Short-Term Caloric Restriction In Mice Promotes Resolution Of Atherosclerosis, While Weight Regain Accelerates Its Progression

ABSTRACTWhile weight loss is highly recommended for those with obesity, >60% will regain their lost weight. This weight cycling is associated with elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss/regain directly influence atherosclerotic inflammation is unknown. Thus, we studied short-term caloric restriction (stCR) in obese hypercholesterolemic mice, without confounding effects from changes in diet composition. Weight loss was found to promote atherosclerosis resolution independent of plasma cholesterol. From single-cell RNA-sequencing and subsequent mechanistic studies, this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fcgr4, help to clear necrotic cores in atherosclerotic plaques. Conversely, weight regain (WR) following stCR accelerated atherosclerosis progression with disappearance of Fcgr4+ macrophages from eWAT and plaques. Furthermore, WR caused reprogramming of immune progenitors, sustaining hyper-inflammatory responsiveness. In summary, we have developed a model to investigate the inflammatory effects of weight cycling on atherosclerosis and the interplay between adipose tissue, bone marrow, and plaques. The findings suggest potential approaches to promote atherosclerotic plaque resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/539777v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@c6e857org.highwire.dtl.DTLVardef@bfd443org.highwire.dtl.DTLVardef@88973org.highwire.dtl.DTLVardef@78198f_HPS_FORMAT_FIGEXP M_FIG C_FIG