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Transcriptome profiling reveal the effect of Sutent in the mice adipose tissues and livers

ABSTRACT: We administered clinically relevant dose of sutent (a small molecule inhibitor of multi-target receptor tyrosine kinases) to mice daliy for 16 weeks. We then compared the effect of sutent on four tissues(BAT,iWAT,eWAT and liver) transcriptome using RNAseq. We found sutent treatment enhances energy expenditure and improves metabolism in mice under HFD. Results provide insight into the molecular mechanisms of sutent in the treatment of obesity.

ORGANISM(S): Mus musculus

PROVIDER: GSE118224 | GEO | 2018/12/26

REPOSITORIES: GEO

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Project description:We show that roscovitine; a cyclin-dependent kinases inhibitor; given to mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation and fibrosis. It also restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that Roscovitine induced a limited set of proteins associated with lipid metabolism, fatty acid oxidation metabolism and adipose tissue remodeling but suppressed expression of a larger array of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. Furthermore, the phosphoproteome analysis identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases [e.g., CDKs and MAPKs], AGC kinases [e.g., S6K and PKC isoforms], and CAMK kinases [e.g., SIK1 and SIK2]). Pathway enrichment analysis of annotated kinase-substrate pairs showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and phosphatidylcholine and creatine biosynthesis are enriched following roscovitine treatment. The increased creatine pathways combined with more active mitochondria in eWAT may contribute to roscovitine-induced weight loss. Surprisingly, we found that unlike for eWAT, roscovitine led to up regulation of large sets of proteins and phosphosites in brown adipose tissue (BAT). Analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups (AGC kinases [e.g., PKD1 and PKA] and CMGC kinases [e.g., CDKs and MAPKs]. Among the top enriched pathways of kinase-substrate pairs were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling, suggesting that roscovitine led to a metabolically more active BAT. Overall, roscovitine treatment led to restoration of mitochondrial activity in BAT and eWAT suppressed by HFD, likely accounting for enhanced energy expenditure and weight loss.

Project description:Objective: Procyanidins are polyphenolic bioactive compounds that exert beneficial effects against obesity and its related diseases. The aim of this study was to evaluate whether the supplementation with low doses of a grape seed procyanidin extract (GSPE) to dams during pre and postnatal periods has biological effects on their offspring at youth. Design: The metabolic imprinting effect of GSPE was evaluated in 30 days-old male offspring of four groups of rats that were fed either a standard diet (STD) or a high-fat diet (HFD) and supplemented with either GSPE at 25 mg per kg of body weight/day or vehicle during pregnancy and lactation. Results: A significant increase in the adiposity index and in the weight of all the white adipose tissue depots studied (retroperitoneal â??RWAT-, mesenteric â??MWAT-, epididymal â??EWAT- and inguinal â??IWAT-) was observed in offspring of dams fed with a HFD and treated with GSPE (HFT group), compared to the offspring of dams fed with the same diet and that do not received procyanidins (HF group). HFT animals also showed a higher number of cells in the EWAT, a sharply decrease of the circulating levels of monocyte chemoattractant protein-1 (MCP-1) as well as a moderate, but significant, decrease of plasma glycerol levels. The transcriptomic analysis performed in the EWAT showed 238 genes differentially expressed between HF and HFT animals, covering an entire range of processes related with the immune function and the inflammatory response (the metabolic pathway mainly reflected in the EWAT), adipose tissue remodeling and function, lipid and glucose homeostasis and metabolism of methyl groups. Conclusion: GSPE treatment to dams fed a HFD during pregnancy and lactation increases adiposity, decreases the circulating levels of MCP-1 and modulates the expression of key genes involved in the adipose tissue metabolism of their offspring. The microarray study was performed with the EWAT RNA samples of rats from the HF and the HFT groups (n=8 animals each).

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Transcriptome profiling reveal the effect of Sutent in the mice adipose tissues and livers

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