SAT-181 Characterization of Adult Growth Hormone Receptor Gene-Disrupted Mice

Abstract

Reduced growth hormone (GH) action can extend life- and health-span. Mice with a disrupted GHR gene since birth are dwarf and obese with low levels of IGF-1 and insulin; high levels of GH; and hold the record for the longest-lived laboratory mouse. They are also somewhat resistant to several age-related diseases including cancer and diabetes. In order to determine if disruption of GHR after birth can also extend lifespan, we previously disrupted the GHR gene at 6 weeks of age and found that females have extended maximal lifespans. In the current study, we wanted to evaluate if disrupting GH action at an adult age (6 months) will lead to the same lifelong benefits seen mice with no GH action since birth, but without dwarfism. In this study, we used the Cre-lox system to ablate the GHR in mice of 6 months (a6mGHRKO mice). Following this, we determined body weights, composition and glucose homeostatic criteria including glucose and insulin tolerance testing. We then dissected the mice 6 months after GHR disruption (1 year of age) to measure circulatory GH, Insulin growth factor 1 (IGF-1), inflammatory factors, as well as the GHR expression levels in different tissues including liver, skeletal muscle and adipose tissue. We found that, the a6mGHRKO mice were not dwarf and have decreased IGF-1 and increased circulating GH levels. We also found that the GHR gene expression was decreased in all the tissues tested, and IGF-1 mRNA levels were reduced in adipose tissue liver and heart, but not in muscle or kidneys when compared to WT mice. Also, circulatory levels of interleukin-6, tumor necrosis alpha and monocyte chemoattractant protein 1 were unchanged between a6mGHRKO mice and controls. Moreover, differences in glucose metabolism can be seen in male and female a6mGHRKO mice. While glucose tolerance was not changed between experimental mice and controls, male a6mGHRKO mice showed increased insulin sensitivity, whereas female a6mGHRKO mice showed no difference in insulin sensitivity with respect to littermate controls. Studies that assess the status of age-related mechanisms such as mechanistic target of rapamycin (mTOR) activity and oxidative stress are being performed. Finally, a separate cohort of the a6mGHRKO mice have been generated and are being evaluated for the life span of these mice. In conclusion, mice that have the GHR gene ablated at 6 months of age have a normal body length, improved insulin sensitivity in males and normal inflammatory status when compared to controls. Molecular mechanisms to determine age-related effects of GH including longevity studies are ongoing.