Oxidative Stress and Mitochondrial Dysfunction in Adipose Biology and Obesity-Induced Insulin Resistance
This group examines cytoplasmic fatty acid binding proteins and their role(s) in mediating fatty acid metabolism in adipocytes and macrophages, particularly leukotriene synthesis. Using a combination of biochemical, biophysical, and molecular methodologies, the researchers study the synthesis of inflammatory lipids in macrophages and other cells. Importantly, animal models either null or transgenic for fatty acid binding proteins reveal that intracellular lipid metabolism control the synthesis and secretion of adipose-derived cytokines (adipokines) linked to glucose and lipid metabolism in muscle and liver. Using a drug discovery approach, small molecule inhibitors of FABPs have been identified that exhibit anti-inflammatory properties in macrophages. Such studies provide a framework for the analysis of obesity-linked insulin resistance.
The researchers are also engaging in a major project on oxidative stress and mitochondrial function in adipocytes. Plasma membrane lipids undergo chemical and enzymatic peroxidation leading to the generation of a,b-unsaturated aldehydes such as 4-hydroxynonenal. Such reactive lipids form chemical cross links with proteins and DNA and are implicated in oxidative diseases such as psoriasis, aging, macular degeneration and type 2 diabetes. Moreover, such protein modification, termed carbonylation, leads to system-wide changes in cellular function including mitochondrial respiration and signal transduction. In this project, the researchers examine antioxidant defense systems operable in adipose tissue and their regulation by pro-inflammatory cytokines. Importantly, loss of antioxidant defenses in type 2 diabetes leads to increased protein carbonylation and decreased mitochondrial function. Such mitochondrial dysfunction may underlie many of the biochemical events linked to insulin resistance and lead to new insight in age and nutrient-dependent diseases.
Both projects use RNA sequence technology as well as proteomics to allow identification of novel genes/proteins that are important for proper adipose function with developing obesity. These more system-wide approaches can only be successful with support from MSI resources.
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