The role of GH in the regulation of energy homeostasis, lipid metabolism and cardiovascular function in transgenic mice

Abstract

The aim of this thesis was, using two transgenic models, to investigate some metabolic diseases associated with acromegaly e.g. hypertension and alterations in lipid and lipoprotein metabolism. We also studied the positive effect of Growth Hormone (GH), and possible molecular causes, on body composition and energy homeostasis using these GH transgenic models.We have used two different GH transgenic mouse models, one model overexpressing GH generally, controlled by the metallothionine promoter (Mt-bGH), and one model where the GH overexpression is restricted to the CNS, using the glial fibrillary acidic protein promoter (GFAP-bGH).Using telemetric technique, we have found that Mt-bGH transgenic mice have a salt-insensitive hypertension. Furthermore, the Mt-bGH transgenic mice have altered lipoprotein profiles and serum lipids, hyperinsulinemia and hyperglycaemia. Moreover, the hepatic gene expression profiles analysed by micro-array, revealed decreased gene expression of PPARa and SREBP-1 together with decreased expression of genes involved in fatty acid activation, b-oxidation, ketone body formation, lipogenesis, cholesterol metabolism, gluconeogenesis and amino acid catabolism. When analysed by indirect calorimetry, the Mt-bGH transgenic mice also had an increased resting metabolic rate on a normal diet that was enhanced by a Western diet, increased body temperature and increased hepatic gene expression of UCP2. Furthermore, the Mt-bGH transgenic mice had an increased respiratory exchange rate and food intake on both diets but still a lean body composition.The GFAP-bGH mice had an increased food intake resulting in massive obesity along with an increased expression of AGRP and NPY. These mice also had alterations in lipid and lipoprotein metabolism, hyperinsulinemia and pancreatic islet hypertrophy but normal blood glucose levels.GH stimulates food intake by increasing the hypothalamic gene expression of AGRP and NPY. This results in obesity in the GFAP-bGH transgenic mice but the high circulating levels of GH in the Mt-bGH mice, resulting in elevated RMR, body temperature, and T3 levels prevent obesity and result in a lean body composition. We have also found several risk factors for cardiovascular disease in these two GH transgenic models, such as high LDL cholesterol, insulin resistance, hypertension and indications of a decreased reverse cholesterol transport. These models may be useful tools in understanding the underlying mechanisms for cardiovascular disease in patients with acromegaly.