GHR disruption in mature adult mice alters xenobiotic metabolism gene expression in the liver.

BACKGROUND: Lifelong reduction of growth hormone (GH) action extends lifespan and improves healthspan in mice. Moreover, congenital inactivating mutations of GH receptor (GHR) in mice and humans impart resistance to age-associated cancer, diabetes, and cognitive decline. To investigate the consequences of GHR disruption at an adult age, we recently ablated the GHR at 6-months of age in mature adult (6mGHRKO) mice. We found that both, male and female 6mGHRKO mice have reduced oxidative damage, with males 6mGHRKO showing improved insulin sensitivity and cancer resistance. Importantly, 6mGHRKO females have an extended lifespan compared to controls. OBJECTIVE AND METHODS: To investigate the possible mechanisms leading to health improvements, we performed RNA sequencing using livers from male and female 6mGHRKO mice and controls. RESULTS: We found that disrupting GH action at an adult age reduced the gap in liver gene expression between males and females, making gene expression between sexes more similar. However, there was still a 6-fold increase in the number of differentially expressed genes when comparing male 6mGHRKO mice vs controls than in 6mGHRKO female vs controls, suggesting that GHR ablation affects liver gene expression more in males than in females. Finally, we found that lipid metabolism and xenobiotic metabolism pathways are activated in the liver of 6mGHRKO mice. CONCLUSION: The present study shows for the first time the specific hepatic gene expression profile, cellular pathways, biological processes and molecular mechanisms that are driven by ablating GH action at a mature adult age in males and females. Importantly, these results and future studies on xenobiotic metabolism may help explain the lifespan extension seen in 6mGHRKO mice.

Mouse models of growth hormone deficiency.

Nearly one century of research using growth hormone deficient (GHD) mouse lines has contributed greatly toward our knowledge of growth hormone (GH), a pituitary-derived hormone that binds and signals through the GH receptor and affects many metabolic processes throughout life. Although delayed sexual maturation, decreased fertility, reduced muscle mass, increased adiposity, small body size, and glucose intolerance appear to be among the negative characteristics of these GHD mouse lines, these mice still consistently outlive their normal sized littermates. Furthermore, the absence of GH action in these mouse lines leads to enhanced insulin sensitivity (likely due to the lack of GH's diabetogenic actions), delayed onset for a number of age-associated physiological declines (including cognition, cancer, and neuromusculoskeletal frailty), reduced cellular senescence, and ultimately, extended lifespan. In this review, we provide details about history, availability, growth, physiology, and aging of five commonly used GHD mouse lines.