The proposed studies will investigate the actions of insulin and IGF-1 and their respective receptors in the CNS of normal animals and the insulin resistant, obese fa/fa Zucker rat. The goals are to add to existing knowledge on the location of the receptors for insulin and IGF-1, the mechanisms by which they provide biological signals, and whether circulating insulin can activate the CNS insulin receptor. A final goal is to determine if an abnormality exists in any of the signalling activities of the insulin receptor of insulin resistant Zucker rats.
The specific aims are to: 1. Determine the locations of insulin and IGF-1 receptors at the cellular and ultrastructural levels by immunocytochemistry and correlate the findings with the location of phosphotyrosine containing proteins. 2. Characterize the structural features of the IGF-1 receptor and evaluate the effects of tyrosine kinase activities of the insulin and IGF-1 receptors on endogenous substrates and on potential receptor signaling mechanisms. 3. Investigate the ability of circulating insulin to elicit a response in the CNS. 4. Evaluate whether the actions of insulin are altered in the CNS of insulin resistant, obese (fa/fa)Zucker rats.
These specific aims will test the following hypotheses: i.Insulin receptors and IGF-I receptors are located in different neuronal populations. ii.Two isoforms exist for the beta subunit of the IGF-I receptor which can generate a hybrid receptor. iii.Both receptors signal via tyrosine kinase activity to enhance the tyrosine phosphorylation of endogenous substrates and PtdIns-3 kinase (type 1). iv.Circulating insulin can directly activate the CNS insulin-receptor. v. The insulin resistance of obese Zucker rats is associated with a defect in the tyrosine kinase signaling pathway for the CNS insulin receptor. The long-term goal of this work is to understand the roles for insulin and IGF-I in the regulation of CNS function.
| Livingston, J N; Unger, J W; Moxley, R T et al. (1993) Phosphotyrosine-containing proteins in the CNS of obese Zucker rats are decreased in the absence of changes in the insulin receptor. Neuroendocrinology 57:481-8 |
| Moss, A M; Livingston, J N (1993) Distinct beta-subunits are present in hybrid insulin-like-growth-factor-1 receptors in the central nervous system. Biochem J 294 ( Pt 3):685-92 |
| Unger, J W; Moss, A M; Livingston, J N (1993) The hypophyseal pars tuberalis is enriched with distinct phosphotyrosine-containing proteins not detected in other areas of the brain and pituitary. Cell Tissue Res 272:499-507 |
