JNK1 Deficient Insulin-Producing Cells Are Protected against Interleukin-1?-Induced Apoptosis Associated with Abrogated Myc Expression.
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ABSTRACT:
SUBMITTER: Prause M
PROVIDER: S-EPMC4745310 | biostudies-literature | 2016
REPOSITORIES: biostudies-literature
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Project description:ObjectiveThe nuclear receptor TAK1/TR4/NR2C2 is expressed in several tissues that are important in the control of energy homeostasis. In this study, we investigate whether TAK1 functions as a regulator of lipid and energy homeostasis and has a role in metabolic syndrome.Research design and methodsWe generated TAK1-deficient (TAK1⁻(/)⁻) mice to study the function of TAK1 in the development of metabolic syndrome in aged mice and mice fed a high-fat diet (HFD). (Immuno)histochemical, biochemical, and gene expression profile analyses were performed to determine the effect of the loss of TAK1 expression on lipid homeostasis in liver and adipose tissues. In addition, insulin sensitivity, energy expenditure, and adipose-associated inflammation were compared in wild-type (WT) and TAK1⁻(/)⁻ mice fed a HFD.ResultsTAK1-deficient (TAK1⁻(/)⁻) mice are resistant to the development of age- and HFD-induced metabolic syndrome. Histo- and biochemical analyses showed significantly lower hepatic triglyceride levels and reduced lipid accumulation in adipose tissue in TAK1⁻(/)⁻ mice compared with WT mice. Gene expression profiling analysis revealed that the expression of several genes encoding proteins involved in lipid uptake and triglyceride synthesis and storage, including Cidea, Cidec, Mogat1, and CD36, was greatly decreased in the liver and primary hepatocytes of TAK1⁻(/)⁻ mice. Restoration of TAK1 expression in TAK1⁻(/)⁻ hepatocytes induced expression of several lipogenic genes. Moreover, TAK1⁻(/)⁻ mice exhibited reduced infiltration of inflammatory cells and expression of inflammatory genes in white adipose tissue, and were resistant to the development of glucose intolerance and insulin resistance. TAK1⁻(/)⁻ mice consume more oxygen and produce more carbon dioxide than WT mice, suggesting increased energy expenditure.ConclusionsOur data reveal that TAK1 plays a critical role in the regulation of energy and lipid homeostasis, and promotes the development of metabolic syndrome. TAK1 may provide a new therapeutic target in the management of obesity, diabetes, and liver steatosis.
| S-EPMC3012170 | biostudies-literature
Project description:BackgroundThe leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins constitute an integral membrane protein family that has three members: LRIG1, LRIG2, and LRIG3. LRIG1 negatively regulates growth factor signaling, but little is known regarding the functions of LRIG2 and LRIG3. In oligodendroglial brain tumors, high expression of LRIG2 correlates with poor patient survival. Lrig1 and Lrig3 knockout mice are viable, but there have been no reports on Lrig2-deficient mice to date.Methodology/principal findingsLrig2-deficient mice were generated by the ablation of Lrig2 exon 12 (Lrig2E12). The Lrig2E12-/- mice showed a transiently reduced growth rate and an increased spontaneous mortality rate; 20-25% of these mice died before 130 days of age, with the majority of the deaths occurring before 50 days. Ntv-a transgenic mice with different Lrig2 genotypes were transduced by intracranial injection with platelet-derived growth factor (PDGF) B-encoding replication-competent avian retrovirus (RCAS)-producing DF-1 cells. All injected Lrig2E12+/+ mice developed Lrig2 expressing oligodendroglial brain tumors of lower grade (82%) or glioblastoma-like tumors of higher grade (18%). Lrig2E12-/- mice, in contrast, only developed lower grade tumors (77%) or had no detectable tumors (23%). Lrig2E12-/- mouse embryonic fibroblasts (MEF) showed altered induction-kinetics of immediate-early genes Fos and Egr2 in response to PDGF-BB stimulation. However, Lrig2E12-/- MEFs showed no changes in Pdgfr? or Pdgfr? levels or in levels of PDGF-BB-induced phosphorylation of Pdgfr?, Pdgfr?, Akt, or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Overexpression of LRIG1, but not of LRIG2, downregulated PDGFR? levels in HEK-293T cells.ConclusionsThe phenotype of Lrig2E12-/- mice showed that Lrig2 was a promoter of PDGFB-induced glioma, and Lrig2 appeared to have important molecular and developmental functions that were distinct from those of Lrig1 and Lrig3.
| S-EPMC3762791 | biostudies-literature
Project description:Oxidative phosphorylation in mitochondria is responsible for 90% of ATP synthesis in most cells. This essential housekeeping function is mediated by nuclear and mitochondrial genes encoding subunits of complex I to V of the respiratory chain. Although complex IV is the best studied of these complexes, the exact function of the striated muscle-specific subunit COX6A2 is still poorly understood. In this study, we show that Cox6a2-deficient mice are protected against high-fat diet-induced obesity, insulin resistance and glucose intolerance. This phenotype results from elevated energy expenditure and a skeletal muscle fiber type switch towards more oxidative fibers. At the molecular level we observe increased formation of reactive oxygen species, constitutive activation of AMP-activated protein kinase, and enhanced expression of uncoupling proteins. Our data indicate that COX6A2 is a regulator of respiratory uncoupling in muscle and we demonstrate that a novel and direct link exists between muscle respiratory chain activity and diet-induced obesity/insulin resistance.
| S-EPMC3584060 | biostudies-literature
Project description:The nuclear receptor TAK1/TR4/NR2C2 is expressed in several tissues that are important in the control of energy homeostasis. TAK1-deficient (TAK1-/-) mice are resistant to the development of age- and high fat diet (HFD)-induced metabolic syndrome. Biochemical analysis showed significantly lower hepatic triglyceride levels and reduced lipid accumulation in adipose tissue in TAK1-/- mice compared to wild type (WT) mice. Gene expression profiling analysis revealed that the expression of several genes encoding proteins involved in lipid uptake and triglyceride synthesis and storage, including Cidea, Cidec, Mogat1, and CD36, was greatly decreased in the liver of TAK1-/- mice. Moreover, TAK1-/- mice exhibit reduced infiltration of inflammatory cells and expression of inflammatory genes in adipose tissue and were resistant to the development of glucose intolerance and insulin resistance. TAK1-/- mice consume more oxygen and produce more carbon dioxide than WT mice suggesting a higher rate of energy expenditure. Together, these results indicate that TAK1 plays a critical role in the regulation of energy and lipid homeostasis and potentiates the development of metabolic syndrome. Our study suggests that TAK1 might provide a novel therapeutic target in the management of metabolic syndrome.
2010-10-01 | GSE21903 | GEO
Project description:The nuclear receptor TAK1/TR4/NR2C2 is expressed in several tissues that are important in the control of energy homeostasis. TAK1-deficient (TAK1-/-) mice are resistant to the development of age- and high fat diet (HFD)-induced metabolic syndrome. Biochemical analysis showed significantly lower hepatic triglyceride levels and reduced lipid accumulation in adipose tissue in TAK1-/- mice compared to wild type (WT) mice. Gene expression profiling analysis revealed that the expression of several genes encoding proteins involved in lipid uptake and triglyceride synthesis and storage, including Cidea, Cidec, Mogat1, and CD36, was greatly decreased in the liver of TAK1-/- mice. Moreover, TAK1-/- mice exhibit reduced infiltration of inflammatory cells and expression of inflammatory genes in adipose tissue and were resistant to the development of glucose intolerance and insulin resistance. TAK1-/- mice consume more oxygen and produce more carbon dioxide than WT mice suggesting a higher rate of energy expenditure. Together, these results indicate that TAK1 plays a critical role in the regulation of energy and lipid homeostasis and potentiates the development of metabolic syndrome. Our study suggests that TAK1 might provide a novel therapeutic target in the management of metabolic syndrome. For microarray liver total RNAs were purified from WT and TAK1 KO mice and applied on Agilent mouse genome chip. Liver from 1 year old- WT and TAK1 KO mice.
2010-09-30 | E-GEOD-21903 | biostudies-arrayexpress
Project description:Stable L-forms are cell wall-deficient bacteria which are able to multiply and propagate indefinitely, despite the absence of a rigid peptidoglycan cell wall. We investigated whether L-forms of the intracellular pathogen L. monocytogenes possibly retain pathogenicity, and if they could trigger an innate immune response. While phagocytosis of L. monocytogenes L-forms by non-activated macrophages sometimes resulted in an unexpected persistence of the bacteria in the phagocytes, they were effectively eliminated by IFN-γ preactivated or bone marrow-derived macrophages (BMM). These findings were in line with the observed down-regulation of virulence factors in the cell-wall deficient L. monocytogenes. Absence of Interferon-β (IFN-β) triggering indicated inability of L-forms to escape from the phagosome into the cytosol. Moreover, abrogated cytokine response in MyD88-deficient dendritic cells (DC) challenged with L. monocytogenes L-forms suggested an exclusive TLR-dependent host response. Taken together, our data demonstrate a strong attenuation of Listeria monocytogenes L-form pathogenicity, due to diminished expression of virulence factors and innate immunity recognition, eventually resulting in elimination of L-form bacteria from phagocytes.
| S-EPMC4033035 | biostudies-literature
Project description:In the absence of exercise training, rats selectively bred for high intrinsic aerobic capacity (high-capacity running (HCR)) are protected against ovariectomy (OVX)-induced insulin resistance (IR) and obesity compared with those bred for low intrinsic aerobic capacity (low-capacity running (LCR)).This study determined whether OVX HCR rats remain protected with exposure to high-fat diet (HFD) compared with OVX LCR rats.Female HCR and LCR rats (n = 36; age, 27-33 wk) underwent OVX and were randomized to a standard chow diet (NC, 5% kcal fat) or HFD (45% kcal fat) ad libitum for 11 wk. Total energy expenditure, resting energy expenditure, spontaneous physical activity (SPA), and glucose tolerance were assessed midway, whereas fasting circulating metabolic markers, body composition, adipose tissue distribution, and skeletal muscle adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial markers were assessed at sacrifice.Both HCR and LCR rats experienced HFD-induced increases in total and visceral adiposity after OVX. Despite similar gains in adiposity, HCR rats were protected from HFD-induced IR and reduced total energy expenditure observed in LCR rats (P < 0.05). This metabolic protection was likely attributed to a compensatory increase in SPA and associated preservation of skeletal muscle AMPK activity in HCR; however, HFD significantly reduced SPA and AMPK activity in LCR (P < 0.05). In both lines, HFD reduced citrate synthase activity, gene expression of markers of mitochondrial biogenesis (tFAM, NRF1, and PGC-1?), and protein levels of mitochondrial oxidative phosphorylation complexes I, II, IV, and V in skeletal muscle (all P < 0.05).After OVX, HCR and LCR rats differentially respond to HFD such that HCR increase while LCR decrease SPA. This "physical activity compensation" likely confers protection from HFD-induced IR and reduced energy expenditure in HCR rats.
| S-EPMC4911303 | biostudies-literature
Project description:Patients with inflammatory bowel disease (IBD) are susceptible to thromboembolism. Interestingly, IBD occurs less frequently in patients with inherited bleeding disorders. Therefore, we analyzed whether F9-deficiency is protective against the onset of acute colitis in a genetic hemophilia B mouse model. In the 3.5% dextran sulfate sodium (DSS)-induced colitis model, F9-deficient mice were protected from body-weight loss and had a reduced disease activity score. We detected decreased colonic myeloperoxidase activity and decreased CXCL1 levels in DSS-treated F9-deficient mice compared with wild-type (WT) littermate controls, indicating decreased neutrophil infiltration. Remarkably, we identified expression of coagulation factor IX (FIX) protein in small intestinal epithelial cells (MODE-K). In epithelial cell cultures, cellular FIX protein expression was increased following stimulation with the bacterial Toll-like receptor agonists lipopolysaccharide, macrophage-activating lipopeptide-2 and Pam3CSK4. Thus, we revealed a protective role of F9-deficiency in DSS-induced colitis and identified the intestinal epithelium as a site of ectopic FIX.This article has an associated First Person interview with the first author of the paper.
| S-EPMC6078354 | biostudies-literature
Project description:Though mitochondrial oxidant stress plays a critical role in the progression of acetaminophen (APAP) overdose-induced liver damage, the influence of mitochondrial bioenergetics on this is not well characterized. This is important, since lifestyle and diet alter hepatic mitochondrial bioenergetics and an understanding of its effects on APAP-induced liver injury is clinically relevant. Pyruvate dehydrogenase (PDH) is critical to mitochondrial bioenergetics, since it controls the rate of generation of reducing equivalents driving respiration, and pyruvate dehydrogenase kinase 4 (PDK4) regulates (inhibits) PDH by phosphorylation. We examined APAP-induced liver injury in PDK4-deficient (PDK4-/-) mice, which would have constitutively active PDH and hence elevated flux through the mitochondrial electron transport chain. PDK4-/- mice showed significant protection against APAP-induced liver injury when compared to wild type (WT) mice as measured by ALT levels and histology. Deficiency of PDK4 did not alter APAP metabolism, with similar APAP-adduct levels in PDK4-/- and WT mice, and no difference in JNK activation and translocation to mitochondria. However, subsequent amplification of mitochondrial dysfunction with release of mitochondrial AIF, peroxynitrite formation and DNA fragmentation were prevented. Interestingly, APAP induced a rapid decline in UCP2 protein levels in PDK4-deficient mice. These data suggest that adaptive changes in mitochondrial bioenergetics induced by enhanced respiratory chain flux in PDK4-/- mice render them highly efficient in handling APAP-induced oxidant stress, probably through modulation of UCP2 levels. Further investigation of these specific adaptive mechanisms would provide better insight into the control exerted by mitochondrial bioenergetics on cellular responses to an APAP overdose.
| S-EPMC6995777 | biostudies-literature
Project description:Mitochondria alter their shape by undergoing cycles of fusion and fission. Changes in mitochondrial morphology impact on the cellular response to stress, and their interactions with other organelles such as the sarcoplasmic reticulum (SR). Inhibiting mitochondrial fission can protect the heart against acute ischemia/reperfusion (I/R) injury. However, the role of the mitochondrial fusion proteins, Mfn1 and Mfn2, in the response of the adult heart to acute I/R injury is not clear, and is investigated in this study. To determine the effect of combined Mfn1/Mfn2 ablation on the susceptibility to acute myocardial I/R injury, cardiac-specific ablation of both Mfn1 and Mfn2 (DKO) was initiated in mice aged 4-6 weeks, leading to knockout of both these proteins in 8-10-week-old animals. This resulted in fragmented mitochondria (electron microscopy), decreased mitochondrial respiratory function (respirometry), and impaired myocardial contractile function (echocardiography). In DKO mice subjected to in vivo regional myocardial ischemia (30 min) followed by 24 h reperfusion, myocardial infarct size (IS, expressed as a % of the area-at-risk) was reduced by 46% compared with wild-type (WT) hearts. In addition, mitochondria from DKO animals had decreased MPTP opening susceptibility (assessed by Ca(2+)-induced mitochondrial swelling), compared with WT hearts. Mfn2 is a key mediator of mitochondrial/SR tethering, and accordingly, the loss of Mfn2 in DKO hearts reduced the number of interactions measured between these organelles (quantified by proximal ligation assay), attenuated mitochondrial calcium overload (Rhod2 confocal microscopy), and decreased reactive oxygen species production (DCF confocal microscopy) in response to acute I/R injury. No differences in isolated mitochondrial ROS emissions (Amplex Red) were detected in response to Ca(2+) and Antimycin A, further implicating disruption of mitochondria/SR tethering as the protective mechanism. In summary, despite apparent mitochondrial dysfunction, hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction due to impaired mitochondria/SR tethering.
| S-EPMC4917668 | biostudies-literature