The overall goal of research in my lab is to determine the cellular and molecular mechanisms for insulin resistance in obesity and type 2 diabetes. Major research areas include:

1) discovering the mechanisms by which novel adipocyte-associated molecules alter insulin action and fuel metabolism in other tissues;
2) determining the molecular mechanisms that render obesity a risk factor for type 2 diabetes;
3) understanding the regulation and biological activities of a novel class of anti-diabetic and anti-inflammatory lipids that we discovered and named branched Fatty Acid Esters of Hydroxy Fatty Acids.
4) determining the therapeutic potential of Fatty Acid Esters of Hydroxy Fatty Acids for both Type 1 and Type 2 diabetes and immune mediated diseases.

Our work has had a major impact on understanding the important role of the adipocyte as an endocrine organ and as a metabolic “factory” consuming nutrients and substrates and producing metabolites that have systemic effects on insulin action, energy balance and inflammation. We use genomic and metabolomics approaches in mouse models we have genetically engineered mice to discover novel adipocyte-associated molecules which have provided important markers and mechanisms for insulin resistance and diabetes in humans. For example, we demonstrated that retinol binding protein 4 levels are elevated in insulin-resistant people and that elevated retinol binding protein 4 causes insulin resistance by activating both the innate and adaptive immune systems in adipose tissue. Lab members also showed that de novo lipogenesis in adipocytes has a major role in regulating systemic insulin sensitivity. These studies focused our interest on identifying novel metabolites which regulate glucose homeostasis.

Glut4 is the major insulin-regulated glucose transporter and is expressed at highest levels in skeletal and cardiac muscle and brown and white adipocytes. Reduced levels of Glut4 in adipocytes is associated with insulin resistance in humans and is a risk factor for developing type 2 diabetes. To understand the role of Glut4 and glucose transport specifically in adipocytes on glucose homeostasis, we engineered mice to have adipose-specific overexpression of Glut4. These mice have markedly enhanced glucose tolerance in spite of obesity. This improved glucose tolerance depends on increased lipogenesis in adipose tissue driven Carbohydrate Response Element Binding Protein, a transcription factor that regulates de novo lipogenesis and glycolysis. Knocking out Carbohydrate Response Element Binding Protein from adipose-specific Glut4- overexpressing mice reverses their enhanced glucose tolerance.

Since plasma fatty acids were elevated in the adipose-specific Glut4-overexpressing mice, we sought to determine whether specific lipids were being synthesized that have beneficial metabolic effects. With Dr. Alan Saghatelian, we used a global lipidomic platform and discovered a novel class of lipids that are made in human tissues, correlate highly with insulin sensitivity in humans, and have anti-diabetic and anti-inflammatory effects. These lipids lower glycemia and improve insulin sensitivity in insulin-resistant obese mice and protect against inflammatory diseases including autoimmune Type 1 diabetes in a mouse model. We are investigating the biology and pharmacokinetics of these lipids and the pathways that regulate their levels and mediate their effects. Because of the constellation of beneficial effects of these lipids and their favorable safety profile, they could lead to new therapeutic agents to prevent and treat diabetes and immune-mediated diseases.

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