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Cold acclimation with shivering improves metabolic health in adults with overweight or obesity

Nature Metabolism volume 6, pages 2246–2253 (2024)Cite this article

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Abstract

Cold acclimation increases insulin sensitivity, and some level of muscle contraction appears to be needed for provoking this effect. Here 15 men and (postmenopausal) women with overweight or obesity, the majority of whom had impaired glucose tolerance, were intermittently exposed to cold to induce 1 h of shivering per day over 10 days. We determined the effect of cold acclimation with shivering on overnight fasted oral glucose tolerance (primary outcome) and on skeletal muscle glucose transporter 4 translocation (secondary outcome). We find that cold acclimation with shivering improves oral glucose tolerance, fasting glucose, triglycerides, non-esterified fatty acid concentrations and blood pressure. Cold acclimation with shivering may thus represent an alternative lifestyle approach for the prevention and treatment of obesity-related metabolic disorders. ClinicalTrials.gov registration: NCT04516018.

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Fig. 1: Plasma glucose and insulin concentrations before and after cold acclimation.
Fig. 2: Serum NEFA and triglyceride concentrations before and after cold acclimation.
Fig. 3: Resting blood pressure and heart rate before and after cold acclimation.

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Data availability

The generated and analysed datasets of the current study are not publicly available. De-identified and processed data can be requested from the corresponding authors for academic purposes after completing a signed data access form. The study team will only provide de-identified data to protect participant privacy. The study protocol is provided with the publication. Skeletal muscle gene expression data have been deposited in GEO under accession code GSE271452. Source data are provided with this paper.

References

  1. Hanssen, M. J. et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat. Med. 21, 863–865 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Remie, C. M. E. et al. Metabolic responses to mild cold acclimation in type 2 diabetes patients. Nat. Commun. 12, 1516 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vallerand, A. L. et al. Plasma glucose turnover during cold stress in humans. J. Appl. Physiol. (1985) 78, 1296–1302 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Haman, F. et al. Partitioning oxidative fuels during cold exposure in humans: muscle glycogen becomes dominant as shivering intensifies. J. Physiol. 566, 247–256 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Blondin, D. P. et al. Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men. J. Physiol. 593, 701–714 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Abdul-Ghani, M. A. et al. Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test. Diabetes Care 30, 89–94 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Eyolfson, D. A. et al. Measurement and prediction of peak shivering intensity in humans. Eur. J. Appl. Physiol. 84, 100–106 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Cao, C. et al. Increased plasma fatty acid clearance, not fatty acid concentration, is associated with muscle insulin resistance in people with obesity. Metabolism 132, 155216 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ferrannini, E. et al. Effect of fatty acids on glucose production and utilization in man. J. Clin. Invest. 72, 1737–1747 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lawler, P. R. et al. Real-world risk of cardiovascular outcomes associated with hypertriglyceridaemia among individuals with atherosclerotic cardiovascular disease and potential eligibility for emerging therapies. Eur. Heart J. 41, 86–94 (2020).

    Article  PubMed  Google Scholar 

  11. Hanssen, M. J. et al. Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes 65, 1179–1189 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Nascimento, E. B. M. et al. Comparative transcriptome analysis of human skeletal muscle in response to cold acclimation and exercise training in human volunteers. BMC Med. Genomics 13, 124 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. van der Lans, A. A. et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J. Clin. Invest. 123, 3395–3403 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Russell, R. D. et al. Oral glucose challenge impairs skeletal muscle microvascular blood flow in healthy people. Am. J. Physiol. Endocrinol. Metab. 315, E307–E315 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Carpentier, A. C. & Blondin, D. P. Human brown adipose tissue is not enough to combat cardiometabolic diseases. J. Clin. Invest. 133, e175288 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mensink, M. et al. Lifestyle intervention according to general recommendations improves glucose tolerance. Obes. Res. 11, 1588–1596 (2003).

    Article  PubMed  Google Scholar 

  17. Sellers, A. J. et al. The effect of cold exposure with shivering on glucose tolerance in healthy men. J. Appl. Physiol. 130, 193–205 (2021).

    Article  PubMed  Google Scholar 

  18. van Ooijen, A. M. et al. Cold-induced heat production preceding shivering. Br. J. Nutr. 93, 387–391 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Blondin, D. P. et al. Four-week cold acclimation in adult humans shifts uncoupling thermogenesis from skeletal muscles to brown adipose tissue. J. Physiol. 595, 2099–2113 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Boettcher, C. E., Ginn, K. A. & Cathers, I. Standard maximum isometric voluntary contraction tests for normalizing shoulder muscle EMG. J. Orthop. Res. 26, 1591–1597 (2008).

    Article  PubMed  Google Scholar 

  21. Kong, P. W. & van Haselen, J. Revisiting the influence of hip and knee angles on quadriceps excitation measured by surface electromyography. Int. Sportmed. J. 11, 313–323 (2010).

    Google Scholar 

  22. Weir, J. B. New methods for calculating metabolic rate with special reference to protein metabolism. J. Physiol. 109, 1–9 (1949).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Brouwer, E. On simple formulae for calculating the heat expenditure and the quantities of carbohydrate and fat oxidized in metabolism of men and animals, from gaseous exchange (oxygen intake and carbonic acid output) and urine-N. Acta. Physiol. Pharmacol. Neerl 6, 795–802 (1957).

    CAS  PubMed  Google Scholar 

  24. Golay, A. et al. Glucose-induced thermogenesis in nondiabetic and diabetic obese subjects. Diabetes 31, 1023–1028 (1982).

    Article  CAS  PubMed  Google Scholar 

  25. Dill, D. B. & Costill, D. L. Calculation of percentage changes in volumes of blood plasma and red cells in dehydration. J. Appl. Physiol. 37, 247–248 (1974).

    Article  CAS  PubMed  Google Scholar 

  26. Bergström, J., Hermansen, L., Hultman, E. & Saltin, B. Diet muscle glycogen and physical performance. Acta. Physiol. Scand. 71, 140–150 (1967).

    Article  PubMed  Google Scholar 

  27. Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671–675 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by the Netherlands Organisation for Health Research and Development (ZonMw) programme for translational research and Diabetes Fonds (project number 95105007). A grant from the Nutrim NWO Graduate Program was also awarded to S.M.M.B. The authors thank P. Schoffelen, M. Souren and W. Bijnens for their technical support, and E. E. Tapia, S. N. González, M. Buitinga and F. Bosschee for their assistance with the muscle biopsies. The authors thank all participants for their participation.

Author information

Author notes

  1. These authors contributed equally: Adam J. Sellers, Sten M. M. van Beek.

  2. These authors jointly supervised this work: Joris Hoeks, Wouter D. van Marken Lichtenbelt.

Authors and Affiliations

  1. Department of Nutrition and Movement Sciences, NUTRIM Institute of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands

    Adam J. Sellers, Sten M. M. van Beek, Dzhansel Hashim, Hannah Pallubinsky, Esther Moonen-Kornips, Gert Schaart, Anne Gemmink, Johanna A. Jörgensen, Matthijs K. C. Hesselink, Joris Hoeks & Wouter D. van Marken Lichtenbelt

  2. Centre for Molecular Medicine, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands

    Rosalie Baak & Eric Kalkhoven

  3. Healthy Living Spaces lab, Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany

    Hannah Pallubinsky

  4. Department of Radiology and Nuclear Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands

    Tineke van de Weijer

  5. Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands

    Guido J. Hooiveld & Sander Kersten

  6. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Patrick Schrauwen

  7. Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

    Patrick Schrauwen

Authors
  1. Adam J. Sellers
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  2. Sten M. M. van Beek
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Contributions

A.J.S., S.M.M.B., H.P., P.S., J.H. and W.D.M.L conceived and designed the research. A.J.S., S.M.M.B., D.H., E.M., G.S., A.G. and J.A.J. performed experiments. A.J.S., S.M.M.B., R.B., E.M., G.S., A.G., J.A.J. and G.H. analysed data. A.J.S., S.M.M.B., R.B., H.P., T.W., E.K., G.H., S.K., P.S., J.H. and W.D.M.L. interpreted results. A.J.S. and S.M.M.B. wrote the original paper draft; A.J.S., S.M.M.B., R.B., H.P., S.K., M.K.C.H., P.S., J.H. and W.D.M.L. edited and revised the paper. All authors approved the final paper version.

Corresponding authors

Correspondence to Joris Hoeks or Wouter D. van Marken Lichtenbelt.

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The authors declare no conflicts of interest.

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Nature Metabolism thanks Jose Galgani and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ashley Castellanos-Jankiewicz, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Effects of one cold exposure with shivering on fasting plasma glucose (A), plasma glucose during an OGTT (B), glucose AUC (C) and iAUC (D), 2-hour glucose concentration (E), fasting plasma insulin (F), plasma insulin during an OGTT (G), and insulin AUC (H) and iAUC (I).

Mean ± SD and individual responses are presented, n = 15. Data in panels (A), (C), (D), (E), (H), and (I) were analysed with a two-sided paired t-test. Data in panel (F) was analysed with a two-sided Wilcoxon signed-rank test. AUC, area under the curve; iAUC, incremental area under the curve; OGTT, oral glucose tolerance test.

Source data

Extended Data Fig. 2 Effects of one cold exposure with shivering on energy expenditure (A) and substrate oxidation (B-D) at baseline, and energy expenditure (E), substrate oxidation (F-H), and glucose-induced thermogenesis (I) during an OGTT.

Mean ± SD and individual responses are presented, n = 14. Data in panels (A), (D), and (I) were analysed with two-sided paired t-tests. Data in panels (B) and (C) were analysed with two-sided Wilcoxon signed-rank test. Data in panels (E), (F), (G), and (H) were analysed with a two-way repeated measures ANOVA with Bonferroni post-hoc analyses to assess differences between groups. CHO, carbohydrate; OGTT, oral glucose tolerance test; RER, respiratory exchange ratio.

Source data

Extended Data Fig. 3 Effects of cold acclimation on energy expenditure (A) and substrate oxidation at baseline (B-D), and energy expenditure (E), substrate oxidation (F-H) and glucose-induced thermogenesis (I) during an OGTT.

Mean ± SD and individual responses are presented, n = 14. Data in panels (A), (B), (D), and (I), were analysed with two-sided paired t-tests. Data in panel (C) was analysed with a two-sided Wilcoxon signed-rank test. Data in panels (E), (F), (G), and (H), were analysed with a two-way repeated measures ANOVA with Bonferroni post-hoc analyses to assess differences between groups. CHO, carbohydrate; OGTT, oral glucose tolerance test; RER, respiratory exchange ratio.

Source data

Extended Data Fig. 4 Effects of one cold exposure with shivering on fasting serum NEFA (A), serum NEFA during an OGTT (B), NEFA AUC (C) and iAUC (D), and fasting serum triglycerides (E).

Mean ± SD and individual responses are presented, n = 15. Data in panels (A) and (C) were analysed with a two-sided paired t-test. Data in panels (D) and (E) were analysed with a two-sided Wilcoxon signed-rank test. AUC, area under the curve; iAUC, incremental area under the curve; NEFA, non-esterified fatty acid; OGTT, oral glucose tolerance test.

Source data

Extended Data Fig. 5 Effects of cold acclimation on skeletal muscle glycogen concentration (A) and GLUT4 content (B-E). Representative images of GLUT4 staining with type 1 fibres stained green (B) and the membranes with caveolin (blue), total GLUT4 content (C), GLUT4 at the membrane (D), and GLUT4 in the cytosol (E).

Mean ± SD and individual responses are presented, n = 15. Data in panels (C), (D), and (E) were analysed with a two-sided paired t-test. Data in panel (A) was analysed with a two-sided Wilcoxon signed-rank test.

Source data

Extended Data Fig. 6 Effects of one cold exposure with shivering on skeletal muscle GLUT4 content (A-D). Representative images of GLUT4 staining with type 1 fibres stained green (A) and the membranes with caveolin (blue), total GLUT4 content (B), GLUT4 at the membrane (C), and GLUT4 in the cytosol (D).

Mean ± SD and individual responses are presented, n = 13. Data in panels (B), (C), and (D) were analysed with a two-sided paired t-test.

Source data

Extended Data Fig. 7 Effects of cold acclimation on the human skeletal muscle transcriptome, volcano plot (A), GSEA on GO-Biological Process terms (B), and KEGG taxonomy (C) of the comparison before and after cold acclimation.

The top 15 upregulated and downregulated gene sets in the 15 participants are shown. Differentially expressed genes were analysed by empirical Bayes moderation with two-sided paired t-tests, unadjusted for multiple comparisons, and defined as significantly changed when p ≤ 0.01 and log2FC > 1.5.

Extended Data Fig. 8 Effects of one cold exposure with shivering on resting systolic (A) and diastolic (B) blood pressure and heart rate (C).

Mean ± SD and individual responses are presented, n = 15. Data in panels (A), (B), and (C) were analysed with two-sided paired t-tests.

Source data

Extended Data Table 1 Participant characteristics at screening
Full size table
Extended Data Table 2 Top 20 upregulated and downregulated genes, ranked according to fold change, after cold acclimation
Full size table

Supplementary information

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Supplementary Figs. 1–9, Supplementary Tables 1–3, Methods reference list, Study protocol

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Sellers, A.J., van Beek, S.M.M., Hashim, D. et al. Cold acclimation with shivering improves metabolic health in adults with overweight or obesity. Nat Metab 6, 2246–2253 (2024). https://doi.org/10.1038/s42255-024-01172-y

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