sciences and Engineering Research Council of Canada (NSERC: 400362); G.J.D. and S.M.F. by NSERC-CGSM scholarships; L.D. by the Fonds de Recherche du Québec-Santé doctoral training award; D.P.B. by the GSK Chair in Diabetes of Université de Sherbrooke and a FRQS J1 salary award. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS.
Funding Information:
S.B.J. and R.E.K. are employees of Novo Nordisk, a pharmaceutical company producing and selling medicine for the treatment of diabetes and obesity. G.R.S. is a co-founder and shareholder of Espervita Therapeutics. McMaster University has received funding from Espervita Therapeutics, Esperion Therapeutics, Poxel Pharmaceuticals and Nestle for research conducted in the laboratory of G.R.S. S.R. is supported by a MITACS postdoctoral fellowship sponsored by Novo Nordisk. H.C.G. holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. G.R.S., G.P. and H.C.G. are inventors listed on a patent for identifying GDF15 as a biomarker for metformin. G.R.S. has received consulting/speaking fees from Astra Zeneca, Eli Lilly, Esperion Therapeutics, Merck, Poxel Pharmaceuticals and Cambrian Biosciences. The other authors declare no competing interests.
Publisher Copyright:
© 2023, The Author(s).
Data Availability Statement
All data supporting the findings in this study are available within the Article and its Supplementary Information. The RNA-seq data of the liver tissue and tibialis anterior muscle have been deposited at the NCBI Gene Expression Omnibus (GEO) and are accessible under accession numbers GSE229708 (liver tissue) and GSE229794 (tibialis anterior muscle) or SuperSeries GSE230208. RNA-seq data of quadriceps samples from mice treated with β-2 agonist clenbuterol were downloaded from the NCBI Sequence Read Archive under reference number PRJNA756816. The data from GTEx Analysis V8 used for the analyses described in this paper were obtained from dbGaP accession number phs000424.v8.p2 on 11 May 2022 (https://www.gtexportal.org/home/). Gel source data are provided in Supplementary Fig. 4. Source data are provided with this paper.Code availability
The code developed for RNA-seq analysis, bioinformatics analysis of the GTEx dataset and 2SMR are freely available at Zenodo (https://doi.org/10.5281/zenodo.7838970).
Keywords
- Diabetes
- fat metabolism
- obesity
- recombinant protein therapy
Access to Document
- Wang_etal_N_GDF15_Promotes_Weight_VOR
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