Aouadi, M. | bioRxiv Science

bioRxiv2023

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

immunology↗

bioRxiv2019

Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity

White adipose tissue (WAT) inflammation contributes to the development of insulin resistance in obesity. While the role of adipose tissue macrophage (ATM) pro-inflammatory signalling in the development of insulin resistance has been established, it is less clear how WAT inflammation is initiated. Here, we show that ATMs from obese mice and humans exhibit markers of increased de novo phosphatidylcholine (PC) biosynthesis rate. Macrophage-specific knockout of phosphocholine-cytidylyltransferase A (CCT), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and insulin resistance. Mechanistically, CCT-deficient macrophages showed reduced ER stress and inflammation in response to palmitate. Surprisingly, this was not due to lower exogenous palmitate incorporation into cellular PCs. Instead, CCT-null macrophages had lower PC turnover, leading to elevated membrane polyunsaturated fatty acids that negated the pro-inflammatory effects of palmitate. Our results reveal a link between obesity-associated increase in PC synthesis, accelerated PC turnover and pro-inflammatory activation of ATMs.

cell biology↗