Sexual dimorphism in the effects of maternal adipose tissue growth hormone receptor deficiency on offspring metabolic health.

Abstract

Background: The global incidence of obesity continues to rise, which increases the prevalence of metabolic diseases. We previously demonstrated the beneficial effect of adipose-specific growth hormone receptor (Ghr) knockout (KO) on metabolic parameters in male mice exposed to high fat diet. Although the effect of the growth hormone (GH) axis on lipid metabolism has been well studied, sexual dimorphism has not been considered. Furthermore, the effects of the GH axis on intergenerational adipose development are understudied. The present study aimed to evaluate whether adipose-specific Ghr knockout is associated with sex-specific differences in metabolic health of female offspring.

Methods: Ghr^flox/flox (LL) mice were crossed with Adipoq-Cre mice to generate adipose-specific Ghr knockout (KO) mice. Physiological phenotype and fertility of female LL and KO mice were measured. Body weight, organ weight, glucose homeostasis, liver and adipose histology, hepatic triglycerides (TG) content, serum TG and low-density lipoprotein cholesterol (LDL-C) levels of female offspring were detected.

Results: We found an increase in adipocyte size in female KO mice, but no change in glucose tolerance or insulin sensitivity. Adipose-specific Ghr deficiency impairs fertility in female KO mice. Maternal adipose-specific Ghr deficiency had a considerable beneficial effect on glucose metabolism in female offspring. The female offspring of the KO mice were protected against diet-induced obesity and the degree of hepatic steatosis and hyperlipidemia was reduced. The adipocyte size of the KO offspring did not change significantly despite the decrease in fat weight. Furthermore, the phenotypes of the offspring of LL mice fostered by the KO mothers differed from those of offspring remaining in the maternal nest.

Conclusions: The findings of our study suggest that adipose GH axis plays a complex and important role in the intergenerational effects of metabolic health and adipocytes on offspring in a sex-specific manner. Future studies are needed to reveal the mechanisms of these sexually dimorphic phenotypes and the feasibility of providing new interventions for improving offspring metabolic health.