So-Young Kwak1, InHyeok Chung1, Joon Kang2, Nikolaos Perakakis3, Eun Hye Yoo1, Juhee Lee1, Hun Taek Jung2, Bo-Ram Mun4, Won-Seok Choi4, Oh Yoen Kim5, Seolsong Kim6, Eun-Kyoung Kim7, Hannah Oh1, Christos S Mantzoros3, Ji Hyung Chung8, Hyeon Soo Kim9, Min-Jeong Shin10. 1. Department of Public Health Sciences, BK21PLUS Program in Embodiment: Health-Society Interaction, Graduate School, Korea University, Seoul 02841, Republic of Korea. 2. Department of Biotechnology, CHA University, Gyeonggi-do 11160, Republic of Korea. 3. Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA 02215, USA. 4. School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea. 5. Department of Food and Nutrition, Dong-A University, Busan 49315, Republic of Korea. 6. Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea. 7. Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea; Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea. 8. Department of Biotechnology, CHA University, Gyeonggi-do 11160, Republic of Korea. Electronic address: jhchung@cha.ac.kr. 9. Department of Anatomy, Korea University College of Medicine, Seoul 02841, Republic of Korea. Electronic address: anatomykim@korea.ac.kr. 10. Department of Public Health Sciences, BK21PLUS Program in Embodiment: Health-Society Interaction, Graduate School, Korea University, Seoul 02841, Republic of Korea. Electronic address: mjshin@korea.ac.kr.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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 A1c, and glucose response area only in male participants. CONCLUSION: IF1 is involved in weight regulation by controlling food intake and potentially sympathetic nerve activation in a sex-specific manner.
BACKGROUND: 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. METHODS: 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. RESULTS: 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 A1c, and glucose response area only in male participants. CONCLUSION:IF1 is involved in weight regulation by controlling food intake and potentially sympathetic nerve activation in a sex-specific manner.