Abstract
Obesity, caused by an increased number and volume of adipocytes, is a global epidemic that seriously threatens human health. Bone marrow mesenchymal stem cells (BMSCs) can differentiate into adipocytes. All-trans retinoic acid (atRA, the active form of vitamin A) inhibits the adipogenic differentiation of BMSCs through its receptor RARG. The expression level of FRA1 (FOS like 1, AP-1 transcription factor subunit) in atRA-treated BMSCs increased, suggesting that atRA-mediated inhibition of BMSCs adipogenesis involves FRA1. BMSCs were transfected with adenovirus overexpressing Fra1 (ad-fra1) or silenced for Fra1 (si-fra1) and then treated with atRA. BMSCs treated with atRA and treated with ad-fra1 showed decreased mRNA and protein levels of key adipogenic genes (Pparg2, Cebpa) and adipogenesis-associated genes (Cd36, Fabp, Lpl, and Plin); atRA had a stronger inhibitory effect on adipogenesis compared with that in the ad-fra1 group. Adipogenic gene expression in Fra1-silenced BMSCs was significantly upregulated. Compared with that in the atRA group, the si-fra1 + atRA also upregulated adipogenic gene expression. However, compared with si-fra1, si-fra1 + atRA significantly inhibited adipogenic differentiation. Chromatin immunoprecipitation showed that RARG directly regulates Fra1 and FRA1 directly regulates Pparg2 and Cebpa. The results supported the conclusion that atRA inhibits BMSC adipogenesis partially through the RARG-FRA1-PPARG2 or the CEBPA axis or both. Thus, vitamin A might be used to treat obesity and its related diseases.
Highlights
Obesity is considered a major health hazard and a global epidemic. e World Health Organization reported that in 2016, there were over 19 billion adults who were overweight, and 6.5 billion adults were obese
Bone marrow-derived Mesenchymal stem cells (MSCs) (BMSCs) are considered the main type of MSCs for laboratory research and clinical application [6]. e important pathophysiological mechanism of obesity is the increase in the number and volume of adipocytes. e increase in adipocytes is caused by the recruitment of new preadipocytes from MSCs [7]. e differentiation of MSCs is regulated by many factors, among which the most critical molecular interactions are the members of the CCAAT/enhancer binding protein (CEBP) and peroxisome proliferator-activated receptors (PPARs) families [8, 9]
Si-fra1 was infected at a Multiplicity of Infection (MOI) 100, 110, 120, 130, 150, 160, 180, and 200, and the intracellular fluorescence intensities were detected after 72 h of adenovirus transfection. e transfection efficiency, as determined by percentage of BMSCs containing green fluorescence, were 8.2%, 18.2%, 51.4%, 58.8%, 59.3%, 56.1%, 52.7%, and 66.1% at MOI of 100, 110, 120, 130, 150, 160, 180, and 200, respectively. ere was a significant difference between the result for a MOI 120 and that for 110
Summary
Obesity is considered a major health hazard and a global epidemic. e World Health Organization reported that in 2016, there were over 19 billion adults who were overweight, and 6.5 billion adults were obese (http://www. who.int/topics/obesity/en/). E differentiation of MSCs is regulated by many factors, among which the most critical molecular interactions are the members of the CCAAT/enhancer binding protein (CEBP) and peroxisome proliferator-activated receptors (PPARs) families [8, 9]. In vitro and in vivo studies have demonstrated atRA as a key regulator in adipose tissue metabolism and obesity [15,16,17]. Our previous study demonstrated that atRA could inhibit the adipogenic differentiation of BMSCs by downregulating the expression level of peroxisome proliferator-activated receptor gamma 2 (PPARG2) via its receptor retinoic acid receptor gamma (RARG) [18]. How atRA plays its role in regulating adipogenic differentiation remains unclear; the present study aimed to research the underlying signals
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