VCD-induced menopause mouse model reveals reprogramming of hepatic metabolism

Abstract

Menopause adversely impacts systemic energy metabolism and increases the risk of metabolic disease(s) including hepatic steatosis, but the mechanisms are largely unknown. Dosing female mice with vinyl cyclohexene dioxide (VCD) selectively causes follicular atresia in ovaries, leading to a murine menopause-like phenotype. In this study, we treated female C57BL6/J mice with VCD (160mg/kg i.p. for 20 consecutive days followed by verification of the lack of estrous cycling) to investigate changes in body composition, energy expenditure (EE), hepatic mitochondrial function, and hepatic steatosis across different dietary conditions. VCD treatment induced ovarian follicular loss and increased follicle-stimulating hormone (FSH) levels in female mice, mimicking a menopause-like phenotype. VCD treatment did not affect body composition, or EE in mice on a low-fat diet or in response to a short-term (1-week) high-fat, high sucrose diet (HFHS). However, the transition to a HFHS lowered cage activity in VCD mice. A chronic HFHS diet (16 weeks) significantly increased weight gain, fat mass, and hepatic steatosis in VCD-treated mice compared to HFHS-fed controls. In the liver, VCD mice showed suppressed hepatic mitochondrial respiration on LFD, while chronic HFHS diet resulted in compensatory increases in hepatic mitochondrial respiration. Also, liver RNA sequencing revealed that VCD promoted global upregulation of hepatic lipid/cholesterol synthesis pathways. Our findings suggest that the VCD- induced menopause model compromises hepatic mitochondrial function and lipid/cholesterol homeostasis that sets the stage for HFHS diet-induced steatosis while also increasing susceptibility to obesity.

Investigating the temporal effects of ovarian failure on single muscle fibre contractility using a chemically-induced ovarian failure model in mice

“…However, other studies using the VCD model have found similar results when force was measured at the onset of ovarian failure (D120; week 0) (Mashouri et al, 2024) but not always (Hinks et al, 2024;Hubbard et al, 2023). The initial increase in force observed at the onset of ovarian failure for the VCD group could be attributed, in part, to the relative increase in androgen levels (Kumari et al, 2023;Mashouri et al, 2024), potentially modulated by aromatization, which is the process of converting androgens to estrogens locally in skeletal muscles (Burger, 2001). Additionally, we found that the VCD group had larger CSA compared to the control group at the onset of (D120; week 0) ovarian failure (Figure 2), with no changes for specific force (Figure 3) for that timepoint, indicating that the increase in fibre CSA is likely not due to an increase in myofibrillar content.…”