The Contribution of Muscle, Liver, and Adipocytes Mitochondria to the Development of Obesity and Insulin Resistance

Project: Research

Investigators

  • Muhammad A Abdul-Ghani (PI)

Description

The prevalence of obesity and T2DM has increased to epidemic proportions over the past two decades. We recently cloned a novel nuclear gene that encodes for a mitochondrial protein of unknown function (the MO-I gene), and demonstrated that a stop codon point mutation in this gene causes morbid obesity in man. To elucidate the role of the MO-I gene in mitochondrial function and pathogenesis of obesity, we created a mouse lacking the MO-I gene (constitutional and tissue-specific). The constitutional MO-I KO mouse has markedly increased body weight compared to the WT and develops severe insulin resistance and hyperglycemia. The aim of the studies described in this grant proposal is to characterize the contribution of the MO-I gene in muscle, liver and adipocytes to the development of obesity and insulin resistance and identify the pathways regulated by the MO-1 gene. We will measure body weight, growth rate, body fat mass, and insulin sensitivity in skeletal muscle, liver and adipocytes with the insulin clamp and radioisotopes, mitochondrial function in isolated mitochondria, insulin signaling, intracellular fat metabolite content and mitochondrial protein level in tissue (skeletal muscle, liver and adipocyte) specific MO-1 KO mice, and compare the results to those in the constitutional MO-1 KO and WT animals. We also will up-and down-regulate MO-1 gene expression in cultured muscle cells and test the effect of these manipulation on mitochondrial function and insulin-stimulated glucose uptake.We believe that the results of these studies will elucidate the role of MO-1 gene in muscle, liver and adipocytes in the development of insulin resistance and the contribution of each organ to the development of obesity.
Award amount$307,080.00
Award date07/01/2010
Program typeScientist Development Grant
Award ID10SDG4470014
Effective start/end date07/01/201006/30/2014
StatusFinished