(A) Illustration of the experimental timeline. OVX was performed on WT or LTCFDN mice at the age of 5 weeks. After 1-week recovery, mice were fed with HFD, with or without E2 injection. (B–E) Comparison of weekly recorded body weight gain (panel B), IPITT (panel C), final-day body weight (panel D), and the liver as well as fat weight (panel E) in OVX-treated and HFD-challenged WT littermate controls, with or without E2 injection. (F–I) The above assessments in LTCFDN female mice. (J–K) Serum and hepatic TG content in indicated group of mice. (L–M) Western blotting shows the detection of p-ACC (Ser79), SREBP-1c and ChREBP in OVX treated and HFD-challenged WT mice (L) or LTCFDN (M), with and without E2 reconstitution. (N–O) Comparison of the 5 lipogenic gene mRNA expression in OVX treated and HFD-challenged WT (N) or LTCFDN (O) mice without and with E2 administration. N = 3–5 for panels B–O. Values represent mean ± SD. Underlying numerical values can be found in S1 Data. ACC, acetyl-coA carboxylase; ChREBP, carbohydrate-responsive element-binding protein; CON, control; E2, estradiol; EHHADH, enoyl-coA hydratase and 3-hydroxyacyl coA; Fas, fatty acid synthase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HFD, high-fat diet; IPITT, intraperitoneal insulin tolerance test; ME1, cytosolic malic enzyme 1; OVX, ovariectomy; p-ACC, phosphorylated acetyl-coA carboxylase; SCD-1, stearoyl-coA desaturase-1; SREBP-1c, sterol regulatory element-binding protein 1-c; TG, triglyceride; WT, wild-type.