Mitochondrial ATP synthase catalyzes the coupling step of oxidative phosphorylation. Under pathologic conditions, ATP synthase hydrolyzes ATP to replenish protons from the matrix into the intermembrane space, sustaining mitochondrial membrane potential. ATPase inhibitory factor 1 (IF1) is an ATP synthase-interacting protein that selectively inhibits the hydrolysis activity of ATP synthase to preserve ATP. The role of IF1 in patients with obesity and type 2 diabetes(T2D) has been reported recently but the in vivo role of IF1 in metabolic regulation in obesity and T2D remains unclear. To understand IF1 in the development of insulin resistance and T2D, we first assess IF1 expression in adipose and skeletal tissues in mice subjected to a high-fat diet (HFD). We found that IF1 transcript expression is upregulated in adipose, but reduced in skeletal muscle of the HFD-fed mice. IF1 knockout mice subjected to HFD showed a substantially slower increase of body weight in adult mice despite a similar food intake and body composition analysis using Magnetic resonance imaging(MRI) revealed that IF1 KO mice had less fat mass than WT mice littermates .Morphometric measurements showed that gonadal, subcutaneous and mesenteric fat mass were relatively lower than those of WT mice. Glucose and insulin tolerance assay revealed that IF1 KO mice impaired glucose and insulin tolerances after HFD feeding. Biochemical assays further revealed that the relatively lower fat mass in the IF1 KO mice was concomitant with increased circulating triglyceride and free fatty acids (FFA) levels. As a result, Gastrocnemius skeletal muscles showed increased triglyceride and FFA contents. Taken together, studies on the IF1 KO mice subjected to HFD uncover that IF1 is an important metabolic regulating factor that affects the development HFD-induced insulin resistance, probably due to an impairment in adipogenesis and skeletal muscle lipid accumulation.
F. Huang: None. K. Yang: None. K. Saja: None. Y. Huang: None. Q. Long: None. M. Yoshida: None. Q. Yang: None.