Large increases in fat mass lead to obesity and adversely alter blood pressure, insulin sensitivity, serum lipid profiles and cardiac function. The research in our laboratory focuses on identifying cellular and molecular mechanisms by which fat mass changes alter medically important traits, including insulin sensitivity and cardiac mass.
Mechanisms of Obesity Induced Complications Insulin sensitivity, lipoprotein homeostasis, blood pressure and cardiac mass are all adversely altered by large increases in adipose mass. However, the mechanisms by which obesity induces these pathologic changes are poorly defined. The primary goal of research in my lab is identifying mechanisms by which alterations in adiposity modify medically important quantitative traits. We have developed a technique, quantitative trait-transcript (QTT) analysis, that identifies genes whose expression correlates with quantitative traits.
Using QTT analysis to study of body mass and adipose tissue gene expression, we have identified a previously unrecognized macrophage-like cell within adipose tissue. The population of these adipose tissue macrophages (ATM’s) increases with increasing obesity, so that in the most severely obese mice >50% of cells within visceral adipose depots are macrophages. Furthermore, ATM’s are preferentially found in visceral adipose tissue where they form multinucleated giant cells in severe obesity. These cells may provide missing mechanistic underpinnings for the production of pro-inflammatory molecules found in obesity and implicated in obesity associated insulin resistance and atherosclerosis. Current work focuses on defining the roles that ATM’s play in regulating adipocyte physiology and in increasing levels of circulating pro-inflammatory cytokines observed in obesity and insulin resistance.
Cardiac hypertrophy (CH) is another common complication of obesity. Our work in obese mice suggests that the molecular mechanism by which obesity induces CH are distinct from those typically seen in hemodynamically induced CH. We have shown that CH in obesity is associated with activation of SREBP1c dependent gene transcription (a lipogenic program), while regression of CH induced by weight loss or leptin treatment is associated with activation of a PPAR-alpha transcriptional program (an oxidative program). Our current efforts are aimed at defining the mechanisms that regulate cardiac mass in parallel with energy balance.
