Aster-B–dependent estradiol synthesis protects female mice from diet-induced obesity
Xu Xiao, … , John W.R. Schwabe, Peter Tontonoz
Xu Xiao, … , John W.R. Schwabe, Peter Tontonoz
Published January 4, 2024
Citation Information: J Clin Invest. 2024;134(4):e173002. https://doi.org/10.1172/JCI173002.
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Research Article Metabolism

Aster-B–dependent estradiol synthesis protects female mice from diet-induced obesity

Abstract

Aster proteins mediate the nonvesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). However, the importance of nonvesicular sterol movement for physiology and pathophysiology in various tissues is incompletely understood. Here we show that loss of Aster-B leads to diet-induced obesity in female but not in male mice, and that this sex difference is abolished by ovariectomy. We further demonstrate that Aster-B deficiency impairs nonvesicular cholesterol transport from the PM to the ER in ovaries in vivo, leading to hypogonadism and reduced estradiol synthesis. Female Aster-B–deficient mice exhibit reduced locomotor activity and energy expenditure, consistent with established effects of estrogens on systemic metabolism. Administration of exogenous estradiol ameliorates the diet-induced obesity phenotype of Aster-B–deficient female mice. These findings highlight the key role of Aster-B–dependent nonvesicular cholesterol transport in regulating estradiol production and protecting females from obesity.

Authors

Xu Xiao, John P. Kennelly, An-Chieh Feng, Lijing Cheng, Beatriz Romartinez-Alonso, Alexander Bedard, Yajing Gao, Liujuan Cui, Stephen G. Young, John W.R. Schwabe, Peter Tontonoz

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Figure 4

Loss of Aster-B causes hypercholesterolemia in female mice.

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Loss of Aster-B causes hypercholesterolemia in female mice. (A) Intraper...
(A) Intraperitoneal insulin tolerance test (1 U kg−1) administered after 10 weeks of WD feeding; n = 6 WT and 10 Aster-B–KO mice. (B) Intraperitoneal glucose tolerance test (1 mg kg−1) administered after 10 weeks of WD feeding; n = 7 WT and 10 Aster-B–KO mice. (C–E) Plasma insulin, glycerol, and NEFA in female WT and Aster-B–KO mice after 24 hours fasting and refeeding for 2 hours; n = 7 WT and 7 Aster-B–KO mice. (F and G) Total liver cholesterol (F) and triglyceride (G) in female WT and Aster-B–KO mice after 10 weeks of WD feeding. n = 10 WT and 10 Aster-B–KO mice. (H) Plasma total cholesterol in female WT and Aster-B–KO mice after 10 weeks of WD feeding; n = 9 WT and 13 Aster-B–KO mice. (I) Cholesterol content of plasma lipoproteins fractionated from female WT and Aster-B–KO mice after 10 weeks of WD feeding by FPLC. (J) Plasma triglyceride in female mice after 10 weeks of WD feeding; n = 10 WT and 12 Aster-B–KO mice. All data are presented as mean ± SEM. P values were determined by 2-tailed t test of the AUC (A and B), 1-way ANOVA (C–E) or 2-sided Student’s t test (F, G, H, and J). *P < 0.05, **P < 0.01.