Adipocyte-Specific GH Receptor-Null (AdGHRKO) Mice Have Enhanced Insulin Sensitivity With Reduced Liver Triglycerides

Global GH receptor-null or knockout (GHRKO) mice have been extensively studied owing to their unique phenotype (dwarf and obese but remarkably insulin sensitive and long-lived). To better understand the influence of adipose tissue (AT) on the GHRKO phenotype, we previously generated fat-specific GHRKO (FaGHRKO) mice using the adipocyte protein-2 (aP2) promoter driving Cre expression. Unlike global GHRKO mice, FaGHRKO mice are larger than control mice and have an increase in white AT (WAT) mass and adipocyte size as well as an increase in brown AT mass. FaGHRKO mice also have an unexpected increase in IGF-1, decrease in adiponectin, no change in insulin sensitivity or liver triglyceride content, and a decreased lifespan. Extensive analysis of the aP2 promoter/enhancer by multiple laboratories has revealed expression in nonadipose tissues, confounding interpretation of results. In the current study, we used the adiponectin promoter/enhancer to drive Cre expression, which better targets mature adipocytes, and generated a new line of adipocyte-specific GHRKO (AdGHRKO) mice. AdGHRKO mice have an increase in adipocyte size and WAT depot mass in all depots except male perigonadal, a WAT accumulation pattern similar to FaGHRKO mice. Likewise, adiponectin levels and WAT fibrosis are decreased in both tissue-specific mouse lines. However, unlike FaGHRKO mice, AdGHRKO mice have no change in IGF-1 levels, improved glucose homeostasis, and reduced liver triglycerides. Thus, AdGHRKO mice should be valuable for future studies assessing the contribution of adipocyte GHR signaling in long-term health and lifespan.