Abstract 153: The Differential Effects Of Weight Loss And Regain On Atherosclerosis

Abstract

Heightened inflammation in obesity is a major contributor to many diseases, including atherosclerosis and other cardiovascular diseases (CVD). Although weight loss is extremely beneficial in improving many obesity-related conditions, weight regain worsens disease outcomes, including CVD, compared to maintenance of an obese state. Nonetheless, how weight loss promotes inflammation resolution and why weight regain worsens inflammation is poorly understood and was investigated here. Using high-fat high-cholesterol diet feeding of atherogenic mice (Ldlr deficient), we promoted weight loss after the establishment of atherosclerosis and obesity by using dietary restriction, e.g. reducing daily food consumption by 30% for 2 weeks, while maintaining hyperlipidemia. For weight regain, some mice were then given free access to food for 6 weeks. Strikingly, after 2 weeks of dietary restriction we observed atherosclerosis resolution, while weight regain accelerated disease re-progression. Single-cell analysis of visceral adipose and plaque leukocytes revealed enrichment in both tissues of a novel macrophage population with dietary restriction, which is distinguished by high expression of the antibody receptor Fcgr4, a known phagocytosis mediator. Conversely, Fcgr4 + macrophages disappeared from plaques and adipose following weight regain. Mechanistically, Fcgr4 + macrophages from the adipose tissue induced clearance of plaque necrotic core via enhanced efferocytosis. Moreover, we discovered that weight loss and regain differentially influence immune progenitors. Bone marrow (BM) transplantation showed that while weight loss and obese BM recipients had similar plaque inflammation, weight regain BM recipients had larger, more inflammatory plaques. In conclusion, our data are the first to directly show that initial weight loss promotes resolution of atherosclerosis, independently of plasma cholesterol changes and through the enrichment of specialized pro-resolving macrophages in adipose tissue that communicate with plaques. Conversely, weight regain accelerates disease progression via inflammatory reprogramming of immune progenitors.