Unknown,Transcriptomics,Genomics,Proteomics

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Two secreted phospholipase A2 enzymes, PLA2G5 and PLA2G2E, are induced in hypertrophic adipocytes and distinctly regulate obesity

ABSTRACT: Metabolic disorders including obesity and insulin resistance have their basis in dysregulated lipid metabolism and low-grade inflammation. In a microarray search of unique lipase-related genes whose expressions are associated with obesity, we found that two secreted phospholipase A2s (sPLA2s), PLA2G5 and PLA2G2E, were robustly induced in adipocytes of obese mice. Analyses of Pla2g5-/- and Pla2g2e-/- mice revealed distinct and previously unrecognized roles of these sPLA2s in diet-induced obesity. PLA2G5 hydrolyzed phosphatidylcholine in fat-overladen low-density lipoprotein to release unsaturated fatty acids, which prevented palmitate-induced M1 macrophage polarization. As such, PLA2G5 tipped the immune balance toward an M2 state, thereby counteracting adipose tissue inflammation, insulin resistance, hyperlipidemia and obesiy. PLA2G2E altered minor lipoprotein phospholipids, phosphatidylserine and phosphatidylethanolamine, and moderately facilitated lipid accumulation in adipose tissue and liver. Collectively, the identification of metabolic sPLA2s adds this gene family to a growing list of lipolytic enzymes that act as metabolic coordinators. white adipose tissues of C57BL/6 mice; two-condition experimentM-bM-^@M-^Shigh fat diet or low fat diet feeding for 18 weeks; 2 replicates, respectively

ORGANISM(S): Mus musculus

SUBMITTER: Yoshitaka Taketomi

PROVIDER: E-GEOD-56038 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Using standardized, semipurified diets is a crucial factor for reproducibility of experimental nutritional studies. For the purpose of comparability and integration of research, two European consortia, Mitofood and BIOCLAIMS, proposed an AIN-93-based standard reference diet, the standardized BIOCLAIMS low-fat diet (LFD) as well as a high-fat diet (HFD). In order to evaluate the BIOCLAIMS LFD and HFD, we performed short-term (5 days) and long-term (12 weeks) feeding experiments using male C57BL/6 mice. The HFD has the same composition as the LFD except the fat content is increased to 40% energy in exchange for carbohydrates. Both diets were accepted by the animals and proof of principle was given that the BIOCLAIMS HFD increases body weight and body fat and affects glucose homeostasis. Short-term feeding trials (5 days) were performed in order to identify metabolic and molecular parameters which can serve as acute predictors for metabolic disorders due to high-fat diet-induced obesity. We analyzed gene expression in gonadal white adipose tissue of short- and long-term fed animals with whole genome microarrays. The BIOCLAIMS HFD strongly influenced gene expression in white adipose tissue after short- and long-term intervention. A total number of 973 and 4678 transcripts were significantly different between both diets after 5 days feeding and 12 weeks feeding, respectively. A total number of 764 transcripts encoding 549 genes were significantly differentially regulated between LF and HF animals after 12 weeks feeding as well as after 5 days feeding. Of these 549 overlapping genes, a substantial number (434 genes) were expressed at a lower level and 115 genes were expressed at a higher level in the HF mice compared to the LF mice. Without exception, all genes were regulated equally. Pathway analysis revealed a prominent role for genes involved in lipid metabolism, carbohydrate metabolism and oxidative phosphorylation. This was confirmed by quantitative real-time reverse transcription PCR. The high predictive value of gene expression changes in our short-term study compared to long-term high fat feeding is a promising step to get well-defined, early biomarkers that could shorten animal trials considerably and allow a more rapid and efficient screening of different compounds. C57BL/6J wildtype male mice, aged 12 weeks, received a low-fat diet or a high-fat diet for 5 days or 12 weeks. After sacrification, white adipose tissue depots were dissected, and immediately snap frozen in liquid nitrogen. Total RNA was isolated, quantified and qualified, and subsequently used for global gene expression profiling using Agilent 4x44K microarrays.

Project description:Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aim to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH. Research Design and Methods: C57Bl/6 mice were chronically fed a high fat diet to induce NAFLD and compared with mice fed low fat diet. Extensive histological and phenotypical analyses coupled with a time-course study of plasma proteins using multiplex assay was performed. Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: LF-low (LFL) responders displaying normal liver morphology, LF-high (LFH) responders showing benign hepatic steatosis, HF-low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and HF-high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared to HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodelling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ and MIP-2, whereas insulin, TIMP-1, GCP-2 and MPO emerged as late markers. Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. Keywords: Expression profiling by array Male wildtype C57Bl/6 mice were fed LFD or HFD for 21 weeks. Mice were divided into 4 groups based on liver histology.

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Two secreted phospholipase A2 enzymes, PLA2G5 and PLA2G2E, are induced in hypertrophic adipocytes and distinctly regulate obesity

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