Chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in ApoE-/- mice

Min Mao; Yalan Deng; Li Wang; Gexin Zhao; Ruomei Qi; Huan Gong; Tao Shen; Yitian Xu; Deping Liu; Beidong Chen

doi:10.7717/peerj.16029

Chronic unpredictable mild stress promotes atherosclerosis via adipose tissue dysfunction in ApoE^-/- mice

PeerJ. 2023 Sep 4:11:e16029. doi: 10.7717/peerj.16029. eCollection 2023.

Authors

Min Mao^#¹, Yalan Deng^#¹, Li Wang², Gexin Zhao³, Ruomei Qi¹, Huan Gong¹, Tao Shen¹, Yitian Xu⁴, Deping Liu⁵, Beidong Chen¹

Affiliations

¹ The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China.
² Department of Neurology, Beijing Hospital, Beijing, China.
³ Department of Orthopedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, United States of America.
⁴ Beijing Union University, Beijing, China.
⁵ Department of Cardiology, Beijing Hospital, Beijing, China.

^# Contributed equally.

Abstract

Background: Chronic unpredictable mild stress (CUMS) has been shown to exacerbate atherosclerosis, but the underlying mechanism remains unknown. Adipose tissue is an energy storage organ and the largest endocrine organ in the human body, playing a key role in the development of cardiovascular disease. In this research, it was hypothesized that CUMS may exacerbate the development of atherosclerosis by inducing the hypertrophy and dysfunction of white adipocytes.

Methods: The CUMS-induced atherosclerosis model was developed in Western diet-fed apolipoprotein E (ApoE)^-/- mice. White adipose tissue (WAT), serum, aortic root, and the brachiocephalic trunk were collected and tested after 12 weeks of CUMS development. The mouse model of CUMS was evaluated for depression-like behavior using the open field test (OFT) and the elevated plus maze (EPM) test. Enzyme-linked immunosorbent assay (ELISA) was conducted to detect serum noradrenaline and urine adrenaline protein levels. Serological assays were used to detect serum low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), and free fatty acid (FFA) concentrations. Hematoxylin and eosin (H&E) staining and oil red O were used to detect atherosclerotic plaque area, lipid deposition, and adipocyte size. The mRNA levels of genes related to aberrant adipose tissue function were determined using real-time PCR. Immunofluorescence assay and western blotting were conducted to examine the expression of proteins in the adipose tissue samples.

Results: CUMS aggravated vascular atherosclerotic lesions in ApoE^-/- mice. It decreased body weight while increasing the percentage of WAT. The serological results indicated that the concentration of HDL decreased in CUMS mice. Notably, adipocyte hypertrophy increased, whereas the mRNA levels of Pparg and its target genes (Slc2a4 (encodes for GLUT4), Adipoq, and Plin1) decreased. Further investigation revealed that CUMS increased subcutaneous inguinal WAT (iWAT) lipid synthesis and adipocyte inflammation while decreasing lipid hydrolysis and the expression of HDL-associated protein ApoA-I. Moreover, CUMS aggravated insulin resistance in mice and inhibited the insulin pathway in iWAT.

Conclusions: These findings indicated that CUMS induces adipose tissue dysfunction via a mechanism that leads to dyslipidemia, increased inflammation, and insulin resistance in the body, thereby exacerbating atherosclerosis. Notably, CUMS that is involved in decreasing the expression of HDL-associated proteins in adipose tissue may be a crucial link between adipose hypertrophy and advanced atherosclerosis. This study reveals a novel mechanism via which CUMS exacerbates atherosclerosis from the novel perspective of abnormal adipose function and identifies a novel potential therapeutic target for this disease.

Keywords: Adipocyte hypertrophy; Adipose tissue dysfunction; Atherosclerosis; CUMS; Insulin resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes, White
Adipose Tissue
Animals
Atherosclerosis* / etiology
Insulin Resistance*
Mice
Mice, Knockout, ApoE
Obesity
Stress, Psychological

Grants and funding

This work was supported by the National Natural Science Foundation of China (Grant no. 82170890 and 81270854), and the National Key Research and Development Program of China (Grant no. 2020YFC2003000). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.