Matthew Brady, PhD

Energy is stored in mammals either as long branching polymers of glucose called glycogen in skeletal muscle and liver, or as triglyceride in densely packed lipid droplets in adipose tissue. The overall focus of the Brady lab is the study of insulin metabolic signaling and the regulation of energy metabolism. We are particularly interested in two general research areas: 1) the spatial organization of enzymes that regulate glycogen metabolism, 2) the connection between glucocorticoid action, adipocytic insulin resistance and obesity in vivo. We study a scaffolding protein termed Protein Targeting to Glycogen (PTG) that assembles glycogen metabolizing enzymes with their immediate upstream regulator protein phosphatase-1 at the glycogen particle. Intracellular enzymes controlling these metabolic pathways act as complexes, interacting with one another in an organized fashion and channeling metabolites down a specific pathway. Although PTG has no inherent enzymatic activity, modulation of PTG levels in cells or in vivo exerts dramatic effects on glycogen metabolic rates and cellular glycogen storage. We are currently the effects of modulating glucose flux into glycogen on lipid metabolism in adipocytes using cell lines and transgenic animal models. A second major project involves the role of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in adipocyte biology. Glucocorticoids play an important role in the differentiation of preadipocytes and acquisition of insulin sensitivity, but paradoxically, promote insulin resistance in mature adipocytes. 11ß-HSD1 largely catalyzes the localized activation of circulating glucocorticoids thus increasing their effects, but under certain cellular conditions the enzyme catalyzes the reverse inactivation of glucocorticoids. Through adenoviral-mediated overexpression and shRNA delivery, we are examining the impact of modulating enzyme levels and extracellular nutrients on glucocorticoid action in preadipocytes and adipocytes.

Finally, we have recently initiated several collaborative projects to examine insulin sensitivity and metabolic action in primary human adipocytes. Subcutaneous biopsies from subjects with various forms of insulin resistance will be taken before and after therapeutic interventions, and results obtained in vitro will be compared to comprehensive metabolic determination in the Clinical Research Center at the University of Chicago. If the changes in insulin sensitivity are observed in primary adipocytes, the potential role of 11ß-HSD1 and glucocorticoid-induced insulin resistance in these processes will be examined. We are extremely excited about these new translational research projects and the potential to examine potential linkages between alterations in global insulin resistance and metabolic dysfunction to changes in insulin action at the cellular level in primary human adipocytes.