Abstract
Obesity‐induced chronic inflammation is associated with endoplasmic reticulum stress (ERS) in adipocytes and changes in both the number and phenotype of adipose tissue macrophages (ATMs). In addition, ERS enhances macrophage activation. So far, the function of Hoxa5 in obesity‐induced chronic inflammation has been poorly understood. Herein, we demonstrate the importance of the transcription factor, Hoxa5, in determining adipose tissue macrophage (ATM) polarity and ERS. Hoxa5 decreased bodyweight, reduced inflammatory cytokine secretion and corresponded with an increased number of M2 macrophages in the adipose tissue of high‐fat diet (HFD) mice. Transcriptome sequencing data showed that overexpression of Hoxa5 in adipocytes changed expression of endoplasmic reticulum (ER) protein processing‐related genes. Based on transcriptome sequencing data and bioinformatics prediction, we have been suggested that Hoxa5 alleviated inflammatory responses by inhibiting ERS and by activating PPARγ pathway in mouse adipose tissue. Hoxa5 alleviated ERS and inflammatory responses by inhibiting the eIF2α/PERK signalling pathway in adipocytes. Hoxa5 also inhibited chronic inflammation of adipocytes by promoting M2 macrophage polarization. In addition, Hoxa5 transcriptionally activated the PPARγ pathway to promote polarization of M2 macrophages, which in turn alleviated chronic inflammation of adipocytes. Taken together, these results shed light on the mechanisms underlying Hoxa5‐dependent inhibition of obesity‐induced chronic inflammation by reducing ERS and promoting polarization of M2 macrophages. These results suggest that Hoxa5 may be a potential therapeutic target for obesity and other metabolic syndromes.
Highlights
Obesity has become a universal health problem worldwide and is considered to be a chronic inflammatory state that is characterized by the infiltration and activation of immune cells in metabolic or‐ gans, such as adipose tissue.[1,2,3] It is well known that metaflammation induced by over‐nutrition of adipose tissue has been recognized as an important link in the pathogenesis of insulin resistance and type 2 diabetes.[4]Various congenital and adaptive immune cells interact with adi‐ pocytes to maintain adipose tissue.[5]
We found that levels of TNF‐α and IL6 in adipocytes co‐cultured with macrophages (RAW264.7) that were transfected with pc‐Hoxa[5] or sh‐Hoxa[5] (n = 4). (B‐C) Macrophages were transfected with pc‐Hoxa[5] or sh‐Homeobox a5 (Hoxa5). (B) Relative mRNA levels of Hoxa[5], PPARγ, TNF‐α, IL4 and CD206 in macrophages incubated with or without rosiglitazone (n = 4). (C) Macrophage morphology visualized by labelling with α‐actin (n = 4). (D) Images showing immunofluorescence of IL4, IL10, CD206, IFNγ and TNF‐α in macrophages (n = 4)
Numerous studies have reported that adipose tissue macrophages (ATMs) in healthy animals are selectively expressed in activated M2 macrophages
Summary
Obesity has become a universal health problem worldwide and is considered to be a chronic inflammatory state that is characterized by the infiltration and activation of immune cells in metabolic or‐ gans, such as adipose tissue.[1,2,3] It is well known that metaflammation induced by over‐nutrition of adipose tissue has been recognized as an important link in the pathogenesis of insulin resistance and type 2 diabetes.[4]. We found that Hoxa[5] alleviates ERS by inhibiting the eIF2α/PERK signalling pathway and transcription‐ ally activated the PPARγ pathway to promote polarization of M2 macrophages. We explored the intrinsic link between Hoxa[5], ERS, chronic inflammation and M2 macrophage polarization to provide a theoretical basis for the treat‐ ment of obesity
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