MON-484 Adipocyte-Specific GH Receptor Knockout Mice (AdGHRKO) Have Enhanced Insulin Sensitivity with Reduced Liver Triglycerides and Depot Specific Analyses in These Mice Suggest that GH May Have a More Substantial Effect on Subcutaneous White Adipose Tissue (WAT) Than Other WAT Depots

Abstract

Global GH receptor “knockout” (GHRKO) mice have enhanced insulin sensitivity despite obesity, with a disproportionate increase in subcutaneous white adipose tissue (WAT). To better understand the direct effects of GH on WAT, we previously generated Fat-specific GHR knockout (FaGHRKO) mice using the aP2 promoter/enhancer driving Cre expression. These mice are obese but show no improvement in insulin sensitivity and have a uniform increase in WAT; therefore, FaGHRKO mice differ from global GHRKO mice with regards to insulin sensitivity and WAT distribution. FaGHRKO mice also have an unexpected increase in IGF-1 and are significantly longer (nasal-anal length). Extensive analysis of the aP2 promotor/enhancer has revealed it to be expressed in non-adipose tissues (such as hypothalamus), confounding interpretation of results when using this promoter to generate adipose-specific mice and may help explain the unexpected increase in IGF-1 and body length observed in FaGHRKO mice. In the current study we used the adiponectin promoter/enhancer to drive Cre expression and generated a new line of adipocyte-specific GHR knockout (AdGHRKO) mice. Body length, GH and IGF-1 levels are unchanged in AdGHRKO mice compared to controls. AdGHRKO mice have an improved metabolic profile with enhanced insulin sensitivity and reduced liver triglycerides despite increased adiposity. Depot specific analysis of WAT in AdGHRKO mice shows that the subcutaneous WAT depot is more dramatically influenced by removal of GHR as 1) subcutaneous depot mass and 2) adipocytes within the subcutaneous depot are enlarged to a greater extent than perigonadal fat, and 3) the subcutaneous depot has a significant reduction in fibrosis while perigonadal fat does not. In conclusion, this mouse line should provide a valuable tool for understanding the direct actions of GH on adipose tissue.