ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition

Abstract

BackgroundEctopic lipid deposition plays a promoting role in many chronic metabolic diseases. Abnormal adipogenic differentiation of mesenchymal stem cells (MSCs) is an important cause of lipid deposition in organs. Studies have shown that serum angiopoietin-like protein 8 (ANGPTL8) levels are increased in patients with many chronic metabolic diseases (such as type 2 diabetes, obesity, and hepatic steatosis), while the role of ANGPTL8 in ectopic lipid accumulation has not been reported.MethodsWe used the Gene Expression Omnibus (GEO) database to analyze the expression of ANGPTL8 in subcutaneous adipose tissue of obese patients and qPCR to analyze the expression of ANGPTL8 in the liver of high-fat diet (HFD)-induced obese mice. To explore the potential roles of ANGPTL8 in the progression of ectopic lipid deposition, ANGPTL8 knockout (KO) mice were constructed, and obesity models were induced by diet and ovariectomy (OVX). We analyzed lipid deposition (TG) in the liver, kidney, and heart tissues of different groups of mice by Oil Red O, Sudan black B staining, and the single reagent GPO-PAP method. We isolated and characterized MSCs to analyze the regulatory effect of ANGPTL8 on Wnt/β-Catenin, a key pathway in adipogenic differentiation. Finally, we used the pathway activator LiCl and a GSK3β inhibitor (i.e., CHIR99021) to analyze the regulatory mechanism of this pathway by ANGPTL8.ResultsANGPTL8 is highly expressed in the subcutaneous adipose tissue of obese patients and the liver of HFD-induced obese mice. Both normal chow diet (NCD)- and HFD-treated ANGPTL8 KO male mice gained significantly less weight than wild-type (WT) male mice and reduced ectopic lipid deposition in organs. However, the female mice of ANGPTL8 KO, especially the HFD group, did not show differences in body weight or ectopic lipid deposition because HFD could induce estrogen overexpression and then downregulate ANGPTL8 expression, thereby counteracting the reduction in HFD-induced ectopic lipid deposition by ANGPTL8 deletion, and this result was also further proven by the OVX model. Mechanistic studies demonstrated that ANGPTL8 could promote the differentiation of MSCs into adipocytes by inhibiting the Wnt/β-Catenin pathway and upregulating PPARγ and c/EBPα mRNA expression.ConclusionsANGPTL8 promotes the differentiation of MSCs into adipocytes, suggesting that ANGPTL8 may be a new target for the prevention and treatment of ectopic lipid deposition in males.

LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis

“…In our previous study (the REACTION study), ANGPTL8 levels are significantly higher in men than in women at almost all age stages, especially in the ≤55-year-old population 55 . This data indicates that female hormones could affect ANGPTL8 levels, which is supported by a recent standpoint that estrogen inhibits ANGPTL8 expression in liver cells 56 . Although metabolic phenotype of Angptl8 HepKO is improved more significantly in male mice than in females, there is no significant difference between males and females regarding the improvement in hepatic inflammation and the reduction in macrophage recruitment and fibrogenesis.…”

Transcriptomic Analyses Reveal the Effects of Walnut Kernel Cake on Adipose Deposition in Pig

“…We found a total of 26 shared genes in the two stages, among which ANGPTL8 is an adipocytokine known to play an important regulatory role in fat metabolism. The study found that ANGPTL8 can promote the maturation of adipocytes and the release of fatty acids, while regulating insulin sensitivity and glucose metabolism [32][33][34][35]. ETV4 may play a role in regulating of adipocyte differentiation and metabolism [36,37].…”

Developmental Programming: Impact of Prenatal Exposure to Bisphenol A on Senescence and Circadian Mediators in the Liver of Sheep

“…Post-transcriptional and post-translational modifications play a key role in the rhythmic expression of circadian genes in the liver [ 147 ], which was not evaluated in this study. Although several studies have reported Sudan black B staining of lipofuscin as a marker of cellular senescence, it also diffusely stains distributed lipids in cells [ 148 ]. Ideally, an assay for β-galactosidase, which is expressed from GLB1 and is a biochemical marker of senescence, would have been more specific.…”