Our goal is to understand the mechanism for how metabolic homeostasis is maintained in normal physiology and the impact of obesity and/or aging to cause metabolic dysfunction. Currently, we are focusing on the molecular and physiological etiology of Type 2 Diabetes Mellitus. We hypothesize that inflammation is an important etiologic component of metabolic dysfunction in obesity. We adopt various interdisciplinary tools to understand how obesity induces inflammation, how inflammation affects metabolic dysfunction, and whether modifying obesity-induced changes can improve metabolic health in obese subjects.

Immunometabolism

The etiology of type 2 diabetes involves insulin resistance and beta cell dysfunction and one typically needs both defects in order to develop the full hyperglycemic diabetic state (refered to as two-hit hypothesis). Accumulating evidence indicates that inflammation is causally associated with the development of both of these two defects. Thus, it was shown that inflammation is induced in the three classical insulin target tissues (adipose tissue, skeletal muscle, and liver), as well as pancreatic islets of obese and/or diabetic patients. Moreover, numerous rodent studies revealed that the inhibition of inflammatory pathways (e.g. depletion of macrophages or systemic or cell type-specific deletion of pro-inflammatory genes) improves glycemic control in obese mice, whereas, overexpression of a chemokine, CCL2 causes insulin resistance and glucose intolerance in mice fed normal chow diet. How obesity induces inflammation and how inflammation affects metabolic dysfunction (two main aspects of immunometabolism) are active research topics in metabolism research area. Early during the development of obesity, inflammation and increased macrophage accumulation can be observed selectively in adipose tissue (as early as 3 days after feeding high fat diet (HFD) in mice) and inflammation locally propages and expand to other tissues in the chronic setting. Interestingly, immuno-suppression improves insulin resistance induced by long-term, but not short-term, HFD, suggesting different nature or metabolic consequences of inflammation induced by short and long term HFD/obesity. We are currently studying the mechanisms for how adipose tissue inflammation propagates in obesity and how it becomes pathogenic to cause insulin resistane and metabolic dysfunction in the chronic setting.

Oxygen Homeostasis in Metabolic Health

Adipose tissue oxygen tension decreases early during the development of obesity and adipose tissue oxygen tension is positively associated metabolic health in obese subjects. We hypothesize that obesity triggers inflammation, insulin resistance, and other metabolic dysregulation, at least partially, by disturbing oxygen homeostasis (microcirculation and intracellular oxygen consumption) and causing aberrant activation of cellular hypoxia response(s). We are currently testing this hypothesis. We are also studying how obesity leads to tissue hypoxia and pseudohypoxia.