Novo Nordisk Fonden - Understanding the involvement of adipose Mdm2 in glucose homeostasis

Projekter: ProjektForskning



The number of people suffering from diabetes mellitus (DM) has in the recent decades reached epidemic proportions. The distinctive characteristic
of DM is constant perturbations in the blood glucose homeostasis. Prolonged elevation in circulating levels of glucose leads to several complications including premature death. The commonness of DM has spurred great interest into the mechanisms maintaining glucose homeostasis.
The tight association of obesity with type II DM has emphasized the importance of functional adipose tissue on glucose homeostasis. We have observed an increased expression of the ubiquitin ligase Mdm2 in adipose stores of obese mice. Interestingly, mice heterozygous for Mdm2 specifically in adipose tissues have an improved level of circulating glucose. In mice kept on a high-fat diet, this was accompanied by augmented glucose tolerance and increased adipose mass. In addition to the lowered glucose level, mice fed a standard chow diet had dramatically decreased level of circulating insulin.
The aim of the current research proposal is to describe the mechanism by which adipose Mdm2 regulates glucose homeostasis. For this we will extend the metabolic analyses of mice heterozygous for Mdm2 in adipose stores. Furthermore, we will recapitulate the physiological findings through modulation of Mdm2 levels in established models of adipocytes in vitro. In order to delineate how Mdm2 contributes to glucose homeostasis we will use cutting edge quantitative mass spectrometry to determine global changes imposed by lack of Mdm2 in the proteomes as well as phosphorylation patterns in adipose stores. Additionally, as adipose tissue regulates several aspects of whole body physiology through secretion of adipokines, we will explore differences in circulating levels of known adipokines.
We hope that increased knowledge on the involvement of this novel regulator of glucose homeostasis can pave way for novel strategies in treating DM.
Effektiv start/slut dato01/01/201331/12/2014