Relevance of IMPACT protein in metabolism regulation

Abstract

Translational control mediated by the phosphorylation of initiation factor 2 (eIF2) is crucial for the adaptation of cells to different stress conditions, and malfunction of this signal pathway can lead to important pathologies. One of the four eIF2 kinases in mammals, GCN2, regulates de expression of large number of genes in response to e.g., amino acid deprivation. GCN2 also determines behavior towards amino acid diet sources, and modulates hippocampal memory. In previous work, we showed that the mammalian protein IMPACT is a GCN2 inhibitor by binding to GCN1, a GCN2 effector. IMPACT is preferentially expressed in neurons, and abundant in the hypothalamus. Studies in mice lacking IMPACT have been done in this laboratory. No major phenotypic difference has been detected, relative to wild type mice. However, it has been noticed that IMPACT-KO mice are slightly leaner than wild type animals. This could be due to alterations in the hypothalamic signaling in these animals. This project aims at the study of the function of IMPACT in animal physiology. Specifically, weight gain and diet intake will be evaluated, using animals fed a high fat diet, or high carbohydrate for 2 months. Levels of blood insulin, glucose and leptin will then be evaluated, as well as the weight of different organs and tissues. The food intake response to intracerebro-ventricular administration of leptin will be studied. Complementing these approaches, at the end of the protocols above, the hypothalamus of the animals will be isolated and the leptin signalling pathway evaluated by immunoblots.