Growth hormone (GH) inhibits fat accumulation and promotes
protein accretion, therefore the fall in GH observed with
weight gain and normal aging may contribute to metabolic dysfunction. To directly test this hypothesis a novel mouse model of adult onset-
isolated GH deficiency (AOiGHD) was generated by cross breeding rat GH promoter-driven
Cre recombinase mice (Cre) with inducible
diphtheria toxin receptor mice (iDTR) and treating adult Cre(+/-),iDTR(+/-) offspring with DT to selectively destroy the somatotrope population of the anterior pituitary gland, leading to a reduction in circulating GH and
IGF-I levels. DT-treated Cre(-/-),iDTR(+/-) mice were used as GH-intact controls. AOiGHD improved whole body
insulin sensitivity in both low-fat and high-fat fed mice. Consistent with improved
insulin sensitivity, indirect calorimetry revealed AOiGHD mice preferentially utilized
carbohydrates for energy metabolism, as compared to GH-intact controls. In high-fat, but not low-fat fed AOiGHD mice, fat mass increased, hepatic
lipids decreased and
glucose clearance and
insulin output were impaired. These results suggest the age-related decline in GH helps to preserve systemic
insulin sensitivity, and in the context of moderate caloric intake, prevents the deterioration in metabolic function. However, in the context of excess caloric intake, low GH leads to impaired
insulin output, and thereby could contribute to the development of diabetes.