Department of Public Health Sciences, BK21PLUS Program in Embodiment: Health-Society Interaction, Graduate School, Korea University, Seoul 02841, Republic of Korea.
Department of Biotechnology, CHA University, Gyeonggi-do 11160, Republic of Korea.
Metabolism. 2020 Apr;105:154171. doi: 10.1016/j.metabol.2020.154171. Epub 2020 Jan 30.
Based on the metabolic effect of exogenous ATPase inhibitory factor 1 (IF1) on glucose metabolism, we tested whether IF1 treatment is effective in ameliorating weight gain and whether its effects are sex specific.
HFD-fed C57BL/6 mice were treated with IF1 (5 mg/kg body weight, injected intraperitoneally). The underlying mechanisms of effect of IF1 on body weight were investigated in vitro and in vivo. Associations between genotypes of IF1 and obesity and relevant phenotype were further tested at the population level.
Chronic treatment with IF1 significantly decreased body weight gain by regulating food intake of HFD-fed male mice. IF1 activated the AKT/mTORC pathway and modulated the expression of appetite genes in the hypothalamus of HFD-fed male mice and its effect was confirmed in hypothalamic cell lines as well as hypothalamic primary cells. This required the interaction of IF1 with β-F1-ATPase on the plasma membrane of hypothalamic cells, which led to an increase in extracellular ATP production. In addition, IF1 treatment showed sympathetic nerve activation as measured by serum norepinephrine levels and UCP-1 expression in the subcutaneous fat of HFD-fed male mice. Notably, administration of recombinant IF1 to HFD-fed ovariectomized female mice showed remarkable reductions in food intake as well as body weight, which was not observed in wild-type 5-week female mice. Lastly, sex-specific genotype associations of IF1 with obesity prevalence and metabolic traits were demonstrated at the population level in humans. IF1 genetic variant (rs3767303) was significantly associated with lower prevalence of obesity and lower levels of body mass index, waist circumference, hemoglobin A, and glucose response area only in male participants.
IF1 is involved in weight regulation by controlling food intake and potentially sympathetic nerve activation in a sex-specific manner.
基于外源性 ATP 酶抑制因子 1（IF1）对葡萄糖代谢的代谢作用，我们测试了 IF1 治疗是否能有效改善体重增加，以及其作用是否具有性别特异性。
用 IF1（5mg/kg 体重，腹腔注射）处理高脂肪饮食喂养的 C57BL/6 小鼠。在体外和体内研究了 IF1 对体重的影响的潜在机制。在人群水平上进一步测试了 IF1 基因型与肥胖症和相关表型之间的关联。
慢性给予 IF1 通过调节高脂肪饮食喂养的雄性小鼠的食物摄入量，显著降低了体重增加。IF1 激活了 AKT/mTORC 通路，并调节了高脂肪饮食喂养的雄性小鼠下丘脑食欲基因的表达，其作用在下丘脑细胞系和下丘脑原代细胞中得到了证实。这需要 IF1 与质膜上的β-F1-ATPase 相互作用，导致细胞外 ATP 产量增加。此外，IF1 治疗显示出交感神经激活，表现为血清去甲肾上腺素水平升高和高脂肪饮食喂养的雄性小鼠皮下脂肪中 UCP-1 的表达增加。值得注意的是，给予重组 IF1 治疗高脂肪饮食喂养的去卵巢雌性小鼠，可显著减少食物摄入量和体重，而在野生型 5 周龄雌性小鼠中则没有观察到这种情况。最后，在人群水平上证明了 IF1 与肥胖症患病率和代谢特征的性别特异性基因型关联。IF1 遗传变异（rs3767303）与肥胖症患病率降低和身体质量指数、腰围、血红蛋白 A 和葡萄糖反应面积降低显著相关，仅在男性参与者中。
IF1 通过控制食物摄入和潜在的交感神经激活来调节体重，其作用具有性别特异性。
