Rationale: In adults, growth hormone (GH) has been shown to have anti-lipogenic, pro-lipolytic and protein anabolic effects, while the metabolic actions of insulin-like growth factor I (IGF-I) resemble those of insulin. GH and IGF-I are also reported to have positive effects on pancreatic 2-cell mass, cardiovascular performance, bone remodeling and immune function. Therefore, the fall in circulating GH/IGF-I levels observed with age is predicted to play a role in the pathophysiology and progression of a variety of age-associated diseases including obesity/diabetes, sarcopenia, cardiomyopathy and osteoporosis. Despite the potential positive effects of GH/IGF-I in adults, there is also evidence that GH/IGF-I can exacerbate cancer and reduce lifespan. Therefore the fall in GH/IGF-I observed with normal aging might, in fact, serve a protective mechanism. Problem: It is difficult to accurately determine the importance of GH in adult physiology because the bulk of our knowledge has been derived from humans and rodent models of 1) developmental GH-deficiency, which may differ from that resulting in GH-deficiency occuring after sexual maturation and 2) adult-onset, GH- deficiency, which is typically associated with panhypopituitarism. For these reasons, a model of adult-onset, isolated GH-deficiency (AOiGHD) would be a unique and informative tool to more accurately define the importance of endogenous GH in age-associated changes in health and disease. Solution: Our laboratory has recently developed and validated a transgenic mouse line that expresses Cre recombinase (Cre) in the GH-producing cells (somatotropes) of the anterior pituitary gland (rGHp-Cre). The rGHp-Cre mouse represents a versatile tool to study various aspects of somatotrope function in that it can be crossbred to mice carrying genetically engineered alleles that contained critical DNA elements flanked by unique Cre recognition sequences referred to as loxP sites; thereby allowing for the Cre-mediated alteration of these genes (activation or inactivation) only in the somatotrope population of the anterior pituitary gland. To generate a model of adult-onset, isolated, GH-deficiency, the rGHp-Cre mice have been crossbred to an existing mouse model carrying a Cre-inducible diphtheria toxin receptor transgene (iDTR). Preliminary results demonstrate that the double transgenic offspring (Cre,iDTR) are normal. After sexual maturation, these mice were injected with a low dose of diphtheria toxin (DT), which binds to the DTR expressed on somatotropes allowing for internalization of the toxin and subsequent apoptosis of the somatotrope population, resulting in AOiGHD.
Specific Aims : I. Finalize the analysis of tissues taken from DT-treated Cre,iDTR male and female adult mice with """"""""partial"""""""" AOiGHD, in order to a) confirm the specificity of somatotrope destruction, and b) provide an initial assessment of the impact of GH/IGF-I reduction on metabolic gene expression. II. Test alternative strategies to maximize DT-mediated somatotrope destruction, to achieve a model of """"""""complete"""""""" AOiGHD, III. Provide a more detailed in vivo analysis of the impact of AOiGHD on metabolic endpoints. IV. Assess the impact of AOiGHD on lifespan.
This proposal will characterize a novel mouse model of adult-onset, isolated GHD (AOiGHD) and examine the effect of AOiGHD on body composition, metabolism and longevity. This model will provide a unique and informative tool to more accurately define the importance of endogenous GH in age-associated changes in health and disease. ? ? ?
