Pseudo-starvation driven energy expenditure negatively affects ovarian follicle development

Objective: Conditions of reduced energy availability negatively affect female fertility. We examined whether a change in whole body energy fluxes away from the ovary could affect follicular development, employing mice ectopically expressing uncoupling protein 1 in skeletal muscle (UCP1-TG). We especially addressed insulin-like growth factor 1 (IGF1), a growth factor playing an important role in the regulation of both substrate metabolism and female fertility. Methods: Female UCP1-TG and wild-type (WT) mice were killed at 12 weeks postpartum. Energy intake, expenditure, activity, body weight and length, and body composition were measured. Plasma insulin, glucose, leptin and IGF1 levels were analysed. Ovaries were serial sectioned and follicle and corpora lutea numbers were counted. IGF1 signalling was analysed by immunohistochemical staining for activation of insulin receptor substrate 1/2 (IRS1/2) and AKT. Results: UCP1-TG female mice had increased energy expenditure, reduced body size, maintained adiposity, and decreased IGF1 concentrations compared to their WT littermates. Preantral and antral follicle numbers were reduced by 40% and 60%, respectively, in UCP1-TG mice, compared to WT mice. Corpora lutea (CL) were absent in 40% of the ovaries of UCP1-TG mice. No difference in total and phospho-IRS2 immunostaining was observed between WT and UCP1-TG ovaries. Phospho-IRS1, phosho-AKT -Ser473 and -Thr308 immunostaining was present in granulosa cells of antral follicles in WT ovaries, but faint to absent in antral follicles of UCP1-TG mice.Conclusion: The reduction in circulating IGF1 levels due to ectopic expression of UCP1 leads to areduced activation of the IRS1-PI3/AKT pathway negatively affecting normal ovarian follicle development and ovulation.