Brd4 modulates diet-induced obesity via PPARγ-dependent Gdf3 expression in adipose tissue macrophages
Xiangming Hu, Xingchen Dong, Guo Li, Yanheng Chen, Jinjing Chen, Xiaoxin He, Hao Sun, Dong-Hyun Kim, Jongsook Kim Kemper, Lin-Feng Chen
Xiangming Hu, Xingchen Dong, Guo Li, Yanheng Chen, Jinjing Chen, Xiaoxin He, Hao Sun, Dong-Hyun Kim, Jongsook Kim Kemper, Lin-Feng Chen
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Research Article Metabolism

Brd4 modulates diet-induced obesity via PPARγ-dependent Gdf3 expression in adipose tissue macrophages

Abstract

Macrophage-mediated inflammatory response has been implicated in the pathogenesis of obesity and insulin resistance. Brd4 has emerged as a key regulator in the innate immune response. However, the role of Brd4 in obesity-associated inflammation and insulin resistance remains uncharacterized. Here, we demonstrated that myeloid lineage-specific Brd4 knockout (Brd4-CKO) mice were protected from high-fat diet–induced (HFD-induced) obesity with less fat accumulation, higher energy expenditure, and increased lipolysis in adipose tissue. Brd4-CKO mice fed a HFD also displayed reduced local and systemic inflammation with improved insulin sensitivity. RNA-Seq of adipose tissue macrophages (ATMs) from HFD-fed WT and Brd4-CKO mice revealed that expression of antilipolytic factor Gdf3 was significantly decreased in ATMs of Brd4-CKO mice. We also found that Brd4 bound to the promoter and enhancers of Gdf3 to facilitate PPARγ-dependent Gdf3 expression in macrophages. Furthermore, Brd4-mediated expression of Gdf3 acted as a paracrine signal targeting adipocytes to suppress the expression of lipases and the associated lipolysis in cultured cells and mice. Controlling the expression of Gdf3 in ATMs could be one of the mechanisms by which Brd4 modulates lipid metabolism and diet-induced obesity. This study suggests that Brd4 could be a potential therapeutic target for obesity and insulin resistance.

Authors

Xiangming Hu, Xingchen Dong, Guo Li, Yanheng Chen, Jinjing Chen, Xiaoxin He, Hao Sun, Dong-Hyun Kim, Jongsook Kim Kemper, Lin-Feng Chen

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Figure 3

Brd4-CKO mice had reduced expression of Gdf3 in ATMs.

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Brd4-CKO mice had reduced expression of Gdf3 in ATMs. (A) PCA of RNA-Se...
(A) PCA of RNA-Seq data derived from CD11b+ ATMs of WT and Brd4-CKO mice fed a HFD for 20 weeks. (B) Volcano plot of mRNA-Seq analysis in ATMs as indicated in A. Brown dots represent genes increased in ATMs of Brd4-CKO mice vs. WT mice (fold change ≥ 2, adjusted P value ≤ 0.001, calculated by raw count value). Blue dots represent genes decreased in ATMs of Brd4-CKO mice vs. WT mice (fold change ≥ 2, adjusted P value ≤ 0.001, calculated by raw count value). Gray dots represent genes without significantly altered expression. Clusters of significantly altered genes (fold change ≥ 2, adjusted P value ≤ 0.001, calculated by raw count value) were identified using gene ontology terms (C) and KEGG pathways (D). (E) Heat map of the relative expression levels (scaled Z-score) of cytokine-cytokine receptor interaction-related genes clustered in (D). (F) mRNA levels of Gdf3 in CD11b+ ATMs isolated from WT or Brd4-CKO mice fed a HFD for 20 weeks. (G) Left panel: Gdf3 or F4/80 IHC staining of eWAT of WT or Brd4-CKO mice fed a HFD for 20 weeks. Right panel: statistical analysis of Gdf3-positive or F4/80-positive area percentage, the ratio of Gdf3-positive cells in F4/80-positive cells in eWAT of WT and Brd4-CKO mice fed a HFD. Data are mean and SD and are determined by an unpaired 2-tailed Student’s t test. n = 3 mice. **P < 0.01. Brd4-CKO, myeloid lineage-specific Brd4 knockout; HFD, high-fat diet–induced; eWAT, epididymal WAT; ATMs, adipose tissue macrophages; PCA, principal component analysis.