Insulin resistance plays a major role in the development of type 2 diabetes and 
obesity and affects a number of biological processes such as mitochondrial 
biogenesis. Though mitochondrial dysfunction has been linked to the development 
of insulin resistance and pathogenesis of type 2 diabetes, the precise mechanism 
linking the two is not well understood. We used high fat diet (HFD)-induced 
obesity dependent diabetes mouse models to gain insight into the potential 
pathways altered with metabolic disease, and carried out quantitative proteomic 
analysis of liver mitochondria. As previously reported, proteins involved in 
fatty acid oxidation, branched chain amino acid degradation, tricarboxylic acid 
cycle, and oxidative phosphorylation were uniformly up-regulated in the liver of 
HFD fed mice compared with that of normal diet. Further, our studies revealed 
that retinol metabolism is distinctly down-regulated and the mitochondrial 
structural proteins-components of mitochondrial inter-membrane space bridging 
(MIB) complex (Mitofilin, Sam50, and ChChd3), and Tim proteins-essential for 
protein import, are significantly up-regulated in HFD fed mice. Structural and 
functional studies on HFD and normal diet liver mitochondria revealed remodeling 
of HFD mitochondria to a more condensed form with increased respiratory capacity 
and higher ATP levels compared with normal diet mitochondria. Thus, it is likely 
that the structural remodeling is essential to accommodate the increased protein 
content in presence of HFD: the mechanism could be through the MIB complex 
promoting contact site and crista junction formation and in turn facilitating 
the lipid and protein uptake.