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Human adipose beiging in response to cold and mirabegron
Brian S. Finlin, … , Esther E. Dupont-Versteegden, Philip A. Kern
Brian S. Finlin, … , Esther E. Dupont-Versteegden, Philip A. Kern
Published August 9, 2018
Citation Information: JCI Insight. 2018;3(15):e121510. https://doi.org/10.1172/jci.insight.121510.
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Clinical Medicine Clinical trials Metabolism

Human adipose beiging in response to cold and mirabegron

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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 β3 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 β3 receptor agonist mirabegron induces UCP1, TMEM26, CIDEA, and phosphorylation of HSL on serine660 in obese subjects. CONCLUSION. Cold or β3 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).

Authors

Brian S. Finlin, Hasiyet Memetimin, Amy L. Confides, Ildiko Kasza, Beibei Zhu, Hemendra J. Vekaria, Brianna Harfmann, Kelly A. Jones, Zachary R. Johnson, Philip M. Westgate, Caroline M. Alexander, Patrick G. Sullivan, Esther E. Dupont-Versteegden, Philip A. Kern

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Figure 5

Cold stimulates s.c. white adipose tissue (WAT) mitochondrial bioenergetics.

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Cold stimulates s.c. white adipose tissue (WAT) mitochondrial bioenerget...
(A) Abdominal s.c. WAT was isolated from subjects before and after cold exposure, mitochondria were purified, and the bioenergetics were analyzed using an Oxytherm system as described in Methods. An example trace shows the O2 level in the chamber during the course of the experiment for 1 subject before and after cold exposure. The substrates pyruvate (Pyr) and malate (Mal), adenosine diphosphate (ADP), oligomycin (Oligo), free fatty acid (FFA; 60 uM linoleic acid), fatty acid free BSA, and trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP; 10 μm) were sequentially added at the indicated times. The oxygen consumption rate (OCR; nmoles/min) was determined during each step. (B and C) Analysis of mitochondrial bioenergetics before and after 10 days of repeated cold exposure. (D) Uncoupled respiration was determined by calculating the difference between the Oligo and FFA OCRs. (E) Maximal respiration was calculated by determining the difference between Oligo and FCCP OCRs. Data are represented as mean ± SEM (n = 11). The data were analyzed by a paired, 2-tailed student’s t test; *P < 0.05; #P < 0.1.

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