Abstract
The additional therapeutic effects of regular exercise during a dietary weight loss program in people with obesity and prediabetes are unclear. Here, we show that whole-body (primarily muscle) insulin sensitivity (primary outcome) was 2-fold greater (P = 0.006) after 10% weight loss induced by calorie restriction plus exercise training (Diet+EX; n = 8, 6 women) than 10% weight loss induced by calorie restriction alone (Diet-ONLY; n = 8, 4 women) in participants in two concurrent studies. The greater improvement in insulin sensitivity was accompanied by increased muscle expression of genes involved in mitochondrial biogenesis, energy metabolism and angiogenesis (secondary outcomes) in the Diet+EX group. There were no differences between groups in plasma branched-chain amino acids or markers of inflammation, and both interventions caused similar changes in the gut microbiome. Few adverse events were reported. These results demonstrate that regular exercise during a diet-induced weight loss program has profound additional metabolic benefits in people with obesity and prediabetes.
Trial Registration: ClinicalTrials.gov (NCT02706262 and NCT02706288)
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Data availability
Source data for Figs. 1, 2, 3, 4, 5c and 6 and Extended Data Tables 1, 2, 3 and 4 are provided with this paper. The RNA-seq data generated during this study are available at the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database under accession number GSE230002. We used DAVID Bioinformatics Resources v6.8 (http://david.ncifcrf.gov) to analyze the muscle RNA-seq data. The 16S data have been uploaded to the European Nucleotide Archive (ENA; https://www.ebi.ac.uk/ena) under the study identifier PRJEB61649. The Greengenes 13_8 database was used for taxonomic assignment of the ASVs detected in this study (https://data.qiime2.org/2022.11/common/gg-13-8-99-515-806-nb-classifier.qza). Source data are provided with this paper.
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Acknowledgements
We thank the staff of the Center for Human Nutrition and the CTRU at Washington University School of Medicine for assistance in conducting the metabolic studies and their technical assistance in processing and analyzing the study samples. We also thank the study participants for their participation. This study was supported by the National Institutes of Health grants P30 DK056341 (Washington University Nutrition and Obesity Research Center to S.K.), P30 DK020579 (Washington University Diabetes Research Center) and R01 DK104995 (NAD+ and metabolic flexibility to S.K.); postdoctoral training grants T32 HL130357 to J.W.B. and B.D.K., and T32 DK007120 to M.L.K.; and UL1 TR000448 (Washington University Institute of Clinical and Translational Sciences), as well as support from the Sam and Marilyn Fox Foundation to S.K.
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J.W.B., B.D.K., G.I.S., G.R., J.Y., R.K. and B.W.P. performed sample and data analyses. J.W.B., B.D.K., G.I.S., G.G.S., K.K. and M.L.K. conducted the clinical studies. G.I.S. and S.K. designed the study. J.W.B., B.D.K., G.I.S., B.W.P., R.K. and S.K. interpreted the data and wrote the manuscript. All authors critically reviewed and edited the paper.
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S.K. serves on scientific advisory boards for Altimmune and Merck. All other authors declare they have no competing interests.
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Extended data
Extended Data Fig. 1
Schematic diagrams of overall study protocol (a), schedule of individual assessments before (b) and after (c) the intervention and the protocol for inpatient 24-h study blood sampling schedule and hyperinsulinemic-euglycemic clamp procedure (HECP) plus muscle biopsy (Bx) (d). Blood sample timepoints are indicated by arrows and running figure indicates time of a 60-min bout of exercise performed in the Diet+EX group after the intervention. M=meal.
Extended Data Fig. 2 Effect of each intervention on the gut microbiome.
Measures of alpha diversity using both Chao richness (top) and Shannon entropy (bottom), before (T0) and at ~1 month (T1, 5.2 ± 0.7% weight loss), ~2 months (T2, 8.6 ± 0.8% weight loss), and ~4-5 months (T3, 10.5 ± 2.7% weight loss) after starting the intervention in the Diet-ONLY (n = 7) and Diet+EX (n = 8) groups. Data are means ± SEM (a). Beta diversity using Distanced-based Redundancy Analysis of the weight UniFrac distance, conditional on the between-person variability (b). Log-ratio analysis of 10 ASVs that increased the most and the 10 ASVs that decreased the most from T0 to T1 with treatment groups combined shown over time when stratified by study group. Data are log-ratio means ± SEM (c).
Extended Data Fig. 3
Flow of study participants.
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Beals, J.W., Kayser, B.D., Smith, G.I. et al. Dietary weight loss-induced improvements in metabolic function are enhanced by exercise in people with obesity and prediabetes. Nat Metab 5, 1221–1235 (2023). https://doi.org/10.1038/s42255-023-00829-4
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DOI: https://doi.org/10.1038/s42255-023-00829-4