Abstract
Obesity is associated with chronic low-grade inflammation, contributing to an increasing prevalence of chronic metabolic diseases, such as insulin resistance, non-alcoholic fatty liver disease (NALFD), and steatohepatitis. Macrophages are the predominant immune cells in adipose tissues. Adipose tissue macrophages (ATMs) would switch to pro-inflammatory M1 state during obesity, causing local and systemic inflammation. However, the regulatory mechanism of ATMs has not yet been well described within this process. Using a high-fat diet (HFD)–induced mouse obesity model, we found that the costimulatory molecule CD226 was highly expressed on ATMs and knockout (KO) of CD226 alleviated obesity caused by HFD. Loss of CD226 reduced the accumulation of ATMs and hindered macrophage M1 polarization, with lower serum proinflammatory cytokine levels. Furthermore, deficiency of CD226 on ATMs decreased the phosphorylation levels of VAV1, AKT, and FOXO1 and thereby upregulated PPAR-γ. Further administration of PPAR-γ inhibitor restored M1 phenotype in CD226KO ATMs. In summary, loss of CD226 alleviates the HFD-induced obesity and systemic inflammation through inhibition of the accumulation and M1 polarization of ATMs in which PPAR-γ-dependent signaling pathway is involved, suggesting that CD226 may be identified as a potential molecular target for the clinical treatment of obesity.
Highlights
Obesity is a chronic systemic inflammatory disorder characterized by the dysfunction of hypertrophied adipocytes and the accumulation of immune cells in adipose tissue [1]
high-fat diet (HFD) increases CD226 expression on Adipose tissue macrophages (ATM) We examined the serum concentration of soluble CD226 in 79 human clinical samples (Normal 35, Overweight 31, Obesity 13), and found that the concentration of serum CD226 was significantly higher in the obesity cohort compared with the both normal and overweight groups (Fig. 1A), suggesting that CD226 might be related to the occurrence of obesity
Through an obese mouse model, the expression of CD226 was comparable between F4/80+ splenic macrophages from HFD-fed mice and those from chowfed mice, its expression on F4/80+ ATMs from epididymal stromal vascular fraction (SVF) of HFD-fed mice was significantly higher than that of chow-fed mice (Fig. 1C, D)
Summary
Obesity is a chronic systemic inflammatory disorder characterized by the dysfunction of hypertrophied adipocytes and the accumulation of immune cells in adipose tissue [1]. Macrophages are the predominant immune cells in adipose tissue, and they accumulate in obese mice and humans [2, 3]. They are classified to be classically (M1) or alternatively (M2) activated based on distinct patterns of gene expression and function [4]. It has been proposed that during obesity, macrophages in adipose tissue (ATMs) undergo a ‘phenotypic switch’ from an anti-inflammatory M2 phenotype to a pro-inflammatory M1 state, and this conversion was a key contributor to the emergence of the local and systemic inflammation of adipose tissues [5].
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