Human adipose beiging in response to cold and mirabegron
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
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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Clinical Research and Public Health Clinical trials Metabolism

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 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 8

Mirabegron treatment increases hormone sensitive lipase (HSL) serine660 (P-Ser660) phosphorylation but does not induce peroxisome proliferator–activated receptor γ coactivator 1-α (PGC1α) expression.

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Mirabegron treatment increases hormone sensitive lipase (HSL) serine660 ...
(A and B) HSL phosphorylation on residue serine660 was characterized in abdominal s.c. white adipose tissue (WAT)before and after mirabegron treatment by IHC and quantified as described in Methods. Scale bars: 10 μM. (C) HSL phosphorylation on serine565 was determined by IHC. (D) PGC1A mRNA expression was determined by quantitative PCR as described in Methods. (E) PGC1α protein expression was determined by immunoblotting as described in Methods. Inset, PGC1α and actin immunoblots (uncropped blots are shown in Supplemental Figure 3). (F) The mitochondrial DNA/nuclear DNA ratio was determined as described in Methods. The data represent mean ± SEM. The data in B–F were analyzed by a paired student’s, 2-tailed t test (n = 6, except E [n = 3]; *P < 0.05).