Variations in muscle or adipose tissue insulin and insulin-like growth factor (IGF) signalling are likely to influence the relative amounts of lean body mass versus body fat. It is clear that obesity results in insulin resistance; alternatively, there is circumstantial evidence to suggest that diminished skeletal muscle insulin sensitivity might contribute to the accumulation of body fat. There is additional evidence to suggest that adipocyte insulin sensitivity may be a determinant of fat accretion. The salutary effect of growth hormone to promote or conserve lean body mass is thought to involve IGF-I, however the ability to address this question has been confounded by the paracrine or autocrine role of IGFs and complex interactions with specific binding proteins which modulate their action. The central objective of this proposal is to further define the role of insulin and IGF-I action in the regulation of body composition by generating and studying unique transgenic mouse models that express specific insulin or IGF-I receptor gene constructs exclusively in skeletal muscle or adipose tissue. There are three components of this project: A. We will develop transgenic mouse models characterized by increased or decreased insulin action in skeletal muscle or adipose tissue. Tissue- specific DNA promoter/enhancer elements will be used to direct the expression of receptor coding sequences to fat or muscle. Three versions of the human insulin receptor will be employed: 1) the intact normal receptor, which we have already successfully expressed in the muscle of transgenic mice; 2) a mutant receptor which we have shown can result in """"""""dominant-negative"""""""" insulin resistance; 3) a truncated membrane-anchored receptor beta-subunit that is constitutively active and ligand- independent. B. We will generate transgenic mice with increased IGF-I sensitivity in skeletal muscle or fat by overexpressing the intact human IGF-I receptor in these tissues. We will also attempt to create a constitutively active IGF-I receptor construct which could then be used to target ligand- independent increased IGF action to muscle or fat. C. Using these defined genetic manipulations, we will address the following principal hypotheses: 1) Alterations in muscle insulin sensitivity or action may influence the relative accretion of adipose tissue. 2) Changes in adipose tissue insulin sensitivity or action can modulate in vivo fat mass. 3) Increased IGF-I sensitivity or action in skeletal muscle will promote a relative increase in lean body mass. 4) Altered insulin or IGF-I receptor signalling in muscle or adipose tissue can modulate body composition by affecting the early development of these tissues.
