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MiR-503 inhibits adipogenesis by targeting bone morphogenetic protein receptor 1a.

ABSTRACT: Adipogenesis plays a key role in the regulation of whole-body energy homeostasis and is critically related to obesity. To overcome obesity and its associated disorders, it is necessary to elucidate the molecular mechanisms involved in adipogenesis. An adipogenesis-related miRNA array analysis demonstrated that miR-503 was differentially expressed before and after adipocyte differentiation; however, the exact role of miR-503 in adipocyte differentiation is unclear. Thus, the objective of this study was to further examine miR-503 in adipocyte differentiation. We found significantly decreased expression of miR-503 during adipocyte differentiation process. Using bioinformatic analysis, miR-503 was identified as a potential regulator of Bone Morphogenetic Protein Receptor 1a (BMPR1a). We then validated BMPR1a as the target of miR-503 using a dual luciferase assay, and found decreased miR-503 and increased BMPR1a expression during adipogenesis. Overexpression of miR-503 in preadipocytes repressed expression of BMPR1a and adipogenic-related factors such as CCAAT/enhancer binding protein a (C/EBP?), proliferator-activated receptor-gamma (PPAR?), and adipocyte protein 2 (AP2). In addition, miR-503 overexpression impaired the phosphoinositol-3 kinase (PI3K)/Akt pathway. Inhibition of miR-503 had the opposite effect. Additionally, BMPR1a interference by siRNA attenuated adipocyte differentiation and the accumulation of lipid droplets via downregulating the PI3K/Akt signaling pathway. Our study provides the first evidence of the role miR-503 plays in adipocyte differentiation by regulating BMPR1a via the PI3K/Akt pathway, which may become a novel target for obesity therapy.

SUBMITTER: Man XF

PROVIDER: S-EPMC4931166 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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MiR-503 inhibits adipogenesis by targeting bone morphogenetic protein receptor 1a.

Man Xiao-Fei XF Tan Shu-Wen SW Tang Hao-Neng HN Guo Yue Y Tang Chen-Yi CY Tang Jun J Zhou Ci-La CL Zhou Hou-De HD

American journal of translational research 20160615 6

Adipogenesis plays a key role in the regulation of whole-body energy homeostasis and is critically related to obesity. To overcome obesity and its associated disorders, it is necessary to elucidate the molecular mechanisms involved in adipogenesis. An adipogenesis-related miRNA array analysis demonstrated that miR-503 was differentially expressed before and after adipocyte differentiation; however, the exact role of miR-503 in adipocyte differentiation is unclear. Thus, the objective of this stu ...[more]

PMID: 27398155

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Project description:BACKGROUND: Bone morphogenetic protein-3b (BMP-3b) is a member of the transforming growth factor-? (TGF-?) superfamily. BMP-3b regulates osteogenesis and has critical roles in developing embryos. BMP-3b is expressed not only in the bone and developing embryos but also in adipose tissues. However, the functions of BMP-3b in adipose tissue are still unknown. METHODS: BMP-3b expression was quantified in various adipose tissues and in the adipose-derived stromal-vascular fraction (SVF) and mature adipocyte fraction (AD.F) of mice. We also used 3T3-L1 preadipocytes to analyze the expression, function and molecular forms of BMP-3b. In order to determine the effects of BMP-3b on the adipogenesis of 3T3-L1 cells, BMP-3b siRNA-mediated knockdown and gene overexpression studies were performed, and a conditioned medium (CM) containing the BMP-3b protein was added to 3T3-L1 cell cultures. Adipocyte differentiation was evaluated by measuring the expression of adipogenic markers or by Oil Red O staining. The molecular form of BMP-3b that was secreted from the 3T3-L1 cells was analyzed by western blotting. RESULTS: BMP-3b is expressed in all adipose tissues and is expressed at higher levels in preadipocytes than in mature adipocytes. In mesenteric adipose tissue, BMP-3b expression was increased in diet-induced obesity (DIO) mice as compared with that in control mice. BMP-3b was also expressed highly in 3T3-L1 cells. We showed that siRNA-mediated knockdown of endogenous BMP-3b expression in 3T3-L1 cells enhanced adipogenesis. Conversely, overexpressing BMP-3b inhibited adipocyte differentiation. We also showed that addition of CM containing the BMP-3b protein inhibited the differentiation of 3T3-L1 cells, and that this inhibitory effect was abolished by removing BMP-3b with an anti-BMP-3b antibody. Furthermore, BMP-3b was secreted from adipocytes as a unique non-covalent complex. CONCLUSION: These data suggest that BMP-3b is secreted from adipocytes and is involved in adipocyte differentiation.

Project description:BACKGROUND:Bone morphogenetic proteins (BMPs) regulate adipogenesis but it is not clear whether they influence regional adipose tissue (AT) development in humans. OBJECTIVE:To characterise BMP2 expression, BMP2-SMAD1/5/8 signalling, and BMP2's potential effect on proliferation and adipogenesis in human subcutaneous abdominal and gluteal AT and its constituent preadipocytes. METHODS:BMP2 expression was measured in whole AT and immortalised preadipocytes via qPCR and Western blot; secreted/circulating BMP2 was measured by ELISA. The effect of BMP2 on preadipocyte proliferation was evaluated using a fluorescent assay. BMP2's effect on adipogenesis in immortalised preadipocytes was determined via qPCR of adipogenic markers and cellular triacylglycerol (TAG) accumulation. BMP2-SMAD1/5/8 signalling was assessed in immortalised preadipocytes via Western blot and qPCR of ID1 expression. RESULTS:BMP2 was expressed and released by abdominal and gluteal AT and preadipocytes. Exogenous BMP2 dose dependently promoted adipogenesis in abdominal preadipocytes only; 50?ng/ml BMP2 increased PPARG2 expression (10-fold compared to vehicle, p?<?0.001) and TAG accumulation (3-fold compared to vehicle; p?<?0.001). BMP2 stimulated SMAD1/5/8 phosphorylation and ID1 expression in abdominal and gluteal preadipocytes but this was blocked by 500?nM K02288, a type 1 BMP receptor inhibitor (p?<?0.001). Co-administration of 500?nM K02288 also inhibited the pro-adipogenic effect of 50?ng/ml BMP2 in abdominal cells; >90% inhibition of TAG accumulation (p?<?0.001) and ~50% inhibition of PPARG2 expression (p?<?0.001). The endogenous iron regulator erythroferrone reduced BMP2-SMAD1/5/8 signalling by ~30% specifically in subcutaneous abdominal preadipocytes (p?<?0.01), suggesting it plays a role in restricting the expansion of the body's largest AT depot during energy deficiency. Additionally, a waist-hip ratio-increasing common polymorphism near BMP2 is an eQTL associated with ~15% lower BMP2 expression in abdominal and gluteal AT (p?<?0.05) as well as altered adipocyte size in male abdominal AT (p?<?0.05). CONCLUSIONS:These data implicate BMP2-SMAD1/5/8 signalling in depot-specific preadipocyte development and abdominal AT expansion in humans.

Project description:Previous work has shown that the soluble murine BMPR1A-fusion protein (mBMPR1A-mFc) binds to BMP2 and BMP4 with high affinity, preventing downstream signaling. Further, treatment of intact and ovariectomized mice with mBMPR1A-mFc leads to increased bone mass, and improved bone microarchitecture and strength, via increased bone formation and reduced resorption. In this study, we tested the effects of mBMPR1A-mFc on disuse-induced bone loss caused by 21 days of hindlimb unloading (HLU) via tail suspension versus cage controls (CONs). Adult female C57BL/6J mice (12 weeks old) were assigned to one of four groups (n?=?10 each): CON-VEH; CON-mBMPR1A-mFc; HLU-VEH; and HLU-mBMPR1A-mFc. Mice were injected subcutaneously with VEH or mBMPR1A-mFc (4.5?mg/kg, 2×/week). Leg BMD declined in the HLU-VEH group (-5.3%?±?1.3%), whereas it was unchanged in HLU-mBMPR1A-mFc (-0.3%?±?0.9%, p?<?0.05 versus HLU-VEH). Leg BMD increased significantly more in CON-mBMPR1A-mFc than CON-VEH (10.2%?±?0.6% versus 4.4%?±?0.8%). In the femur, trabecular, and cortical bone microarchitecture was worse in the HLU-VEH compared to CON-VEH mice, whereas mBMPR1A-mFc treatment for 3 weeks led to greater Tb.BV/TV, Tb.Th, and midshaft Ct.Th in both the HLU and CON groups compared to comparable VEH-treated counterparts (p?<?0.05). HLU-mBMPR1A-mFc mice also had 21% greater failure load (p?<?0.05) compared to their VEH-treated counterparts. Dynamic histomorphometry indicated that treatment with mBMPR1A-mFc led to significantly greater mineralizing surface and mineral apposition rate, resulting in a 3.5-fold and fivefold higher bone formation rate in the mBMPR1A-mFc-treated CON and HLU animals versus VEH groups, respectively. mBMPR1A-mFc-treated mice had a similar osteoblast surface but significantly lower osteoclast surface than VEH-treated animals in both the CON and HLU groups. Altogether, these findings suggest that treatment with the soluble BMPR1A fusion protein may be useful for maintenance of skeletal integrity in the setting of disuse-induced bone loss.

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MiR-503 inhibits adipogenesis by targeting bone morphogenetic protein receptor 1a.

Publications

MiR-503 inhibits adipogenesis by targeting bone morphogenetic protein receptor 1a.

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