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Human adipose beiging in response to cold and mirabegron
Abstract
BACKGROUND. The induction of beige adipocytes in s.c. white adipose tissue (WAT) depots of humans is postulated to improve glucose and lipid metabolism in obesity. The ability of obese, insulin-resistant humans to induce beige adipose tissue is unknown. METHODS. We exposed lean and obese research participants to cold (30-minute ice pack application each day for 10 days of the upper thigh) or treated them with the β 3 agonist mirabegron. We determined beige adipose marker expression by IHC and quantitative PCR, and we analyzed mitochondrial bioenergetics and UCP activity with an Oxytherm system. RESULTS. Cold significantly induced UCP1 and TMEM26 protein in both lean and obese subjects, and this response was not associated with age. Interestingly, these proteins increased to the same extent in s.c. WAT of the noniced contralateral leg, indicating a crossover effect. We further analyzed the bioenergetics of purified mitochondria from the abdominal s.c. WAT of cold-treated subjects and determined that repeat ice application significantly increased uncoupled respiration, consistent with the UCP1 protein induction and subsequent activation. Cold also increased State 3 and maximal respiration, and this effect on mitochondrial bioenergetics was stronger in summer than winter. Chronic treatment (10 weeks; 50 mg/day) with the β 3 receptor agonist mirabegron induces UCP1, TMEM26, CIDEA, and phosphorylation of HSL on serine 660 in obese subjects. CONCLUSION. Cold or β 3 agonists cause the induction of beige adipose tissue in human s.c. WAT; this phenomenon may be exploited to increase beige adipose in older, insulin-resistant, obese individuals. TRIAL REGISTRATION. Clinicaltrials.gov NCT02596776, NCT02919176. FUNDING. NIH (DK107646, DK112282, P20GM103527, and by CTSA grant UL1TR001998).
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Cited by
Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation
Blondin, D. P., Nielsen, S., Kuipers, E. N., Severinsen, M. C., Jensen, V. H., Miard, S., Jespersen, N. Z., Kooijman, S., Boon, M. R., Fortin, M., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.07.005 · Cited by 331
Obesity and Exercise: New Insights and Perspectives
James, N. M., & Stanford, K. I. (2025) · Endocrine Reviews · doi:10.1210/endrev/bnaf017 · Cited by 20
Perez, L. C., Perez, L. T., Nene, Y., Umpierrez, G. E., Davis, G. M., & Pasquel, F. J. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1037458 · Cited by 17
Metadata
- Authors
- Finlin, B. S., Memetimin, H., Confides, A. L., Kasza, I., Zhu, B., Vekaria, H. J., Harfmann, B., Jones, K. A., Johnson, Z. R., Westgate, P. M., Alexander, C. M., Sullivan, P. G., Dupont-Versteegden, E. E., & Kern, P. A.
- Venue
- JCI Insight
- Published
- 2018-08-09
- Volume
- 3
- Issue
- 15
- ISSN
- 2379-3708
- Cited by
- 184
- References
- 9
- Language
- en
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- Finlin, B. S., Memetimin, H., Confides, A. L., Kasza, I., Zhu, B., Vekaria, H. J., Harfmann, B., Jones, K. A., Johnson, Z. R., Westgate, P. M., Alexander, C. M., Sullivan, P. G., Dupont-Versteegden, E. E., & Kern, P. A. (2018). Human adipose beiging in response to cold and mirabegron. JCI Insight. https://doi.org/10.1172/jci.insight.121510
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