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

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.

Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity

“…Expression of all 3 genes was elevated in AT of DKO-HFD mice. In gonadal and subcutaneous AT, expression of several beige/brown fat markers [ 31 , 58 ] including Slc29a1 and Hoxa5 [ 59 ], was increased in DKO mice, even on the CD, consistent with the other changes in gene expression that we observed.…”

Necroptosis: A Novel Pathway in Neuroinflammation

“…A variety of immunocytes are involved in inflammation ( Mack, 2018 ; Tsai et al, 2018 ). Acute inflammation is dominated by neutrophil infiltration ( Pinho-Ribeiro et al, 2018 ; Kapur et al, 2019 ), whereas chronic inflammation is often accompanied by macrophage and lymphocyte infiltration ( Cao et al, 2019 ; Faissner et al, 2019 ; Lodygin et al, 2019 ; Na et al, 2019 ).…”

“…, whereas chronic inflammation is often accompanied by macrophage and lymphocyte infiltration (Cao et al, 2019;Faissner et al, 2019;Lodygin et al, 2019;Na et al, 2019).…”

Low-intensity pulsed ultrasound upregulates osteogenesis under inflammatory conditions in periodontal ligament stem cells through unfolded protein response

“…However, the effect of LIPUS on P-PDLSCs was unclear, which has limited the application of LIPUS in the treatment of periodontitis, because the inflammatory environment is unavoidable during periodontitis treatment. A study by Cao et al has shown that suppression of ERS could alleviate chronic inflammation in adipocytes [31]. As a molecular chaperone, 4-PBA reduced excessive ER load caused by mutations or mislocated proteins in the study of liver injury [32] and could inhibit ERS-mediated apoptosis and prevent cerebral ischemia [33].…”