Abstract
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.
Highlights
Circulating growth hormone (GH) and insulin-like growth factor I (IGF-I) levels steadily rise after birth, plateau around puberty, decline thereafter at a rate of,14% for every decade of life [1]
Mice were maintained on a standard rodent chow diet or fed a low fat diet (LF: fat, 10% kcal%; carbohydrate, 70 kcal%; protein, 20 kcal% - Research Diets, New Brunswick, NJ) starting at 4 weeks of age, where a subset of mice were switched to a high fat diet fat (HF: fat, 45% kcal; carbohydrate, 35 kcal%; protein 20 kcal% Research Diets), immediately following DT treatment
Despite these differences in insulin sensitivity, the response to GTT deteriorated in HF-fed adult onset-isolated GH deficiency (AOiGHD) mice relative to controls (Fig. 4A, AUC HF-controls 3639862835 vs. HFAOiGHD 4304661590, p,0.05). These differences may be attributed to the fact that the compensatory rise in insulin was blunted in HF-fed AOiGHD mice, resulting in a significant difference in insulin levels between AOiGHD and controls, under fasted and fed conditions (Fig. 4B). These results suggest that Growth hormone (GH)/IGF-I may be important in maintaining ß cell function, which is supported by the observation that the level of whole pancreatic INS-2 mRNA, the primary transcript contributing to circulating insulin in mice, was significantly suppressed by AOiGHD (Fig. 4C)
Summary
Circulating growth hormone (GH) and insulin-like growth factor I (IGF-I) levels steadily rise after birth, plateau around puberty, decline thereafter at a rate of ,14% for every decade of life [1]. The true impact of age and weightrelated alterations in endogenous GH levels on adult health and disease remains to be clarified, because the bulk of our knowledge is based on studies of 1) short-term GH administration in normal subjects, 2) prolonged GH excess due to GH-producing pituitary tumors, 3) developmental GHD, that might not reflect the consequences of GH decline after sexual maturation and 4) adult onset GHD (AOGHD) due to pituitary surgery or head trauma, which is frequently accompanied by other pituitary defects, making it difficult to determine what changes are due to GH loss For these reasons, this report describes the development and characterization of a mouse model of adultonset, isolated GHD (AOiGHD), where experiments were conducted to determine the impact of AOiGHD on whole body insulin sensitivity and glucose tolerance, body composition and circulating and hepatic fat accumulation. Results revealed a partial reduction in endogenous GH levels has both positive and negative effects on metabolic function depending on nutritional status
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