Abstract
Adipose tissue is a key determinant of whole-body metabolism and energy homeostasis. Unravelling the transcriptional regulatory process during adipogenesis is therefore highly relevant from a biomedical perspective. In these studies, zinc finger protein B-cell lymphoma 6 (Bcl6) was demonstrated to have a role in early adipogenesis of mesenchymal stem cells. Bcl6 is enriched in preadipose versus non-preadipose fibroblasts and shows upregulated expression in the early stage of adipogenesis. Gain- and loss-of-function studies revealed that Bcl6 acts as a key regulator of adipose commitment and differentiation both in vitro and ex vivo. RNAi-mediated knockdown of Bcl6 in C3H10T1/2 cells greatly inhibited adipogenic potential, whereas Bcl6 overexpression enhanced adipogenic differentiation. This transcription factor also directly or indirectly targets and controls the expression of some early and late adipogenic regulators (i.e. Zfp423, Zfp467, KLF15, C/EBPδ, C/EBPα and PPARγ). We further identified that Bcl6 transactivated the signal transducers and activators of transcription 1 (STAT1), which was determined as a required factor for adipogenesis. Moreover, overexpression of STAT1 rescued the impairment of adipogenic commitment and differentiation induced by Bcl6 knockdown in C3H10T1/2 cells, thereby confirming that STAT1 is a downstream direct target of Bcl6. This study identifies Bcl6 as a positive transcriptional regulator of early adipose commitment.
Highlights
Obesity is a serious health problem worldwide caused by a chronic imbalance between energy expenditure and energy storage by adipose tissue and often promotes a range of chronic diseases, including atherosclerosis, hypertension and type 2 diabetes [1]
B-cell lymphoma 6 (Bcl6) mRNA was highly expressed in the 3T3-L1 preadipocytes, which have the greatest adipogenic potential in response to the standard hormonal cocktail when compared with the non-adipogenic fibroblasts; Bcl6 mRNA was expressed at moderate levels in multipotent C3H10T1/ 2 cells
The protein expression pattern during adipogenesis of C3H10T1/2 cells was significantly upregulated in the early stage, with the highest expression at day 2 detected by western blot analysis. These results indicate that Bcl6 is enriched in preadipocytes and adipose tissue, and its expression is upregulated during the early stage of mesenchymal stem cell (MSC) adipogenesis
Summary
Obesity is a serious health problem worldwide caused by a chronic imbalance between energy expenditure and energy storage by adipose tissue and often promotes a range of chronic diseases, including atherosclerosis, hypertension and type 2 diabetes [1]. Adipogenesis, which plays a key role in the hyperplasia of the fat cell, is defined as a two-step developmental process in which an undifferentiated mesenchymal stem cell (MSC) commits into a preadipocyte, which undergoes a terminal differentiation step to become a lipid-filled adipocyte [3,4]. Over the past two decades, the transcriptional networks controlling the process of terminal adipocyte differentiation have been extensively studied in committed preadipocyte cell lines, such as 3T3-L1 or 3T3-F442A [5,6]. This process is orchestrated by a transcriptional cascade involving the nuclear receptor peroxisome proliferator activated receptor-g (PPARg) and members of the CCAAT/enhancer-binding proteins (C/EBPs) family [7]. Recent efforts have focused on determining molecular factors that define the committed
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