Mechanisms underlying caloric restriction-mediated resolution of atherosclerosis

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PARENT PROJECT SUMMARY Obesity and atherosclerosis are frequently comorbid conditions contributing to substantial morbidity and mortality worldwide. The processes are characterized by inflammation in the adipose tissue and vasculature, respectively, that share many pathophysiologic pathways. Although processes underlying obesity and atherosclerosis-related inflammation are well studied, the signals that promote disease resolution and remission are largely unknown, especially in the context of concomitant inflammation resolution. As a postdoctoral fellow, I investigated how weight loss influences cardiovascular disease and found that caloric restriction-induced weight loss in obese mice promotes resolution of atherosclerosis, independent of plasma cholesterol. One critical aspect of atherosclerosis resolution with weight loss was the decrease in plaque necrotic core content, which is believed to be the most dangerous, unstable area of plaques. Mechanistically, we found that weight loss promotes beneficial changes to immune progenitors, as well as induces the accumulation of a new macrophage subtype (highly expressing Fcgr4) that is unique to tissues following weight loss. The R00 will build upon these exciting findings, and we will further determine how these two immunological aspects contribute to weight loss- induced resolution of atherosclerosis. I propose in Aim 1 to evaluate the necessity of Fcgr4 macrophages accumulation in the adipose tissue with weight loss for resolution of atherosclerosis. Additionally, we will examine the transcriptome and epigenome of obese humans and mice immune progenitors following weight loss, to further understand what facilitates their alteration and decreased inflammatory output. In Aim 2, I propose to further investigate the function of Fcgr4 macrophages, particularly in the context of necrotic core reduction that is associated with weight loss. These studies will identify novel molecular pathways that may be targeted for the treatment of atherosclerosis-related inflammation in obese subjects.