Pseudo-Starvation Driven Energy Expenditure Negatively Affects Ovarian Follicle Development.

Li Meng,Yu Zhao,Susanne Klaus,Annelies Bunschoten,Jaap Keijer,Katja Teerds,Verena Coleman,Anja Voigt,Mario Ost

doi:10.3390/ijms22073557

Abstract

In the present investigation, we examined whether a change in whole body energy fluxes could affect ovarian follicular development, employing mice ectopically expressing uncoupling protein 1 in skeletal muscle (UCP1-TG). Female UCP1-TG and wild-type (WT) mice were dissected at the age of 12 weeks. Energy intake and expenditure, activity, body weight and length, and body composition were measured. Plasma insulin, glucose, leptin, plasma fibroblast growth factor 21 (FGF21) and plasma insulin-like growth factor 1 (IGF1) levels were analyzed and ovarian follicle and corpus luteum numbers were counted. IGF1 signaling was analyzed by immunohistochemical staining for the activation of insulin receptor substrate 1/2 (IRS1/2) and AKT. UCP1-TG female mice had increased energy expenditure, reduced body size, maintained adiposity, and decreased IGF1 concentrations compared to their WT littermates, while preantral and antral follicle numbers were reduced by 40% and 60%, respectively. Corpora lutea were absent in 40% of the ovaries of UCP1-TG mice. Phospho-IRS1, phospho-AKT -Ser473 and -Thr308 immunostaining was present in the granulosa cells of antral follicles in WT ovaries, but faint to absent in the antral follicles of UCP1-TG mice. In conclusion, the reduction in circulating IGF1 levels due to the ectopic expression of UCP1 is associated with reduced immunostaining of the IRS1-PI3/AKT pathway, which may negatively affect ovarian follicle development and ovulation.

Highlights

Female reproduction, including folliculogenesis, ovulation, fertilization, embryo development, parturition, and lactation, is one of the most energy-costly biological processes that a female mammal can undertake [1] and is proposed to be a driving force in evolution [2]
We especially address the role of insulin-like growth factor 1 (IGF1), as plasma concentrations of this fertility-related peptide hormone are strongly reduced in uncoupling protein 1 transgene (UCP1-TG) male mice [37]
Lean body mass percentage was decreased (Figure 1F), while the percentage of body fat mass was increased (Figure 1G) in the UCP1-TG mice from week 7 onwards compared to WT litterwas mateincreased controls. (Figure 1G) in the UCP1-TG mice from week 7 onwards compared to WT

Summary

Introduction

Female reproduction, including folliculogenesis, ovulation, fertilization, embryo development, parturition, and lactation, is one of the most energy-costly biological processes that a female mammal can undertake [1] and is proposed to be a driving force in evolution [2]. Reproduction can only be successful when sufficient energy resources guarantee the metabolic demands imposed by pregnancy and, especially, lactation [3,4]. CR is an intervention that reduces energy intake, resulting in decreased adiposity, increased metabolic rate and decreased availability of oxidizable energy (fuel) [7]. It has been suggested that the reduced fuel availability is responsible for the observed negative effects on fecundity [8]. This agrees with the rapid restoration of fertility upon return to ad libitum feeding [9,10], which occurs before restoration of adiposity [9]

Methods

Results

Conclusion