scholarly journals Hepatic Nfe2l2 Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1788
Author(s):  
Han Fang ◽  
Kirsten P. Stone ◽  
Sujoy Ghosh ◽  
Laura A. Forney ◽  
Landon C. Sims ◽  
...  
Keyword(s):  
Biological Significance ◽  
Metabolic Effects ◽  
Metabolic Phenotype ◽  
Transcriptional Responses ◽  
Metabolism Pathway ◽  
Reduce Body Weight ◽  
Increase Energy Expenditure ◽  
Methionine Restriction ◽  
Hepatic Transcriptome ◽  
Specific Deletion

The principal sensing of dietary methionine restriction (MR) occurs in the liver, where it activates multiple transcriptional programs that mediate various biological components of the response. Hepatic Fgf21 is a key target and essential endocrine mediator of the metabolic phenotype produced by dietary MR. The transcription factor, Nfe2l2, is also activated by MR and functions in tandem with hepatic Atf4 to transactivate multiple, antioxidative components of the integrated stress response. However, it is unclear whether the transcriptional responses linked to Nfe2l2 activation by dietary MR are essential to the biological efficacy of the diet. Using mice with liver-specific deletion of Nfe2l2 (Nfe2l2fl/(Alb)) and their floxed littermates (Nfe2l2fl/fl) fed either Control or MR diets, the absence of hepatic Nfe2l2 had no effect on the ability of the MR diet to increase FGF21, reduce body weight and adiposity, and increase energy expenditure. Moreover, the primary elements of the hepatic transcriptome were similarly affected by MR in both genotypes, with the only major differences occurring in induction of the P450-associated drug metabolism pathway and the pentose glucuronate interconversion pathway. The biological significance of these pathways is uncertain but we conclude that hepatic Nfe2l2 is not essential in mediating the metabolic effects of dietary MR.

scholarly journals The Role of Reduced Methionine in Mediating the Metabolic Responses to Protein Restriction Using Different Sources of Protein

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2609
Author(s):  
Han Fang ◽  
Kirsten P. Stone ◽  
Sujoy Ghosh ◽  
Laura A. Forney ◽  
Thomas W. Gettys
Keyword(s):  
Amino Acids ◽  
Dietary Protein ◽  
Target Genes ◽  
Protein Restriction ◽  
Metabolic Phenotype ◽  
Sulfur Amino Acids ◽  
Transcriptional Responses ◽  
Similar Reduction ◽  
Dietary Protein Restriction ◽  
Methionine Restriction

Dietary protein restriction and dietary methionine restriction (MR) produce a comparable series of behavioral, physiological, biochemical, and transcriptional responses. Both dietary regimens produce a similar reduction in intake of sulfur amino acids (e.g., methionine and cystine), and both diets increase expression and release of hepatic FGF21. Given that FGF21 is an essential mediator of the metabolic phenotype produced by both diets, an important unresolved question is whether dietary protein restriction represents de facto methionine restriction. Using diets formulated from either casein or soy protein with matched reductions in sulfur amino acids, we compared the ability of the respective diets to recapitulate the metabolic phenotype produced by methionine restriction using elemental diets. Although the soy-based control diets supported faster growth compared to casein-based control diets, casein-based protein restriction and soy-based protein restriction produced comparable reductions in body weight and fat deposition, and similar increases in energy intake, energy expenditure, and water intake. In addition, the prototypical effects of dietary MR on hepatic and adipose tissue target genes were similarly regulated by casein- and soy-based protein restriction. The present findings support the feasibility of using restricted intake of diets from various protein sources to produce therapeutically effective implementation of dietary methionine restriction.

scholarly journals The acute transcriptional responses to dietary methionine restriction are triggered by inhibition of ternary complex formation and linked to Erk1/2, mTOR, and ATF4

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kirsten P. Stone ◽  
Sujoy Ghosh ◽  
Jean Paul Kovalik ◽  
Manda Orgeron ◽  
Desiree Wanders ◽  
...  
Keyword(s):  
Stress Response ◽  
Complex Formation ◽  
Ternary Complex ◽  
Target Genes ◽  
Bioinformatic Analysis ◽  
Transcriptional Responses ◽  
Metabolomics Data ◽  
Ternary Complex Formation ◽  
Methionine Restriction

AbstractThe initial sensing of dietary methionine restriction (MR) occurs in the liver where it activates an integrated stress response (ISR) that quickly reduces methionine utilization. The ISR program is regulated in part by ATF4, but ATF4’s prototypical upstream regulator, eIF2α, is not acutely activated by MR. Bioinformatic analysis of RNAseq and metabolomics data from liver samples harvested 3 h and 6 h after initiating MR shows that general translation is inhibited at the level of ternary complex formation by an acute 50% reduction of hepatic methionine that limits formation of initiator methionine tRNA. The resulting ISR is induced by selective expression of ATF4 target genes that mediate adaptation to reduced methionine intake and return hepatic methionine to control levels within 4 days of starting the diet. Complementary in vitro experiments in HepG2 cells after knockdown of ATF4, or inhibition of mTOR or Erk1/2 support the conclusion that the early induction of genes by MR is partially dependent on ATF4 and regulated by both mTOR and Erk1/2. Taken together, these data show that initiation of dietary MR induces an mTOR- and Erk1/2-dependent stress response that is linked to ATF4 by the sharp, initial drop in hepatic methionine and resulting repression of translation pre-initiation.

scholarly journals Interaction of CREB and PGC-1α Induces Fibronectin Type III Domain-Containing Protein 5 Expression in C2C12 Myotubes

2018 ◽  
Vol 50 (4) ◽  
pp. 1574-1584 ◽  
Author(s):  
Xiu-ying Yang ◽  
Margaret C.L. Tse ◽  
Xiang Hu ◽  
Wei-hua Jia ◽  
Guan-hua Du ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Metabolic Effects ◽  
Hek293 Cells ◽  
Metabolic Phenotype ◽  
C2c12 Myotubes ◽  
Type Iii ◽  
Fibronectin Type Iii ◽  
Fibronectin Type Iii Domain ◽  
Fibronectin Type

Background/Aims: Fibronectin type III domain-containing protein 5 (FNDC5), also known as irisin, is a myokine secreted from muscle in response to exercise. However, the molecular mechanisms that regulate FNDC5 expression and the functional significance of irisn in skeletal muscle remain unknown. In this study, we explored the potential pathways that induce FNDC5 expression and delineated the metabolic effects of irisin on skeletal muscle. Methods: C2C12 myotubes were treated with drugs at various concentrations and durations. The expression and activation of genes were measured by real-time polymerase chain reaction (qRT-PCR) and Western blotting. Oxidative phosphorylation was quantified by measuring the oxygen consumption rate (OCR). Results: We found that the exercise-mimicking treatment (cAMP, forskolin and isoproterenol) increased Fndc5 expression in C2C12 myotubes. CREB over-expressed C2C12 myotubes displayed higher Fndc5 expression. CREB over-expression also promoted peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) expression. PGC-1α-induced Fndc5 expression was blocked when the dominant negative form of CREB (S133A) was present. PGC-1α mutation (S570A) also decreased Fndc5 expression. Immunoprecipitation showed that overexpressed PGC-1α complexed with CREB in HEK293 cells. C2C12 myotubes treated with forskolin also increased endogenous CREB and PGC-1α binding. Functionally, irisin treatment increased mitochondrial respiration, enhanced ATP production, promoted fatty acid oxidation but decreased glycolysis in myotubes. Conclusion: Our observation indicates that cAMP-mediated PGC-1α/CREB interaction triggers Fndc5 expression, which acts as an autocrine/paracrine to shape the metabolic phenotype of myotubes.

scholarly journals Nuclear magnetic resonance metabolic fingerprint of bevacizumab in mutant IDH1 glioma cells

2018 ◽  
Vol 52 (4) ◽  
pp. 392-398 ◽  
Author(s):  
Tanja Mesti ◽  
Nadia Bouchemal ◽  
Claire Banissi ◽  
Mohamed N. Triba ◽  
Carole Marbeuf-Gueye ◽  
...  
Keyword(s):  
Tricarboxylic Acid Cycle ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Magic Angle Spinning ◽  
Idh1 Mutation ◽  
Metabolic Effects ◽  
Metabolic Phenotype ◽  
Magic Angle ◽  
Metabolic Fingerprint ◽  
U87 Cells

AbstractBackgroundMalignant gliomas are rapidly growing tumours that extensively invade the brain and have bad prognosis. Our study was performed to assess the metabolic effects of bevacizumab on the glioma cells carrying the IDH1 mutation, a mutation, associated with better prognosis and treatment outcome. Bevacizumab is known to inhibit tumour growth by neutralizing the biological activity of vascular endothelial growth factor (VEGF). However, the direct effects of bevacizumab on tumour cells metabolism remain poorly known.Materials and methodsThe immunoassay and MTT assay were used to assess the concentration of secreted VEGF and cell viability after bevacizumab exposure. Metabolomic studies on cells were performed using high resolution magic angle spinning spectroscopy (HRMAS).ResultsmIDH1-U87 cells secreted VEGF (13 ng/mL). Regardless, bevacizumab had no cytotoxic effect, even after a 72h exposure and with doses as high as 1 mg/mL. Yet, HRMAS analysis showed a significant effect of bevacizumab (0.1 mg/mL) on the metabolic phenotype of mIDH1-U87 cells with elevation of 2-hydroxyglutarate and changes in glutamine group metabolites (alanine, glutamate, glycine) and lipids (polyunsaturated fatty acids [PUFA], glycerophosphocholine, and phosphocholine).ConclusionsIn mIDH1-U87 cells, changes in glutamine group metabolites and lipids were identified as metabolic markers of bevacizumab treatment. These data support the possibility of a functional tricarboxylic acid cycle that runs in reductive manner, as a probable mechanism of action of bevacizumab in IDH1 mutated gliomas and propose a new target pathway for effective treatment of malignant gliomas.

Combined intermittent and sustained hypoxia is a novel and deleterious cardio-metabolic phenotype

SLEEP ◽  
2021 ◽  
Author(s):  
Xin Zhen ◽  
Esteban A Moya ◽  
Mary Gautane ◽  
Huayi Zhao ◽  
Elijah S Lawrence ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Intermittent Hypoxia ◽  
Systolic Pressure ◽  
Metabolic Effects ◽  
Metabolic Phenotype ◽  
Glucose Disposal ◽  
Chronic Obstructive ◽  
Ventricular Systolic Pressure ◽  
Obstructive Sleep ◽  
Sustained Hypoxia

Abstract Study objectives Chronic obstructive pulmonary disease and obstructive sleep apnea overlap syndrome is associated with excess mortality, and outcomes are related to the degree of hypoxemia. People at high altitude are susceptible to periodic breathing, and hypoxia at altitude is associated with cardio-metabolic dysfunction. Hypoxemia in these scenarios may be described as superimposed sustained plus intermittent hypoxia, or overlap hypoxia (OH), the effects of which have not been investigated. We aimed to characterize the cardio-metabolic consequences of OH in mice. Methods C57BL/6J mice were subjected to either sustained hypoxia (SH, FiO2=0.10), intermittent hypoxia (IH, FiO2=0.21 for 12 hours, and FiO2 oscillating between 0.21 and 0.06, 60 times/hour, for 12 hours), OH (FiO2=0.13 for 12 hours, and FiO2 oscillating between 0.13 and 0.06, 60 times/hour, for 12 hours), or room air (RA), n=8/group. Blood pressure and intraperitoneal glucose tolerance test were measured serially, and right ventricular systolic pressure (RVSP) was assessed. Results Systolic blood pressure transiently increased in IH and OH relative to SH and RA. RVSP did not increase in IH, but increased in SH and OH by 52% (p<0.001) and 20% (p=0.001). Glucose disposal worsened in IH and improved in SH, with no change in OH. Serum LDL and VLDL increased in OH and SH, but not in IH. Hepatic oxidative stress increased in all hypoxic groups, with the highest increase in OH. Conclusions Overlap hypoxia may represent a unique and deleterious cardio-metabolic stimulus, causing systemic and pulmonary hypertension, and without protective metabolic effects characteristic of sustained hypoxia.

scholarly journals Methionine Restriction Alleviates Aging-related Cognitive Dysfunction via Stimulating FGF21-driven Mitochondrial Biogenesis (P14-026-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Bo Ren ◽  
Luanfeng Wang ◽  
Zhigang Liu ◽  
Xuebo Liu
Keyword(s):  
Amino Acid ◽  
Cognitive Function ◽  
Signaling Pathway ◽  
Mitochondrial Biogenesis ◽  
Metabolic Phenotype ◽  
Fibroblast Growth Factor 21 ◽  
Behavioral Tests ◽  
Mice Model ◽  
Neuroprotective Effects ◽  
Methionine Restriction

Abstract Objectives Moderate dietary methionine restriction (MR) extends life span in various animal models and delays the onset of aging-associated pathologies. However, the neuroprotective effects and underlying mechanism of MR on age and age-related diseases still remain to be investigated. Notably, fibroblast growth factor-21 (FGF21), a MR responding hormone mostly generated from liver, plays a critical role in neuronal mitochondrial function. Here, we aimed to reveal the neuroprotective effects of MR and the mediating role of FGF21 in aging mice model. Methods Male C57BL/6 mice (2-, 12-, and 15- month-old) were treated with control methionine diet (0.86% methionine) and methionine restriction diet (0.17% methionine) for 3 months. Adeno-associated virus was employed to build FGF21 knockdown mice model. Behavioral tests, synapse ultrastructure detection, and amino acid metabolomics were performed to evaluate cognitive function, neuron damage and signaling pathway activation. Results In behavioral tests, we found that MR significantly improved aging-induced decreased in spatial memory and cognitive function. Meanwhile, MR ameliorated neuronal damage and synapses structure damages in aging mice hippocampus. Moreover, MR significantly improved the mRNA expression of mitochondrial biogenesis and dynamics related genes such as COX2/fis1/pink1/binp1/drp1 in aging mice brain. MR also altered plasma amino acid metabolic phenotype-related glutathione synthesis, energy metabolism, and nervous system function. Furthermore, we found that MR could significant increase FGF21 level in both liver and serum of aging mice. Knockdown of FGF21 dramatically diminished the benefits of MR on cognitive impairments. Conclusions These results showed that MR mitigated aging-induced memory impairment and synapses structure damages via activating FGF21 signaling pathway. The study suggest that this dietary restriction might be plausible therapeutic intervention for aging and other neurodegenerative diseases such AD and PD. Funding Sources This work was financially supported by the National Key Research and Development Program of China, National Natural Science Foundation of China. Supporting Tables, Images and/or Graphs

P6276Impact of the cardiac specific deletion of AMPKalpha2 on the contractile and metabolic phenotype of the heart in male and female mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Grimbert ◽  
M N Sanz ◽  
C Rucker-Martin ◽  
M Novotova ◽  
M Gressette ◽  
...  
Keyword(s):  
Contractile Function ◽  
Left Ventricular ◽  
Metabolic Phenotype ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Male And Female ◽  
Female Mice ◽  
Sex Specificity ◽  
Specific Deletion

Abstract Introduction Mitochondrial dysfunction plays a major role in the Heart Failure (HF) pathophysiology.The AMP activated protein kinase (AMPK) is activated by a high AMP-ADP/ATP ratio and regulates a number of metabolic pathways. Many studies have highlighted a protective role of AMPK in HF, but its relevance to cardiac tissue, its metabolic part and its sex specificity are not well established. Purpose Then, the aim of this study is to determine the role of AMPK in the healthy and failing heart in male and female mice. Methods We developed and validated a mouse strain with an adult-inducible cardiac-specific deletion of AMPKα2, the major cardiac isoform, using the Cre-Lox system (40mg/kg tamoxifen injection on two consecutive days at adult age). At four months after the deletion, cardiac contractility, morphology and metabolism were studied in control and KO mice from both sexes. Results We observed only in male KO mice a decrease of left ventricular ejection fraction (−10%), an increase of the total fibrosis (+64%) and defects in mitochondrial structures. Male KO mice also showed a reduced (−28%) mitochondrial respiration via complex I associated with a different cardiolipin species distribution. Conclusion Our results reveal in adult healthy hearts, a sex-specificity in the effects of AMPKα2 deletion, leading to impaired contractile function related to metabolic and non-metabolic alterations only in male mice.

scholarly journals Clinical and Metabolic Effects of Alpha-Lipoic Acid Associated with Two Different Doses of Myo-Inositol in Women with Polycystic Ovary Syndrome

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Franca Fruzzetti ◽  
Elena Benelli ◽  
Tiziana Fidecicchi ◽  
Massimo Tonacchera
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Lipoic Acid ◽  
Polycystic Ovary ◽  
Insulin Response ◽  
Reproductive Hormones ◽  
Metabolic Effects ◽  
Metabolic Phenotype ◽  
Ovary Syndrome ◽  
Before And After ◽  
Different Doses

The aim of this retrospective study was to evaluate the effects of a treatment with α-lipoic acid (ALA) associated with two different doses of myo-inositol (MI) on clinical and metabolic features of women with polycystic ovary syndrome (PCOS). Eighty-eight women received the treatment, and 71 among them had complete clinical charts and were considered eligible for this study. All women were treated with 800 mg of ALA per day: 43 patients received 2000 mg of MI and 28 received 1000 mg of MI per day. Menstrual cyclicity, BMI, FSH, LH, estradiol, testosterone, androstenedione, fasting insulin, HOMA-IR, and insulin response to a 2 h OGTT were evaluated before and after 6 months of treatment. The presence of diabetic relatives (DRs) was investigated. Cycle regularity was improved in 71.2% of women. The improvement of menstrual cyclicity occurred regardless of the state of IR and the presence of DRs of the patients. Women with IR mainly showed a significant improvement of metabolic parameters, while those without IR had significant changes of reproductive hormones. Patients with DRs did not show significant changes after the treatment. 85.7% of women taking 2000 mg of MI reported a higher improvement of menstrual regularity than those taking 1000 mg of MI (50%; p<0.01). In conclusion, ALA + MI positively affects the menstrual regularity of women with PCOS, regardless of their metabolic phenotype, with a more evident effect with a higher dose of MI. This effect seems to be insulin independent. The presence of IR seems to be a predictor of responsivity to the treatment in terms of an improvement of the metabolic profile.

scholarly journals IL-15 Mediates Mitochondrial Activity through a PPARδ-Dependent-PPARα-Independent Mechanism in Skeletal Muscle Cells

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Shantaé M. Thornton ◽  
James E. Krolopp ◽  
Marcia J. Abbott
Keyword(s):  
Skeletal Muscle ◽  
Citrate Synthase ◽  
Metabolic Effects ◽  
Mitochondrial Activity ◽  
Mrna Levels ◽  
Metabolic Processes ◽  
Atp Production ◽  
Positive Effects ◽  
Increase Energy Expenditure ◽  
Interleukin 15

Molecular mediators of metabolic processes, to increase energy expenditure, have become a focus for therapies of obesity. The discovery of cytokines secreted from the skeletal muscle (SKM), termed “myokines,” has garnered attention due to their positive effects on metabolic processes. Interleukin-15 (IL-15) is a myokine that has numerous positive metabolic effects and is linked to the PPAR family of mitochondrial regulators. Here, we aimed to determine the importance of PPARαand/or PPARδas targets of IL-15 signaling. C2C12 SKM cells were differentiated for 6 days and treated every other day with IL-15 (100 ng/mL), a PPARαinhibitor (GW-6471), a PPARδinhibitor (GSK-3787), or both IL-15 and the inhibitors. IL-15 increased mitochondrial activity and induced PPARα, PPARδ, PGC1α, PGC1β, UCP2, and Nrf1 expression. There was no effect of inhibiting PPARα, in combination with IL-15, on the aforementioned mRNA levels except for PGC1βand Nrf1. However, with PPARδinhibition, IL-15 failed to induce the expression levels of PGC1α, PGC1β, UCP2, and Nrf1. Further, inhibition of PPARδabolished IL-15 induced increases in citrate synthase activity, ATP production, and overall mitochondrial activity. IL-15 had no effects on mitochondrial biogenesis. Our data indicates that PPARδactivity is required for the beneficial metabolic effects of IL-15 signaling in SKM.

scholarly journals Anti-Mullerian Hormone Protein-Altering Variants Are Associated With Hypertriglyceridemia in the General Population

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A737-A738
Author(s):  
Sydney Chang ◽  
Alan Copperman ◽  
Andrea Elizabeth Dunaif
Keyword(s):  
General Population ◽  
Hemoglobin A1c ◽  
Sequence Data ◽  
Metabolic Effects ◽  
Metabolic Phenotype ◽  
European Ancestry ◽  
Functional Protein ◽  
Antihypertensive Medications ◽  
Health And Nutrition ◽  
Elevated Cholesterol

Abstract We found 17 rare PCOS-specific functional protein-altering variants (PAVs) or mutations in the gene, AMH, that decrease the biologic activity of the encoded protein, anti-Müllerian hormone (AMH), in the heterozygous state. Approximately 3% of European ancestry PCOS cases in our cohort of ~700 were affected. Our preliminary studies found evidence for a metabolic phenotype in both PCOS as well as their male first-degree relatives who were heterozygous carriers of these AMH PAVs. We performed this study to test the hypothesis that AMH mutations are associated with metabolic abnormalities in the general population. The Mount Sinai BioMe Biobank is an electronic health record (EHR)-linked biobank, containing anonymized whole exome sequences from 30,813 participants of diverse ancestries. We interrogated the sequence data to identify individuals with PCOS-related AMH PAVs. IRB-approval was obtained to review the linked EHR. Outcomes were the presence of obesity (BMI ≥ 30 kg/m2), type 2 diabetes (hemoglobin A1C ≥ 6.5%), prediabetes (hemoglobin A1C 5.7% - 6.4%), elevated cholesterol (total cholesterol ≥ 200 mg/dL), hypertriglyceridemia (TG ≥ 150 mg/dL), and hypertension (≥2 blood pressure values ≥140/90, or administration of antihypertensive medications). Control subjects were obtained from the National Health and Nutrition Examination Survey using propensity score matching (for sex, age, and BMI) with a 1:4 case:control ratio. A total of 292 individuals with AMH PAVs were identified, resulting in a combined 0.95% prevalence of AMH PAVs in an unselected population (1.07% in Europeans, 0.28% in African Americans, 0.54% in Hispanics, and 0.07% in Asians). After adjusting for age, BMI, and race/ethnicity, there was a statistically significant increased prevalence of hypertriglyceridemia in both women (OR 7.29, 95% CI 3.77-14.00) and men (OR 10.15, 95% CI 4.68-22.00) with AMH PAVs compared to sex-, age- and BMI-matched controls. There was also a statistically significant increased prevalence of elevated cholesterol in men with AMH PAVs compared to controls (OR 2.48, 95% CI 1.15-5.34). There were no significant differences between individuals with AMH PAVs and matched controls with respect to the other outcomes. These findings suggest that decreased bioactivity of AMH is causally related to dyslipidemia in the general population. TG levels are elevated in both sexes, whereas increases in cholesterol are only seen in men. The mechanisms by which decreases in AMH bioactivity alter circulating lipid levels are of considerable interest since AMH has no known metabolic actions. It is possible that the putative metabolic effects of AMH are mediated by increases in circulating testosterone (T) levels that in turn alter lipid metabolism. Since T levels are not commonly available in EHR, future studies will be needed to investigate this hypothesis as well as to explore metabolic actions of AMH.

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