GH Knockout Mice Have Increased Subcutaneous Adipose Tissue With Decreased Fibrosis and Enhanced Insulin Sensitivity

Abstract

Abstract In 1997, our laboratory used targeted gene disruption of the GH receptor (GHR) to generate GHR knockout (GHR−/−) mice, which have been used in >127 published studies to help elucidate GH’s numerous activities. However, because GH replacement studies cannot be performed using this line, a GH knockout mouse line via targeted disruption of the GH gene is needed. Therefore, we created and characterized GH gene–disrupted (GH−/−) mice. GH−/− mice have severely decreased IGF-1 levels, small body size, and altered body composition with increased adiposity. GH−/− mice are extremely insulin sensitive but glucose intolerant, with a dramatic reduction in pancreatic islet size. Importantly, disruption of the GH gene had profound and depot-specific effects on white adipose tissue (WAT). Subcutaneous WAT from male and female GH−/− mice have significantly larger adipocytes and reduced fibrosis, neither of which occurred in perigonadal WAT, suggesting that GH has a more pronounced effect on subcutaneous WAT. Comparisons of GH−/− mice to previously published data on GHR−/− mice show a remarkably similar phenotype. Finally, we demonstrate that GH−/− mice are responsive to GH treatment, as shown by changes to serum IGF-1 levels; body length, weight, and composition; and insulin sensitivity. This study not only provides characterization of the first mouse line with targeted mutation of the GH gene but also indicates that GH gene disruption dramatically influences fibrosis of subcutaneous WAT.