The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis
Xin Cui, Qiang Cao, Fenfen Li, Jia Jing, Zhixue Liu, Xiaosong Yang, Gary J. Schwartz, Liqing Yu, Huidong Shi, Hang Shi, Bingzhong Xue
Xin Cui, Qiang Cao, Fenfen Li, Jia Jing, Zhixue Liu, Xiaosong Yang, Gary J. Schwartz, Liqing Yu, Huidong Shi, Hang Shi, Bingzhong Xue
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Research Article Metabolism

The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis

Abstract

Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Here we discover that histone methyltransferase suppressor of variegation 4–20 homolog 2 (Suv420h2) expression parallels that of Ucp1 in brown and beige adipocytes and that Suv420h2 knockdown significantly reduces — whereas Suv420h2 overexpression significantly increases — Ucp1 levels in brown adipocytes. Suv420h2 knockout (H2KO) mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study shows that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4e-bp1) promoter, leading to downregulated expression of 4e-bp1, a negative regulator of the translation initiation complex. This in turn upregulates PGC1α protein levels, and this upregulation is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.

Authors

Xin Cui, Qiang Cao, Fenfen Li, Jia Jing, Zhixue Liu, Xiaosong Yang, Gary J. Schwartz, Liqing Yu, Huidong Shi, Hang Shi, Bingzhong Xue

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Figure 4

AH2Tg mice have enhanced cold-induced thermogenesis.

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AH2Tg mice have enhanced cold-induced thermogenesis. (A and B) Core body...
(A and B) Core body temperature (A) and fat pad weight (B) in 3-month-old male WT and AH2Tg mice during a 7-day cold challenge at 5°C. In A, n = 6–7/group. In B, n = 7/group. (C and D) H&E staining (C) and adipocyte size (D) in iBAT and iWAT of WT and AH2Tg mice after the 7-day cold challenge. In C, scale bar: 70µm for iBAT and 140μm for iWAT. In D, n = 3/group in iBAT and n = 4/group in iWAT. (E and F) Gene expression analysis in iBAT (E) and iWAT (F) of WT and AH2Tg mice after the 7-day cold challenge, n = 7/group in E and n = 8/group in F.(G and H) UCP1 protein and H4K20me3 levels in iBAT (G) and iWAT (H) of WT and AH2Tg mice after the 7-day cold challenge, n = 3/group. (I) UCP1 immunostaining in iBAT and iWAT of WT and AH2Tg mice after the 7-day cold challenge (representative images from 3 replicate animals/group). Images from additional animals can be found in Supplemental Figure 10, A–C. UCP1+ multilocular brown/beige adipocytes are shown in dark purplish red color and are indicated with black arrows; UCP1– unilocular white adipocytes are shown in light color and are indicated with red arrows. Scale bar: 70 µm for iBAT and 140 μm for iWAT. (J) Oxygen consumption rate (OCR) in primary brown adipocytes isolated from iBAT of male WT and AH2Tg mice measured by a Seahorse XF 96 Extracellular Flux Analyzer, n = 8 (WT) and 9 (H2KO). All data are expressed as mean ± SEM. *P < 0.05 by 2-way ANOVA with repeated measures followed by Tukey’s multiple-comparison test in A and in left panel of J; *P < 0.05 by unpaired 2-tailed Student’s t test in E–H and in right 2 panels of J; *P < 0.05 by 2-way ANOVA followed by Tukey’s multiple-comparison test in E.