Caloric restriction promotes resolution of atherosclerosis in obese mice, while weight regain accelerates its progression
Bianca Scolaro, Franziska Krautter, Emily J. Brown, Aleepta Guha Ray, Rotem Kalev-Altman, Marie Petitjean, Sofie Delbare, Casey Donahoe, Stephanie Pena, Michela L. Garabedian, Cyrus A. Nikain, Maria Laskou, Ozlem Tufanli, Carmen Hannemann, Myriam Aouadi, Ada Weinstock, Edward A. Fisher
Bianca Scolaro, Franziska Krautter, Emily J. Brown, Aleepta Guha Ray, Rotem Kalev-Altman, Marie Petitjean, Sofie Delbare, Casey Donahoe, Stephanie Pena, Michela L. Garabedian, Cyrus A. Nikain, Maria Laskou, Ozlem Tufanli, Carmen Hannemann, Myriam Aouadi, Ada Weinstock, Edward A. Fisher
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Research Article Cardiology Inflammation Metabolism

Caloric restriction promotes resolution of atherosclerosis in obese mice, while weight regain accelerates its progression

Abstract

While weight loss is highly recommended for those with obesity, >60% regain their lost weight. This weight cycling is associated with an elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss and 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 promoted atherosclerosis resolution independent of plasma cholesterol. Single-cell RNA sequencing and subsequent mechanistic studies indicated that this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal white adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fc γ receptor 4 (Fcgr4), helped 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 hyperinflammatory 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 atherosclerosis resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming.

Authors

Bianca Scolaro, Franziska Krautter, Emily J. Brown, Aleepta Guha Ray, Rotem Kalev-Altman, Marie Petitjean, Sofie Delbare, Casey Donahoe, Stephanie Pena, Michela L. Garabedian, Cyrus A. Nikain, Maria Laskou, Ozlem Tufanli, Carmen Hannemann, Myriam Aouadi, Ada Weinstock, Edward A. Fisher

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Figure 5

WR reverts Fcgr4+ macrophage levels to obese proportions and accelerates atherosclerosis progression.

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WR reverts Fcgr4+ macrophage levels to obese proportions and accelerates...
(A) Schematic of WR experiment. WR was induced by allowing ad libitum access to HFHC diet after a 2-week weight loss period achieved by stCR. Mice in the PR group were allowed to continue to eat ad libitum after the BL time point. (B–G) Rates of change in plaque (B and C) macrophages, (D and E) necrotic core, and (F and G) collagen areas in weight cycling versus non–weight cycling. Data are expressed as (B, D, and F) absolute area and (C, E, and G) change from respective BL (BL for PR and stCR for WR) (n = 11–15). (H) Representative aortic root images. Scale bars: 0.5 mm (top), 0.25 mm (bottom). (I) Flow cytometry analysis of FCGR4+ macrophages in eWAT and plaques (n = 6). (J) Simple linear regression showing correlation between Fcgr4+ macrophages from eWAT and plaques with plaque necrotic core. P values were determined via (B–G and J) simple linear regression and (I) 1-way ANOVA with Tukey’s multiple-comparison test. Data are shown as the mean ± SEM.