Lee Kyoungran, Um Sung Hee, Rhee Dong Kwon, Pyo Suhkneung
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea.
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 16419, Republic of Korea.
Biochim Biophys Acta. 2016 Nov;1860(11 Pt A):2416-2427. doi: 10.1016/j.bbagen.2016.07.009. Epub 2016 Jul 15.
Adipose tissue regulates energy metabolism by means of adipocyte hypertrophy and/or the differentiation of pre-existing adipocytes. Excessive production of some cytokines in adipose tissue is known to be a negative regulator of adipocyte differentiation, and the resulting impaired adipogenesis contributes to disorders like insulin resistance. IFN-α is a key immunoregulatory cytokine in the development of type 1 diabetes, lipid disorders and insulin resistance; however, its effect on adipogenesis remains unknown.
We examined the effect of IFN-α on adipocyte differentiation and its mechanisms. The effect of IFN-α on adipogenesis was evaluated by Western blotting, qRT-PCR, flow cytometric analysis and Oil Red O staining. We also investigated the role of STAT1 in adipogenesis using gene silencing analysis.
IFN-α inhibited the accumulation of lipid droplets and the expression of adipogenesis related genes. The inhibition of adipocyte differentiation by IFN-α occurred in the early stages of differentiation. IFN-α arrested the cell cycle at the G0/G1 phase and regulated the expression of CDK2 and p21. These results were confirmed in MEF cells. Treatment with IFN-α increased STAT1 phosphorylation, and STAT1 siRNA or inhibitor prevented IFN-α from inhibiting the expression of PPARγ and C/EBPα as well as cell cycle progression in 3T3-L1 cells.
We suggest that IFN-α inhibits adipocyte differentiation during the early stage of adipogenesis by regulating the expression of PPARγ and C/EBPα as well as the cell cycle through JAK/STAT1 signaling pathways.
Our study provides new insights into possible mechanisms of the anti-adipogenetic effects of IFN-α.
脂肪组织通过脂肪细胞肥大和/或已存在的脂肪细胞分化来调节能量代谢。已知脂肪组织中某些细胞因子的过度产生是脂肪细胞分化的负调节因子，由此导致的脂肪生成受损会引发胰岛素抵抗等疾病。IFN-α是1型糖尿病、脂质紊乱和胰岛素抵抗发生发展过程中的关键免疫调节细胞因子；然而，其对脂肪生成的影响尚不清楚。
我们研究了IFN-α对脂肪细胞分化及其机制的影响。通过蛋白质免疫印迹法、定量逆转录聚合酶链反应、流式细胞术分析和油红O染色评估IFN-α对脂肪生成的影响。我们还使用基因沉默分析研究了信号转导和转录激活因子1（STAT1）在脂肪生成中的作用。
IFN-α抑制脂滴积累和脂肪生成相关基因的表达。IFN-α对脂肪细胞分化的抑制发生在分化早期。IFN-α使细胞周期停滞在G0/G1期，并调节细胞周期蛋白依赖性激酶2（CDK2）和p21的表达。这些结果在小鼠胚胎成纤维细胞（MEF细胞）中得到证实。IFN-α处理可增加STAT1磷酸化，而STAT1小干扰RNA或抑制剂可阻止IFN-α抑制3T3-L1细胞中过氧化物酶体增殖物激活受体γ（PPARγ）和CCAAT增强子结合蛋白α（C/EBPα）的表达以及细胞周期进程。
我们认为，IFN-α在脂肪生成早期通过JAK/STAT1信号通路调节PPARγ和C/EBPα的表达以及细胞周期，从而抑制脂肪细胞分化。
我们的研究为IFN-α抗脂肪生成作用的可能机制提供了新的见解。
