RESUMEN
Adipocytes and immune cells are vital for the development of adipose tissue. Adipokines secreted by adipocytes regulate adipogenesis and body metabolism. Chemerin is one of the adipokines. However, the function and mechanism of chemerin in adipose tissue are not fully illuminated. Compared with wild type (WT) mice, Rarres2 -/- mice gained weight and significantly increased fat distribution in subcutaneous adipose tissue (SAT), rather than visceral adipose tissue (VAT) on high fat diet (HFD). PPARγ and C/EBPα, the master regulators of adipogenesis, were up-regulated in SAT and down-regulated in VAT in Rarres2 -/- mice comparing with WT mice. Inspite of chemerin deficiency or not, the ratio of adipocyte-progenitors to total cells and the differentiation capacity of adipocyte-progenitors were similar in SAT and VAT, but macrophage infiltration in VAT was more severe than in SAT in Rarres2 -/- mice. Furthermore, CD45+ immune cells supernatant from Rarres2 -/- SAT promoted the differentiation of adipocyte-progenitors and 3T3-L1 cells. Adipokine array assay of CD45+ immune cells supernatant revealed that metalloproteinase inhibitor 1 (TIMP1), an inhibitor of adipogenesis, was reduced in Rarres2 -/- SAT, but increased in Rarres2 -/- VAT. As we specifically knocked down chemerin in SAT, TIMP1 was down-regulated and adipogenesis was promoted with reducing infiltration of macrophages. The present study demonstrates that the effects of chemerin on adipose tissue is depot different, and specific knock down chemerin in SAT promote adipogenesis and improve glucose tolerance test (GTT) and insulin tolerance test (ITT). This suggests a potential therapeutic target for chemerin in the treatment of obesity related metabolic disorder.
RESUMEN
Protein glycosylation is an important post-translational modification. Aberrant glycosylation has been implicated in many diseases because of associated changes in protein distribution and biological function. We showed that the expression of ß1, 4-galactosyltransferase 5 (B4GalT5) was positively correlated with diabetes and obesity. In vivo, B4GalT5 knockdown in subcutaneous adipose tissue alleviated insulin resistance and adipose tissue inflammation, and increased adipogenesis in high-fat diet (HFD)-fed mice and ob/ob mice. Downregulation of B4GalT5 in preadipocyte cells induced commitment to the adipocyte lineage in the absence of bone morphogenetic protein (BMP) 2/4 treatment, which is typically essential for adipogenic commitment. RNAi silencing experiments showed B4GalT5 knockdown activated Smad and p38 MPAK signaling pathways through both type 1A and 2 BMP receptors. Remarkably, B4GalT5 knockdown decreased BMPRIA glycosylation but increased BMPRIA stability and cellular location, thus leading to redistribution of BMPRIA and activation of the BMP signaling pathway. Meanwhile, downregulation of B4GalT5 decreased the infiltration of macrophages and the markers of M1 macrophages in subcutaneous adipose tissue of HFD mice and ob/ob mice. In bone marrow-derived macrophages (BMDMs) and RAW264.7cells, B4GalT5 knockdown also repressed the markers of M1 by reducing NFκB and JNK signaling. These results demonstrated B4GalT5 downregulation improved insulin resistance by promoting adipogenic commitment and decreasing M1 macrophage infiltration.
Asunto(s)
Adipocitos/metabolismo , Galactosiltransferasas/metabolismo , Inflamación/genética , Inflamación/metabolismo , Resistencia a la Insulina/genética , Animales , Regulación hacia Abajo , Humanos , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BLRESUMEN
BACKGROUND & AIMS: Due to the protective effect of estrogen against hepatic fat accumulation, the prevalence of non-alcoholic fatty liver disease (NAFLD) in premenopausal women is lower than that in men at the same age and in postmenopausal women. Our study was to further elucidate an underlying mechanism by which estrogen prevents NAFLD from miRNA perspective in female mice. METHODS: miRNA expression was evaluated by TaqMan miRNA assay. Luciferase and ChIP assay were done to validate regulation of miR-125b by estrogen via estrogen receptor alpha (ERα). Nile red and Oil red O staining were used to check lipid content. Overexpressing or inhibiting the physiological role of miR-125b in the liver of mice through injecting adenovirus were used to identify the function of miR-125b in vivo. RESULTS: miR-125b expression was activated by estrogen via ERα in vitro and in vivo. miR-125b inhibited lipid accumulation both in HepG2 cells and primary mouse hepatocytes. Consistently, ovariectomized or liver-specific ERα knockdown mice treated with miR-125b overexpressing adenoviruses were resistant to hepatic steatosis induced by high-fat diet, due to decreased fatty acid uptake and synthesis and decreased triglyceride synthesis. Conversely, inhibiting the physiological role of miR-125b with a sponge decoy slightly promoted liver steatosis with a high-fat diet. Notably, we provided evidence showing that fatty acid synthase was a functional target of miR-125b. CONCLUSION: Our findings identify a novel mechanism by which estrogen protects against hepatic steatosis in female mice via upregulating miR-125b expression.