Dataset Information

A long non-coding RNA specifically expressed in early embryos programs the metabolic balance in adult mice

ABSTRACT: Long non-coding RNAs (lncRNAs) display higher tissue-specificity than mRNAs. In particular, many lncRNAs are specifically expressed in early embryos, but the physiological functions of most of them remain largely unknown. Here, we show that deficiency of Lncenc1, a lncRNA specifically expressed in early embryos, results in an altered glucose and lipid balance in adult mice. Newly weaned lncenc1-deficient mice have been shown to display higher fasting blood glucose levels and to prefer to use lipids as a fuel source. When mice were fed a normal chow diet (NCD), in which glucose was the main energy source, glucose intolerance and insulin resistance were observed in adult lncenc1-deficient mice. Under high-fat diet (HFD) conditions, however, lncenc1-deficient mice became healthier and could resist food-induced obesity and metabolic disturbances, including liver steatosis and hypercholesterolmia. Furthermore, PPARγ-regulated lipogenesis in liver was reduced in lncenc1-deficient mice fed an HFD, as shown by transcriptome analyses. Interestingly, lncenc1-deficient mouse embryonic fibroblasts (MEFs) showed impaired glycolysis and lipogenesis, suggesting that the metabolic defects may already exist in embryos. Our study provides the first piece of evidence showing the essential roles of embryo-specific lncRNAs in adult metabolism, verifying the “fetal origin” of adult metabolic disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE135314 | GEO | 2022/08/02

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:High Fructose Corn Syrup (HFCS), a sweetener rich in glucose and fructose, is nowadays widely used in beverages and processed foods, and its consumption has been correlated to the emergence and progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Nevertheless, the exact molecular mechanisms by which HFCS impacts hepatic metabolism are still unclear, especially in the context of obesity. In contrast, the vast majority of current studies in the field focus either on the detrimental role of fructose on NAFLD or compare the additive impact of fructose versus glucose in this process. Besides, studies elaborating on the role of fructose in NAFLD utilize molecular fructose, rather than HFCS, thus lacking simulation of human NAFLD in a more realistic way. Herein, by engaging combined omic approaches, we sought to characterize the additive impact of HFCS on NAFLD during obesity and recognize candidate pathways and molecules which could mediate the exaggeration of steatosis under these conditions. To achieve this goal, C57BL/6 male mice were fed a normal-fat (ND), a high-fat (HFD) or a HFD supplemented with HFCS (HFD-HFCS) and upon examination of their metabolic and NAFLD phenotype, proteomic and lipidomic analyses were conducted and utilized separately or in an integrated mode to identify HFCS-related molecular alterations of the hepatic metabolic landscape. Although HFD and HFD-HFCS mice displayed comparable obesity, HFD-HFCS mice showed greater aggravation of hepatic steatosis. Importantly, the HFD-HFCS hepatic proteome was characterized by an upregulation of the enzymes implicated in de novo lipogenesis (DNL), while palmitic-acid containing diglycerides were significantly increased in the HFD-HFCS hepatic lipidome, as compared to the HFD group. Integrated omic analysis further suggested that TCA cycle overstimulation, is likely contributing towards the intensification of steatosis in the HFD-HFCS dietary theme. Overall, our results imply that HFCS may significantly contribute to NAFLD aggravation during obesity, with its fructose-rich properties being the main suspect.

Project description:In an effort to reduce hepatic glucose production and lower plasma glucose levels that are characteristics of diabetes, we have devised a treatment whereby we enhance glycolysis in the liver of a type 2 diabetic mouse model (KK/H1J). We achieve this by raising the levels of a potent regulator of glucose metabolism, fructose-2,6-bisphosphate (F26BP). Treating the mice in this way, we have demonstrated amelioration of the diabetic phenotype in terms of lowering plasma glucose and insulin levels. These treated mice also display reduced weight gain, reduced adiposity, and normalized plasma and hepatic lipid levels. These latter metabolic changes brought about by raising F26BP levels are counterintuitive. A concurrent increase in glycolysis and lipogenesis is expected, however, we observe an increase in glycolysis with a concurrent decrease in lipogenesis. Preliminary analysis of gene expression in these mice has revealed alterations in gene expression of several genes that support the therapeutic effect of raising F26BP levels. To further profile F26BP effects on hepatic gene expression, we have applied a comprehensive approach to identify sets of genes and thereby biological pathways that are differentially regulated when hepatic glycolysis is accelerated in diabetic mice. Comparing diabetic and treated animals, we hope to further clarify the molecular and genetic signature of type 2 diabetes and obesity and elucidate how this signature is affected by raising F26BP levels. Our study examining gene array as well as the hepatic proteome has identified multiple gene and protein expression changes. Of particular relevance, we note that fatty acid metabolism and cholesterol metabolism pathways are significantly down-regulated in diabetic mice treated with a PFK-2 mutant engineered to raise F26BP levels, which underlie the changes we see in the metabolic parameters. 6 KK/H1J mice, a polygenic model of type 2 diabetes and obesity, weighing approximately 35g were used in this study. 3 mice were injected with GFP control adenovirus and 3 mice were injected with bisphosphatase deficient PFK-2 adenovirus (BPD). Mice were followed for 7 days before livers were extracted. Total cellular RNA was extracted from each mouse and analyzed by microarray separately.

Dataset Information

A long non-coding RNA specifically expressed in early embryos programs the metabolic balance in adult mice

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure