Dataset Information

A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism: Liver RNA profiles of lean non-diabetic, obese non-diabetic as well as obese diabetic humans.

ABSTRACT: Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcrips with elusive functions in metabolism. Here we report that an unexpectedly high fraction of lncRNAs, but not protein-coding mRNAs, is repressed during diet-induced obesity (DIO) and refeeding, whilst nutrient deprivation specifically induced lncRNAs in mouse liver. Similarly, lncRNAs were lost in diabetic humans. LncRNA promoter analyses, global cistrome and gain-of-function analyses confirmed that increased MAFG signaling during DIO curbs lncRNA expression. Silencing Mafg in primary hepatocytes and in vivo elicited a fasting-like expression profile, improved glucose metabolism, derepressed lncRNAs and prevented mammalian target of rapamycin (mTOR)-driven protein translation. We found that obesity-repressed lincIRS2 is controlled by MAFG and observed that genetic and RNAi-mediated lincIRS2 loss causes hyperglycemia, insulin resistance and aberrant glucose output in lean mice. Taken together, we identify a novel MAFG-lncRNA axis controlling hepatic glucose metabolism in health and metabolic disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE121344 | GEO | 2019/12/18

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Activated brown adipose tissue contributes to control of energy and glucose homeostasis in rodents and humans. Defining cell-autonomous processes underlying BAT differentiation and activation may thus reveal novel therapeutic targets for obesity and type 2 diabetes mellitus intervention. Here we show that ageing- and obesity-associated demises in BAT function coincide with down-regulation of mature microRNAs in BAT in the presence of reduced expression of the critical microRNA processing enzyme Dicer1. To mimic this partial down-regulation of microRNA processing in obesity and ageing, we inactivated one allele of Dicer1 selectively in BAT of mice. BAT- restricted heterozygosity of Dicer1 caused glucose intolerance in lean mice and aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose homeostasis. Using combinatorial analyses of altered microRNA-expression in BAT during in vitro preadipocyte commitment and mouse models of progeria, longevity and DIO, we identified 23 microRNAs dysregulated among these conditions. Of these, we identified miR-328 as a novel regulator of BAT differentiation. miR-328 over-expression promotes BAT-differentiation and impairs muscle progenitor commitment, while reducing miR-328 expression blocks BAT specification. We validated the ß-Secretase Bace1 as a target of miR-328, which is consequently over-expressed in BAT of obese and premature ageing mice. Reducing Bace1 expression enhances brown adipocyte, while impairing myogenic differentiation in vitro. In vivo small-molecule Bace1 inhibition in obese mice delayed DIO-induced weight gain, ameliorated obesity-associated deterioration of glucose metabolism and improved insulin sensitivity. Collectively, these experiments reveal reduced Dicer1-miR-328-Bace1 axis in presence of generalized impairment of microRNA processing in ageing and obesity as a novel determinant of ageing- and obesity-associated decline in BAT function. This may define in vivo Bace1-inhibition as an innovative therapeutic approach to not only target age-related neurodegenerative diseases but at the same time improving age-related impairment of BAT-function and metabolism. C57BL/6 mice ( 4 weeks of age) were treated with a calory-rich, high-sugar high-fat diet (HFD) for a course of 4 weeks. Then groups were stratified and one group continued to receive HFD (BAT13-15) or HFD supplemented with an experimental small-molecule Bace 1 inhibitor (BAT17, 33, 35).

Project description:To profile the expression of circulating miRNAs in a mouse model of diet-induced obesity (DIO) with subsequent weight-reduction with low-fat diet (LFD), eighteen C57BL/6 male mice were grouped into three subgroups as: (1) Control: the mice fed with the standard AIN-76A (fat: 11.5 kcal%) diet for 12 wks; (2) DIO: the mice fed with 58 kcal% high-fat diet for 12 wks; (3) DIO+LFD: the mice fed with high-fat diet for 8 wks to induce obesity, then changed to 10.5 kcal% low-fat diet for subsequent 4 wks. C57BL/6 mice were purchased from BioLasco (Taipei, Taiwan). All housing conditions were maintained, and surgical procedures, including analgesia, were performed in an Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC)-accredited SPF facility according to national and institutional guidelines. In this experiment, eighteen C57BL/6 wild type male mice were randomly grouped into three subgroups (n=6 in each group): (1) Control: the control mice were fed ad libitum a standard AIN-76A (fat: 11.5 kcal%) diet for 12 wks; (2) DIO: the mice were fed ad libitum a 58 kcal% HFD (D12331; Research Diets Inc., New Brunswick, NJ) for 12 wks to induce obesity; (3) DIO+LFD: the mice fed ad libitum a 58 kcal% HFD (D12331) for 8 wks to induce obesity, then continued the feeding of 10.5 kcal% LFD (D 12329; Research Diets Inc.) for additional 4 wks. Weight measurements were performed on a weekly basis to for these three groups of mice. Evaluation of blood glucose levels was performed at the beginning and in the end of the experiment to confirm that the HFD-fed mice developed an obese and insulin resistant phenotype. After the end of experiment at 12w, all mice were killed. The abdominal WAT of each mice was removed and weighted. Paraffin-embedded abdominal WAT was sectioned at 5 M-NM-<m and stained with hematoxylin and eosin to measure mean adipocyte area. A volume of 1 mL of whole blood was collected into a plain tube and allowed to clot for 1 hour. The sera samples were aliquoted after centrifugation at 3,000 M-CM-^W g for 10 minutes and stored at M-bM-^HM-^R80M-BM-0C until further analysis.

Dataset Information

A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism: Liver RNA profiles of lean non-diabetic, obese non-diabetic as well as obese diabetic humans.

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets