Hoxa5 inhibits adipocyte proliferation through transcriptional regulation of Ccne1 and blocking JAK2/STAT3 signaling pathway in mice.

The highly regulated proliferation of adipocytes plays a momentous role in fat development and obesity. Hoxa5 is an important member of the Hox family, its encoded protein is an important transcription factor related to development, and its differential expression in different adipose tissues seems to indicate that Hoxa5 may be involved in the regulation of adipocyte proliferation. To evaluate the regulatory mechanism of Hoxa5 on adipocyte proliferation, we constructed a variety of Hoxa5 expression vectors in vivo and in vitro to explore its mechanism on adipocyte proliferation and its potential impact on obesity. We observed that the overexpression of Hoxa5 strongly reduces cell counts and Hoxa5 can inhibit cell proliferation and block cell cycle progression by regulating the expression of genes such as Cyclin E, Cyclin D1, and p53. Most importantly, we demonstrated that Hoxa5 exerts its effect by regulating the signaling pathway of Janus kinase 2 (JAK2) signal transduction and transcription 3 (STAT3) activator, as well as binding to the promoter region of Ccne1 and inhibiting the transcription of Ccne1. This study provides an in-depth understanding of the potential molecular mechanism of Hoxa5 inhibiting adipocyte proliferation. Our results suggest the importance of Hoxa5 in the treatment of obesity.

Collagen XV Promotes ER Stress-Induced Inflammation through Activating Integrin ß1/FAK Signaling Pathway and M1 Macrophage Polarization in Adipose Tissue.

Collagen XV (Col XV), a basement membrane (BM) component, is highly expressed in adipose tissue, and studies have found that Col XV is related to extracellular matrix (ECM) remodeling involving in adipose tissue fibrosis and inflammation. Furthermore, the ECM is essential for maintaining normal development and tissue function. In this study, we found that Col XV is related to the endoplasmic reticulum stress (ERS) and inflammation of adipose tissue. Moreover, we found that overexpression of Col XV in mice could cause macrophages to infiltrate white adipose tissue (iWAT). At the same time, the expression of the ERS sensor IRE1α (Inositol-Requiring Enzyme-1α) was significantly up-regulated, which intensified the inflammation of adipose tissue and the polarization of M1 macrophages after the overexpression of Col XV in mice. In addition, after overexpression of Col XV, the intracellular Ca2+ concentration was significantly increased. Using focal adhesion kinase (FAK) inhibitor PF573228, we found that PF-573228 inhibited the phosphorylation of FAK and reversed the upward trend of Col XV-induced protein expression levels of IRE1α, C/EBP-homologous protein (CHOP), and 78 kDa glucose-regulated protein (GRP78). After treatment with IRE1α inhibitor STF-083010, the results showed that the expression of adipocyte inflammation-related genes interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) significantly were decreased. Our results demonstrate that Col XV induces ER-stress in adipocytes by activating the Integrinß1/FAK pathway and disrupting the intracellular Ca2+ balance. At the same time, Col XV regulates the inflammation induced by ER stress in adipocytes by promoting IRE1α/XBP1 (X-Box binding protein 1) signaling. Our study provides new ideas for solving the problems of adipose tissue metabolism disorders caused by abnormal accumulation of ECM.

Adipose-derived stem cells and obesity: The spear and shield relationship.

With the transformation of modern lifestyles and population ageing, obesity has become a global epidemic, as one of the important threat to human health of chronic non-communicable diseases (NCD). Stem cell therapy seems promising as an alternative strategy for managing obesity and related metabolic problems. Adipose tissue-derived stem cells (ADSCs) have received widespread attention, which provides new ideas for the treatment of obesity and various metabolic-related diseases, due to their abundant reserves, easy acquisition, rapid expansion, and multi-directional differentiation potential, low immunogenicity and many other advantages. Accordingly, there seems to be a "shield and spear paradox" in the relationship between ADSCs and obesity. In this review, we emphatically summarized the role of ADSCs in the occurrence and development of obesity and related metabolic disease processes, in order to pave the way for clinical practice.

Lnc-hipk1 inhibits mouse adipocyte apoptosis as a sponge of miR-497.

Noncoding RNAs (ncRNAs) such as microRNAs (miRNAs), long noncoding RNAs (lncRNA), and circular RNAs are closely related to the biological processes related to obesity. As a miRNA that widely present in different cell types, miR497 is proved to be involved in cell development. However, research on the role of miR-497 as a key factor in regulating the development of adipocytes is still in gap. The role of miR-497 in the apoptosis and proliferation of mouse-derived adipocytes was detected by RNA-seq analysis, RT-qPCR, Western blot, immunofluorescence, and dual-luciferase reporter assay. Using miR-497 mimics to treat 3T3-L1 cells, we found that miR-497 targeted Bcl-2 to promote adipocyte apoptosis through the mitochondrial pathway, and this effect was consistent in the apoptosis model composed of palmitic acid (PA) and hydrogen peroxide (H2 O2 ). LncRNA homeodomain-interacting protein kinase 1 (lnc-hipk1) sponged miR-148b to weaken its silencing of Bcl-2, forming the competitive endogenous RNAs (CeRNAs) regulatory network. Furthermore, overexpression of lnc-hipk1 inhibited the apoptosis of adipocytes by targeting miR-497/Bcl-2. Co-treatment of miR-497 and lnc-hipk1 showed that lnc-hipk1 reversed the apoptosis of adipocytes caused by miR-497 overexpression. And in vivo experiments further confirmed that this effect was also achieved by the CeRNA system of lnc-hipk1/miR-497/Bcl-2. In summary, lnc-hipk1 targets miR-497/Bcl-2 to regulate adipocyte apoptosis through the mitochondrial pathway. This research enriches the research content of ncRNAs and CeRNA in adipocyte development, and provides new targets for the treatment of obesity and other metabolic syndromes.