Sex specific effect of ATPase inhibitory factor 1 on body weight: studies in high fat diet induced obese mice and genetic association studies in humans

Kwak, So Young; Chung, In Hyeok; Kang, Joon Ho; Perakakis, Nikolaos; Yoo, Eun Sun; Lee, Juhee; Jung, Hun Taek; Mun, Bo Ram; Choi, Won Seok; Kim, Oh Yoen; Kim, Seolsong; Kim, Eun Kyoung; Oh, Hyuncheol; Mantzoros, Christos S.; Chung, Ji Hyung; Kim, Hyeon Soo; Shin, Min Jeong

doi:10.1016/j.metabol.2020.154171

Cited by 8 publications

(6 citation statements)

References 37 publications

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“…Obesity and impairment in glucose metabolism have been established as risk factors for type 2 diabetes, 25,26 of which the age standardized prevalence worldwide has increased since 1980. 27 BGN has recently been suggested as a signaling molecule distinct from its role as an ECM component. 28 Nevertheless, the metabolic effects of BGN as a ligand have remained unknown.…”

Section: Discussionmentioning

confidence: 99%

Biglycan reduces body weight by regulating food intake in mice and improves glucose metabolism through AMPK/AKT dual pathways in skeletal muscle

Chung

Kim

et al. 2021

FASEB j.

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While biglycan (BGN) is suggested to direct diverse signaling cascades, the effects of soluble BGN as a ligand on metabolic traits have not been studied. Herein, we tested the effects of BGN on obesity in high-fat diet (HFD)-induced obese animals and glucose metabolism, with the underlying mechanism responsible for observed effects in vitro. Our results showed that BGN administration (1 mg/kg body weight, intraperitoneally) significantly prevented HFD-induced obesity, and this was mainly attributed to reduced food intake. Also, intracerebroventricular injection of BGN reduced food intake and body weight. The underlying mechanism includes modulation of neuropeptides gene expression involved in appetite in the hypothalamus in vitro and in vivo. In addition, BGN regulates glucose metabolism as shown by improved glucose tolerance in mice as well as AMPK/AKT dual pathway-driven enhanced glucose uptake and GLUT4 translocation in L6 myoblast cells. In conclusion, our 2 of 14 | CHUNG et al.

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Section: Discussionmentioning

confidence: 99%

Biglycan reduces body weight by regulating food intake in mice and improves glucose metabolism through AMPK/AKT dual pathways in skeletal muscle

Chung

Kim

et al. 2021

FASEB j.

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“…The relationship between IF1 and glucose homeostasis is also supported by genetics in humans. In a Korean male population, the IF1 genetic variant rs3767303 was independently associated with a lower prevalence of obesity and lower BMI, waist circumference, and HbA 1c [34]. More importantly, our study found that the plasma IF1 level was lower in diabetic participants from the MAPT study and in pre-diabetic individuals from the IT-DIAB study who later developed T2D.…”

Section: Discussionmentioning

confidence: 47%

“…In this respect, recombinant IF1 (rIF1), produced without an MTS has been reported to compete the with apoA-I binding site on ecto-F 1 -ATPase [28] and to control different physiological processes. For instance, treatment of mice with rIF1, which solely targets ecto-F 1 -ATPase, has been shown to inhibit hepatic HDL uptake and apoA-I-mediated nitric oxide production while also improving glucose tolerance [24,25,34]. As a marker, plasma IF1 may re ect both cell surface and mitochondrial ATP synthase activity.…”

Section: Discussionmentioning

confidence: 99%

Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: a prospective cohort study

Silva

Wargny

Raffin

et al. 2022

Preprint

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Background: Mitochondrial dysfunction is associated with the development of type 2 diabetes (T2D). It is thus of clinical relevance to identify plasma biomarkers of mitochondrial dysfunction associated with the risk of T2D.ATPase inhibitory factor 1 (IF1) endogenously inhibits mitochondrial ATP synthase activity. Here, we analyzed association of the plasma IF1 level with markers of glucose homeostasis and with the conversion to new-onset diabetes (NOD) in individuals with prediabetes.Methods: In the IT-DIAB prospective study, the plasma level of IF1 was measured at baseline in 307 participants with prediabetes, defined as a moderately elevated fasting plasma glucose, i.e., 110–125 mg/dL (6.0–7.0 mmol/L). The primary outcome was the incidence of NOD, defined as the first fasting plasma glucose value ≥ 1.26 g/L (7.0 mmol/L) within five years of follow-up. Cross-sectional analysis of the IF1 level was also done in two independent interventional studies. Correlations between plasma IF1 and metabolic parameters at baseline were assessed by Spearman’s correlation coefficients, and the association with the risk of NOD was determined using Cox proportional‐hazards models.Results: In IT-DIAB, the mean IF1 plasma level was lower in participants who developed NOD than in those who did not (537 ± 248 versus 621 ± 313 ng/mL, p=0.01). The plasma IF1 level negatively correlated with clinical variables associated with obesity and insulin resistance, including the BMI (r = -0.20, p=0.0005) and HOMA-IR (r = -0.37, p<0.0001). Conversely, IF1 was positively associated with plasma markers of cardiometabolic health, such as HDL-C (r = 0.63, p<0.0001) and apoA-I (r = 0.33, p<0.0001). These correlations were confirmed in cross-sectional analyses. In IT-DIAB, the IF1 level was significantly associated with a lower risk of T2D after adjustment for age, sex, and fasting plasma glucose (HR [95% CI] per 1 SD = 0.76 [0.64; 0.94], p=0.012).Conclusion: We identified for the first time the mitochondrial-related biomarker IF1 as being associated with the risk of T2D. As a biomarker, circulating IF1 can be considered to be a surrogate of mitochondrial energetics. IF1 can potentially be used to select patients for clinical trials of therapeutics that target mitochondrial function.

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“…The relationship between IF1 and glucose homeostasis is also supported by genetics in humans. In a Korean male population, the IF1 genetic variant rs3767303 was independently associated with a lower prevalence of obesity and lower BMI, waist circumference, and HbA 1c [34]. More importantly, our study found that the plasma IF1 level was lower in diabetic participants from the MAPT study and in prediabetic individuals from the IT-DIAB study who later developed T2D.…”

Section: Discussionmentioning

confidence: 47%

Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: A prospective cohort study

Silva

Wargny²,

Raffin³

et al. 2023

Diabetes & Metabolism

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Sex specific effect of ATPase inhibitory factor 1 on body weight: studies in high fat diet induced obese mice and genetic association studies in humans

Cited by 8 publications

References 37 publications

Biglycan reduces body weight by regulating food intake in mice and improves glucose metabolism through AMPK/AKT dual pathways in skeletal muscle

Biglycan reduces body weight by regulating food intake in mice and improves glucose metabolism through AMPK/AKT dual pathways in skeletal muscle

Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: a prospective cohort study

Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: A prospective cohort study

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