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.
Bibliographical noteFunding Information:
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [ NRF-2018R1D1A1B07042376 ]; the Ministry of Science and ICT [ NRF-2019R1F1A1063744 ].
This study was conducted with bioresources from National Biobank of Korea, the Centers for Disease Control and Prevention, Republic of Korea (KBP-2018-037, KBP-2019-041). So-Young Kwak: Formal analysis, Investigation, Resources, Writing - Original Draft, Writing - Review & Editing and Visualization; InHyeok Chung: Investigation, Resources, Writing - Review & Editing and Visualization; Joon Kang: Investigation and Resources; Nikolaos Perakakis: Writing - Original Draft; Eun Hye Yoo: Investigation, Resources and Visualization; Juhee Lee: Investigation, Resources and Visualization; Hun Taek Jung: Investigation and Resources; Bo-Ram Mun: Resources; Won-Seok Choi: Resources; Oh Yoen Kim: Resources; Seolsong Kim: Resources and Visualization; Eun-Kyoung Kim: Resources and Visualization; Hannah Oh: Writing - Original Draft; Christos S. Mantzoros: Writing - Original Draft; Ji Hyung Chung: Conceptualization, Investigation, Methodology, Resources, Writing - Original Draft and Project administration: Hyeon Soo Kim: Conceptualization, Methodology, and Project administration; Min-Jeong Shin: Conceptualization, Methodology, Investigation, Writing - Original Draft, Writing - Review & Editing, Project administration and Funding acquisition. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [NRF-2018R1D1A1B07042376]; the Ministry of Science and ICT [NRF-2019R1F1A1063744]. The authors declare no conflict of interest.
© 2020 Elsevier Inc.
- ATPase inhibitory factor 1
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism