Zic1 Negatively Regulates The Brown Adipogenesis Differentiation In C3H10T1/2

When energy intake is greater than the total energy consumption, the excess energy will be stored as triglyceride. Obesity occurs when energy intake exceeds energy expenditure. The rates of obesity continue to increase exponentially, and reached epidemic proportions worldwide, exerting major health consequences at an individual and public health level alike. These findings are particularly alarming, as obesity is a major risk factor for insulin resistance and T2DM. An important public health goal, then, should be to prevention obesity and its related disease.Brown adipose tissue (BAT) has received great attention for the treatment of obesity. As a thermogenicadipose tissue, brown adipose tissuecould release chemical energy in the form of heat by comsuming excess fat. Results from our rodent studies indicate that BAT transplantation ameliorate insulin resistance and improvesthe glycemic index in both Diet-induced obesity (DIO) and genetic obesity (Ob/Ob). Thus, BAT may be a promising target to treat obesity and its related diseases.If BAT can be activated efficiently or trans-differentiate a portion of white adipose tissue to BAT, a significant advance would be made in the prevention and treatment of obesity. Recently, C/EBP and PRDM16 were showed that could convert fibroblasts to brown adipocytes.Zinc fingers in the cerebellum 1 (Zic1), is known to regulate neurogenesis and myogenesis in the developmental stage, is widely used as one of brown adipocyte specific markers. However, the function of Zicl in brown adipogenesis is unknown. Therefore, we examined the effect of Zicl on brown adipogenesis in C3H10T1/2 mesenchymal stem cells. Interestingly, lipid accumulation and the expressions of PPARy2 and C/EBPa that are master regulators of adipogenesis were attenuated by Zicl overexpression. In addition, the expressions of PRDM16, PGC-la and UCP1, BAT specific thermogenic genes, also decreased by Zic1 overexpression. In parallel, the levels of the fatty acid oxidation regulatory genes such as PPARα, CPT1α, CPT1β and COX7α1 were decreased by Zicl overexpression. Moreover, Zic1 suppressed the protein expressions of ATP5a, UQCRC2, SDHB and NDUFB5, mitochondrial OXPHOS regulatory proteins.Taken together, our results clearly show that Zicl is a negative regulator of brown adipogenesis by suppressing adipogenesis, fatty acid oxidation and OXPHOS. Thus discover Zic1 inhibito(s) that effectively increase amount of BAT, might open up new methods to prevent or treat obesity.