WISP1/CCN4 inhibits adipocyte differentiation through repression of PPARγ activity.
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ABSTRACT:
SUBMITTER: Ferrand N
PROVIDER: S-EPMC5431985 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BMPs have been shown to promote adipocyte differentiation through SMAD-dependent signaling. However, the role of TGF-β-activated kinase 1 (TAK1) in non-canonical BMP signaling in adipocyte differentiation remains unclear. Here, we show that TAK1 inhibition decreases lipid accumulation in C3H10T1/2 mesenchymal stem cells (MSCs) induced to differentiate into adipocytes. TAK1 knockdown by siRNA further confirms that TAK1 is required for adipocyte commitment of MSCs. Additionally, TAK1 knockdown inhibits adipogenesis of 3T3-L1 preadipocytes, indicating that TAK1 is not only needed for adipocyte commitment, but also required for adipocyte terminal differentiation. Furthermore, TAK1 ablation specifically in adipocytes reduced high fat diet-induced weight gain and improved glucose tolerance. Mechanistically, we demonstrate that TAK1 is required for PPARγ transactivation and promotes PPARγ transcriptional activity synergistically with TAK1 binding protein 1 (TAB1). Collectively, our results demonstrate that TAK1 plays a critical role in BMP-mediated adipocyte differentiation. J. Cell. Biochem. 118: 204-210, 2017. © 2016 Wiley Periodicals, Inc.
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Project description:ObjectivesPreviously, we have shown the involvement of cellular communication network factor 4/Wnt-activated protein Wnt-1-induced signaling protein 1 (CCN4/WISP1) in osteoarthritic (OA) cartilage and its detrimental effects on cartilage. Here, we investigated characteristics of CCN4 in chondrocyte biology by exploring correlations of CCN4 with genes expressed in human OA cartilage with functional follow-up.DesignSpearman correlation analysis was performed for genes correlating with CCN4 using our previously established RNA sequencing dataset of human preserved OA cartilage of the RAAK study, followed by a pathway enrichment analysis for genes with ρ ≥|0.6.| Chondrocyte migration in the absence or presence of CCN4 was determined in a scratch assay, measuring scratch size using a live cell imager for up to 36 h. Changes in expression levels of 12 genes, correlating with CCN4 and involved in migratory processes, were determined with reverse transcription-quantitative polymerase chain reaction (RT-qPCR).ResultsCorrelation of CCN4 with ρ ≥|0.6| was found for 58 genes in preserved human OA cartilage. Pathway analysis revealed "neural crest cell migration" as most significant enriched pathway, containing among others CORO1C, SEMA3C, and SMO. Addition of CCN4 to primary chondrocytes significantly enhance chondrocyte migration as demonstrated by reduced scratch size over the course of 36 h, but at the timepoints measured no effect was observed on mRNA expression of the 12 genes.ConclusionCCN4 increases cell migration of human primary OA chondrocytes. Since WISP1 expression is known to be increased in OA cartilage, this may serve to direct chondrocytes toward cartilage defects and orchestrate repair.
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Project description:The mechanism by which adipocyte-derived endocrine factors promote insulin resistance in skeletal muscle are not fully understood. MiR-27a is highly expressed in sera of obese individuals with prediabetes and T2DM, and mainly derived by adipose tissues. Thus, miR-27a secreted into circulation by adipose tissue may regulate insulin resistance in skeletal muscle. Methods: The association between miR-27a and insulin resistance in skeletal muscle was determined in obese children, high-fat diet-induced miR-27a knockdown obese mice, db/db mice and C2C12 cells overexpressing miR-27a. The crosstalk mediated by exosomal miR-27a between adipose tissue and skeletal muscle was determined in C2C12 cells incubated with conditioned medium prepared from palmitate-treated 3T3-L1 adipocytes. Results: We showed that serum miR-27a level correlated positively with obesity and insulin resistance in obese children, and that elevated serum miR-27a levels correlated with insulin resistance in leptin receptor-deficient db/db mice, and with obesity and insulin resistance in high-fat diet-fed C57BL/6J mice. MiR-27a released from adipocytes of high-fat diet-fed C57BL/6J mice was associated with triglyceride accumulation. MiR-27a derived from these adipocytes induced insulin resistance in C2C12 skeletal muscle cells through miR-27a-mediated repression of PPARγ and its downstream genes involved in the development of obesity. Conclusions: These results identify a novel crosstalk signaling pathway between adipose tissue and skeletal muscle in the development of insulin resistance, and indicate that adipose tissue-derived miR-27a may play a key role in the development of obesity-triggered insulin resistance in skeletal muscle.
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