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 2

Suv420h2 regulates brown and beige fat development.

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Suv420h2 regulates brown and beige fat development. (A–D) UCP1 protein ...
(A–D) UCP1 protein levels (A), UCP1 immunostaining (B), H&E staining (C), and adipocyte size (D) in iBAT of 20-day-old H2KO and WT mice. In A, n = 4–5/group; in D, n = 3/group. In B, images are representatives from 3 replicate animals/group. Images from additional animals are located in Supplemental Figure 6A. Scale bar: 70µm in B and C. (E–H) UCP1 protein levels (E), UCP1 immunostaining (F), H&E staining (G) ,and adipocyte size (H) in iWAT of 20-day-old H2KO and WT mice. In E, n = 3/group; in H, n = 4/group. In F, images are representatives from 3 replicate animals/group. Images from additional animals are located in Supplemental Figure 6, B and C. Scale bar: 140 µm in F and G. (I–L) UCP1 protein levels (I), UCP1-immunostaining (J), H&E staining (K), and adipocyte size (L) in iBAT of 20-day-old AH2Tg and WT mice. In I, n = 4–5/group; in L, n = 3/group. In J, images are representatives from 3 replicate animals/group). Images from additional animals are located in Supplemental Figure 8A. Scale bar: 70 µm in J and K. (M–P) UCP1 protein levels (M), UCP1-immunostaining (N), H&E staining (O), and adipocyte size (P) in iWAT of 20-day-old AH2Tg and WT mice. In M and P, n = 3/group. In N, images are representatives from 3 replicate animals/group. Images from additional animals are located in Supplemental Figure 8, B and C. Scale bar: 140 µm in N and O. All data are expressed as mean ± SEM. 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. *P < 0.05 by unpaired 2-tailed Student’s t test in A, E, I, and M; *P < 0.05 as analyzed by 2-way ANOVA followed by Tukey’s multiple-comparison test in D, H, L, and P.