Hoxa5 alleviates obesity‐induced chronic inflammation by reducing ER stress and promoting M2 macrophage polarization in mouse adipose tissue

• Published in: Journal of cellular and molecular medicine Vol. 23; no. 10; pp. 7029 - 7042
• Main Authors: Cao, Weina, Zhang, Tiantian, Feng, Ruonan, Xia, Tianyu, Huang, Hongtao, Liu, Chenlong, Sun, Chao
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2019; John Wiley and Sons Inc
• Subjects: Adenoviruses; adipocyte; Adipocytes; Adipocytes - metabolism; Adipocytes - pathology; Adipose tissue; Adipose Tissue - pathology; Animals; Bioinformatics; Body fat; Cell activation; Cell Polarity; Chronic Disease; Conflicts of interest; Correlation analysis; Cytokines - metabolism; Diabetes; Diet, High-Fat; eIF-2 Kinase - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2 - metabolism; Gene expression; Genotype & phenotype; HEK293 Cells; High fat diet; Homeodomain Proteins - metabolism; Hoxa5; Humans; Inflammation; Inflammation - pathology; Inflammation Mediators - metabolism; Insulin resistance; macrophage; Macrophages; Macrophages - pathology; Male; Metabolic disorders; Metabolism; Mice, Inbred C57BL; Models, Biological; Nutrition research; Obesity; Obesity - pathology; Original; Phenotypes; Polarity; Polarization; PPAR gamma - metabolism; Proteins; Secretion; Signal Transduction; Therapeutic applications; Transcription factors; Transcription Factors - metabolism; macrophage; endoplasmic reticulum stress; obesity; adipocyte; Hoxa5
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.14600

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.