Energy supplementation rescues growth restriction and female infertility of mice with hepatic HRD1 ablation.

Severe dietary restriction, catabolic states and even short-term caloric deprivation impair fertility in mammals including human, which is often reversible by restoration of the energy supplementation. The dysregulated crosstalk among multiple organs is possibly involved in this process. However, ideal experimental animal models are needed to illuminate functional crosstalk among distal organs during the starvation pathogenesis. We have recently discovered that conditional hepatic HRD1 gene deletion results in elevated energy expenditure and consequently leads to growth retardation and female fertility. Herein, we discovered that both growth retardation and female infertility of liver-specific HRD1 knockout mice could be fully rescued by additional energy supplementation upon HFD feeding. Hepatic HRD1 deletion appears to impair by the pituitary gland functions in secreting critical hormones in growth and female fertility including growth hormone (GH), follicle-stimulating hormone (FSH) and luteinizinghormone (LH) because a dramatic reduction in the sera levels of all three hormones were detected in liver HRD1 KO mice, which consequently shortened their tibia lengths and impaired the ovary functions in females. HFD feeding for six weeks largely restored all three hormones in liver HRD1 KO mice back to levels comparable with those in WT mice. In addition, the growth hormone induced activation of JAK-STAT5 pathway was inhibited by HRD1 deletion, and additional energy supplementation upon HFD feeding restored STAT5 transcriptional activation. Our studies establish a unique mouse model to study liver crosstalk with distal organs in regulating energy balance in growth and female fertility.