Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The liver X receptor agonist T0901317 protects mice from high fat diet-induced obesity and insulin resistance.

ABSTRACT: The effect of activation of liver X receptor by N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]phenyl] benzenesulfonamide (T0901317) on high fat diet (HFD)-induced obesity and insulin resistance was examined in C57BL/6 mice. When on HFD continuously for 10 weeks, C57BL/6 mice became obese with an average body weight of 42 g, insulin resistant, and glucose intolerant. Twice weekly intraperitoneal injections of T0901317 at 50 mg/kg in animals on the same diet completely blocked obesity development, obesity-associated insulin resistance, and glucose intolerance. Quantitative real-time PCR analysis showed that T0901317-treated animals had significantly higher mRNA levels of genes involved in energy metabolism, including Ucp-1, Pgc1a, Pgc1b, Cpt1a, Cpt1b, Acadm, Acadl, Aox, and Ehhadh. Transcription activation of Cyp7a1, Srebp-1c, Fas, Scd-1, and Acc-1 genes was also seen in T0901317-treated animals. T0901317 treatment induced reversible aggregation of lipids in the liver. These results suggest that liver X receptor could be a potential target for prevention of obesity and obesity-associated insulin resistance.

SUBMITTER: Gao M

PROVIDER: S-EPMC3535091 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity.

Project description:Obesity is associated with low-grade inflammation that leads to insulin resistance and type 2 diabetes via Toll-like Receptor (TLR) and TNF-family cytokine receptor (TNFR) signaling pathways. Ubc13 is an ubiquitin-conjugating enzyme responsible for non-canonical K63-linked polyubiquitination of TNF receptor-associated factor (TRAF)-family adapter proteins involved in TLR and TNFR pathways. However, the relationship between Ubc13 and metabolic disease remains unclear. In this study, we investigated the role of Ubc13 in insulin resistance and high-fat diet (HFD)-induced obesity. We compared wild-type (WT) and Ubc13 haploinsufficient (ubc13(+/-)) mice under normal diet (ND) and HFD, since homozygous knockout mice (ubc13(-/-)) are embryonic lethal. Male and female ubc13(+/-) mice were protected against age-related insulin resistance under ND and HFD compared to WT mice. Interestingly, only female ubc13(+/-) mice were protected against HFD-induced obesity and hepatic steatosis. Moreover, only female HFD-fed ubc13(+/-) mice showed lower expression of inflammatory cytokines that was secondary to reduction in weight gain not present in the other groups. In summary, our results indicate that suppression of Ubc13 activity may play a metabolic role independent of its inflammatory function. Thus, Ubc13 could represent a therapeutic target for insulin resistance, diet-induced obesity, and associated metabolic dysfunctions.

| S-EPMC5086849 | biostudies-other

Vimentin Deficiency Prevents High-Fat Diet-Induced Obesity and Insulin Resistance in Mice.

Project description:BackgroundObesity and type 2 diabetes mellitus are world-wide health problems, and lack of understanding of their linking mechanism is one reason for limited treatment options. We determined if genetic deletion of vimentin, a type 3 intermediate filament, affects obesity and type 2 diabetes mellitus.MethodsWe fed vimentin-null (Vim-/-) mice and wild-type mice a high-fat diet (HFD) for 10 weeks and measured weight change, adiposity, blood lipids, and glucose. We performed intraperitoneal glucose tolerance tests and measured CD36, a major fatty acid translocase, and glucose transporter type 4 (GLUT4) in adipocytes from both groups of mice.ResultsVim-/- mice fed an HFD showed less weight gain, less adiposity, improved glucose tolerance, and lower serum level of fasting glucose. However, serum triglyceride and non-esterified fatty acid levels were higher in Vim-/- mice than in wild-type mice. Vimentin-null adipocytes showed 41.1% less CD36 on plasma membranes, 27% less uptake of fatty acids, and 50.3% less GLUT4, suggesting defects in intracellular trafficking of these molecules.ConclusionWe concluded that vimentin deficiency prevents obesity and insulin resistance in mice fed an HFD and suggest vimentin as a central mediator linking obesity and type 2 diabetes mellitus.

| S-EPMC7850873 | biostudies-literature

Blocking high-fat diet-induced obesity, insulin resistance and fatty liver by overexpression of Il-13 gene in mice.

Project description:The objective of this study was to assess the activity of anti-inflammatory cytokine IL-13 (interleukin-13) in blocking high-fat diet-induced obesity and obesity-associated insulin resistance and liver steatosis.C57BL/6 mice were fed a high-fat diet and received hydrodynamic delivery of plasmids carrying the mouse Il-13 or Gfp (control) gene. IL-13 blood protein levels, food consumption and body weight of mice were continuously monitored for 8 weeks. Fat and lean masses of treated and control animals were determined at the end of the experiment. Serum concentrations of glucose, insulin and lipids were determined, and mRNA levels of macrophage marker genes in adipose tissue and genes involved in energy metabolism were examined using real-time PCR. Glucose tolerance and insulin sensitivity tests were performed to determine glucose homeostasis. Histochemistry and lipid assays were performed to determine the hepatic lipid accumulation.Blood concentration of IL-13 was 20?ng?ml(-1) 1 week after gene delivery and declined with time. Overexpression of Il-13 prevented high-fat diet-induced weight gain without affecting food consumption. Mice that underwent Il-13 gene transfer showed regular body weight and normal serum concentrations of glucose and insulin, and less lipid accumulation in the liver. Overexpression of Il-13 blocked macrophage infiltration in adipose tissue and suppressed high-fat diet-induced expression of inflammatory F4/80, Cd68 and Mcp1, and elevated the expression of Ucp1 (uncoupling protein 1 gene) responsible for energy expenditure.These results suggest that suppression of diet-induced inflammation by IL-13 is an effective strategy in preventing diet-induced obesity and obesity-associated insulin resistance and fatty liver.

| S-EPMC4595909 | biostudies-literature

Loss of mitochondrial protease ClpP protects mice from diet-induced obesity and insulin resistance.

Project description:Caseinolytic peptidase P (ClpP) is a mammalian quality control protease that is proposed to play an important role in the initiation of the mitochondrial unfolded protein response (UPRmt), a retrograde signaling response that helps to maintain mitochondrial protein homeostasis. Mitochondrial dysfunction is associated with the development of metabolic disorders, and to understand the effect of a defective UPRmt on metabolism, ClpP knockout (ClpP-/-) mice were analyzed. ClpP-/- mice fed ad libitum have reduced adiposity and paradoxically improved insulin sensitivity. Absence of ClpP increased whole-body energy expenditure and markers of mitochondrial biogenesis are selectively up-regulated in the white adipose tissue (WAT) of ClpP-/- mice. When challenged with a metabolic stress such as high-fat diet, despite similar caloric intake, ClpP-/- mice are protected from diet-induced obesity, glucose intolerance, insulin resistance, and hepatic steatosis. Our results show that absence of ClpP triggers compensatory responses in mice and suggest that ClpP might be dispensable for mammalian UPRmt initiation. Thus, we made an unexpected finding that deficiency of ClpP in mice is metabolically beneficial.

| S-EPMC5836096 | biostudies-literature

CREG1 heterozygous mice are susceptible to high fat diet-induced obesity and insulin resistance.

Project description:Cellular repressor of E1A-stimulated genes 1 (CREG1) is a small glycoprotein whose physiological function is unknown. In cell culture studies, CREG1 promotes cellular differentiation and maturation. To elucidate its physiological functions, we deleted the Creg1 gene in mice and found that loss of CREG1 leads to early embryonic death, suggesting that it is essential for early development. In the analysis of Creg1 heterozygous mice, we unexpectedly observed that they developed obesity as they get older. In this study, we further studied this phenotype by feeding wild type (WT) and Creg1 heterozygote (Creg1+/-) mice a high fat diet (HFD) for 16 weeks. Our data showed that Creg1+/- mice exhibited a more prominent obesity phenotype with no change in food intake compared with WT controls when challenged with HFD. Creg1 haploinsufficiency also exacerbated HFD-induced liver steatosis, dyslipidemia and insulin resistance. In addition, HFD markedly increased pro-inflammatory cytokines in plasma and epididymal adipose tissue in Creg1+/- mice as compared with WT controls. The activation level of NF-κB, a major regulator of inflammatory response, in epididymal adipose tissue was also elevated in parallel with the cytokines in Creg1+/- mice. These pro-inflammatory responses elicited by CREG1 reduction were confirmed in 3T3-L1-derived adipocytes with CREG1 depletion by siRNA transfection. Given that adipose tissue inflammation has been shown to play a key role in obesity-induced insulin resistance and metabolic syndrome, our results suggest that Creg1 haploinsufficiency confers increased susceptibility of adipose tissue to inflammation, leading to aggravated obesity and insulin resistance when challenged with HFD. This study uncovered a novel function of CREG1 in metabolic disorders.

| S-EPMC5411056 | biostudies-literature

Notoginsenoside Ft1 acts as a TGR5 agonist but FXR antagonist to alleviate high fat diet-induced obesity and insulin resistance in mice.

Project description:Obesity and its associated complications are highly related to a current public health crisis around the world. A growing body of evidence has indicated that G-protein coupled bile acid (BA) receptor TGR5 (also known as Gpbar-1) is a potential drug target to treat obesity and associated metabolic disorders. We have identified notoginsenoside Ft1 (Ft1) from Panax notoginseng as an agonist of TGR5 in vitro. However, the pharmacological effects of Ft1 on diet-induced obese (DIO) mice and the underlying mechanisms are still elusive. Here we show that Ft1 (100 mg/100 diet) increased adipose lipolysis, promoted fat browning in inguinal adipose tissue and induced glucagon-like peptide-1 (GLP-1) secretion in the ileum of wild type but not Tgr5 -/- obese mice. In addition, Ft1 elevated serum free and taurine-conjugated bile acids (BAs) by antagonizing Fxr transcriptional activities in the ileum to activate Tgr5 in the adipose tissues. The metabolic benefits of Ft1 were abolished in Cyp27a1 -/- mice which have much lower BA levels. These results identify Ft1 as a single compound with opposite activities on two key BA receptors to alleviate high fat diet-induced obesity and insulin resistance in mice.

| S-EPMC8245856 | biostudies-literature

Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice.

Project description:Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway that converts cholesterol into bile acids in the liver. Recent studies have shown that bile acids may play an important role in maintaining lipid, glucose, and energy homeostasis. However, the role of CYP7A1 in the development of obesity and diabetes is currently unclear. In this study, we demonstrated that transgenic mice overexpressing Cyp7a1 in the liver [i.e., Cyp7a1 transgenic (Cyp7a1-tg) mice] were resistant to high-fat diet (HFD)-induced obesity, fatty liver, and insulin resistance. Cyp7a1-tg mice showed increased hepatic cholesterol catabolism and an increased bile acid pool. Cyp7a1-tg mice had increased secretion of hepatic very low density lipoprotein but maintained plasma triglyceride homeostasis. Gene expression analysis showed that the hepatic messenger RNA expression levels of several critical lipogenic and gluconeogenic genes were significantly decreased in HFD-fed Cyp7a1-tg mice. HFD-fed Cyp7a1-tg mice had increased whole body energy expenditure and induction of fatty acid oxidation genes in the brown adipose tissue.This study shows that Cyp7a1 plays a critical role in maintaining whole body lipid, glucose, and energy homeostasis. The induction of CYP7A1 expression with the expansion of the hydrophobic bile acid pool may be a potential therapeutic strategy for treating metabolic disorders such as fatty liver diseases, obesity, and diabetes in humans.

| S-EPMC3700412 | biostudies-literature

Deficiency of phosphoinositide 3-kinase enhancer protects mice from diet-induced obesity and insulin resistance.

Project description:Phosphoinositide 3-kinase enhancer A (PIKE-A) is a proto-oncogene that promotes tumor growth and transformation by enhancing Akt activity. However, the physiological functions of PIKE-A in peripheral tissues are unknown. Here, we describe the effect of PIKE deletion in mice and explore the role of PIKE-A in obesity development.Whole-body PIKE knockout mice were generated and subjected to high-fat-diet feeding for 20 weeks. The glucose tolerance, tissue-specific insulin sensitivity, adipocyte differentiation, and lipid oxidation status were determined. The molecular mechanism of PIKE in the insulin signaling pathway was also studied.We show that PIKE-A regulates obesity development by modulating AMP-activated protein kinase (AMPK) phosphorylation. PIKE-A is important for insulin to suppress AMPK phosphorylation. The expression of PIKE-A is markedly increased in adipose tissue of obese mice, whereas depletion of PIKE-A inhibits adipocyte differentiation. PIKE knockout mice exhibit a prominent phenotype of lipoatrophy and are resistant to high-fat diet-induced obesity, liver steatosis, and diabetes. PIKE knockout mice also have augmented lipid oxidation, which is accompanied by enhanced AMPK phosphorylation in both muscle and adipose tissue. Moreover, insulin sensitivity is improved in PIKE-A-deficient muscle and fat, thus protecting the animals from diet-induced diabetes.Our results suggest that PIKE-A is implicated in obesity and associated diabetes development by negatively regulating AMPK activity.

| S-EPMC2844836 | biostudies-other

Increased 4E-BP1 Expression Protects against Diet-Induced Obesity and Insulin Resistance in Male Mice.

Project description:Obesity is a major risk factor driving the global type II diabetes pandemic. However, the molecular factors linking obesity to disease remain to be elucidated. Gender differences are apparent in humans and are also observed in murine models. Here, we link these differences to expression of eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which, upon HFD feeding, becomes significantly reduced in the skeletal muscle and adipose tissue of male but not female mice. Strikingly, restoring 4E-BP1 expression in male mice protects them against HFD-induced obesity and insulin resistance. Male 4E-BP1 transgenic mice also exhibit reduced white adipose tissue accumulation accompanied by decreased circulating levels of leptin and triglycerides. Importantly, transgenic 4E-BP1 male mice are also protected from aging-induced obesity and metabolic decline on a normal diet. These results demonstrate that 4E-BP1 is a gender-specific suppressor of obesity that regulates insulin sensitivity and energy metabolism.

| S-EPMC4988876 | biostudies-literature

Skeletal muscle-targeted delivery of Fgf6 protects mice from diet-induced obesity and insulin resistance.

Project description:Obesity, a major health care issue, is characterized by metabolic abnormalities in multiple tissues, including the skeletal muscle. Although dysregulation of skeletal muscle metabolism can strongly influence the homeostasis of systemic energy, the underlying mechanism remains unclear. We found promoter hypermethylation and decreased gene expression of fibroblast growth factor 6 (FGF6) in the skeletal muscle of individuals with obesity using high-throughput sequencing. Reduced binding of the cyclic AMP responsive element binding protein-1 (CREB1) to the hypermethylated cyclic AMP response element, which is a regulatory element upstream of the transcription initiation site, partially contributed to the downregulation of FGF6 in patients with obesity. Overexpression of Fgf6 in mouse skeletal muscle stimulated protein synthesis, activating the mammalian target of rapamycin pathway, and prevented the increase in weight and the development of insulin resistance in high-fat diet-fed mice. Thus, our findings highlight the role played by Fgf6 in regulating skeletal muscle hypertrophy and whole-body metabolism, indicating its potential in strategies aimed at preventing and treating metabolic diseases.

| S-EPMC8525645 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data