Abstract
High-mobility group box 2 (HMGB2) is an abundant, chromatin-associated protein that plays an essential role in the regulation of transcription, cell proliferation, differentiation, and tumorigenesis. However, the underlying mechanism of HMGB2 in adipogenesis remains poorly known. Here, we provide evidence that HMGB2 deficiency in preadipocytes impedes adipogenesis, while overexpression of HMGB2 increases the potential for adipogenic differentiation. Besides, depletion of HMGB2 in vivo caused the decrease in body weight, white adipose tissue (WAT) mass, and adipocyte size. Consistently, the stromal vascular fraction (SVF) of adipose tissue derived from hmgb2−/− mice presented impaired adipogenesis. When hmgb2−/− mice were fed with high-fat diet (HFD), the body size, and WAT mass were increased, but at a lower rate. Mechanistically, HMGB2 mediates adipogenesis via enhancing expression of C/EBPβ by binding to its promoter at “GGGTCTCAC” specifically during mitotic clonal expansion (MCE) stage, and exogenous expression of C/EBPβ can rescue adipogenic abilities of preadipocytes in response to HMGB2 inhibition. In general, our findings provide a novel mechanism of HMGB2-C/EBPβ axis in adipogenesis and a potential therapeutic target for obesity.
Highlights
White adipose tissue (WAT) involves in caloric storage and consumption and plays a considerable role in regulating energy balance and glucose homeostasis [1, 2]
Transcriptome analysis was performed on inguinal WAT (ingWAT) derived from hmgb2−/− mice and WT mice, and the results indicated that the key genes closely related to adipogenesis, such as CCAAT/enhancer-binding protein-β (C/EBPβ), C/EBPδ, peroxisome proliferator-activated receptor-γ (PPARγ), KLF4, and C/EBPα, were all downregulated in hmgb2−/− mice (Supplementary Fig. 4a–f)
These results indicated that the effective studies have focused on C/EBPβ as a target gene bound by other promoter regions of C/EBPβ bound by High-mobility group box 2 (HMGB2) was mainly located transcription factor in adipocyte differentiation, except KLF4 [48]
Summary
White adipose tissue (WAT) involves in caloric storage and consumption and plays a considerable role in regulating energy balance and glucose homeostasis [1, 2]. After being stimulated by adipogenic inducers, the growth-arrested 3T3-L1 preadipocytes re-enter a specific cell-cycle period, termed as mitotic clonal expansion (MCE) [12, 13] In this stage, the number of cells increases about fourfold and terminal differentiation is activated [14, 15]. HMGB2 regulates muscle regeneration and enhance human topoisomerase in tumors [31, 32] It highly expresses in undifferentiated mesenchymal stem cells (MSC) and coordinates with platelet-derived growth factor receptor-α (PDGFRα) to regulate adipocytes differentiation through early adipogenic signal cascade [33].
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