Altered Fatty Acid Metabolism Research Articles

Cardiac Glucolipotoxicity and Cardiovascular Outcomes.

Cardiac insulin signaling can be impaired due to the altered fatty acid metabolism to induce insulin resistance. In diabetes and insulin resistance, the metabolic, structural and ultimately functional alterations in the heart and vasculature culminate in diabetic cardiomyopathy, coronary artery disease, ischemia and eventually heart failure. Glucolipotoxicity describes the combined, often synergistic, adverse effects of elevated glucose and free fatty acid concentrations on heart structure, function, and survival. The quality of fatty acid shapes the cardiac structure and function, often influencing survival. A healthy fatty acid balance is therefore critical for maintaining cardiac integrity and function.

Particulate Air Pollution Exposure during Pregnancy and Mitochondrial-Associated Plasma Metabolites in Mothers at 48 Months Postpartum: A Pilot Study

BackgroundPregnancy and early postpartum life are periods of major metabolic change in women and may be critical windows of susceptibility for longer-term metabolic changes induced by inflammatory exposures, such as PM2.5 (ambient particulate matter <2.5 µm in diameter).HypothesisAs mitochondria are sensitive to inflammation, we hypothesized that gestational/early postpartum PM2.5 exposure would predict metabolomic profiles of small molecules in mitochondrial-associated pathways measured years after pregnancy.MethodsIn a pilot study, we randomly selected 50 mothers from the Programming Research on Obesity, GRowth, Environment and Social Stress (PROGRESS) cohort based in Mexico City. We estimated PM2.5 exposure using a satellite-based spatiotemporally-resolved prediction model. In maternal plasma collected at 48 months postpartum, we assessed 110 metabolites in mitochondrial pathways (TCA cycle, fatty acid β-oxidation, and branched chain amino acid catabolism) using Metabolon’s Discovery HD4™ platform.ResultsIn robust regression models adjusted for age, secondhand smoke exposure, socioeconomic status, alcohol consumption, and parity, average PM2.5 during the first year postpartum was associated with 17 metabolites (p<0.05). The majority were long chain fatty acids and polyunsaturated fatty acids, which were negatively associated with PM2.5. No associations were observed for these fatty acids with average PM2.5 during pregnancy. Further, fewer metabolites overall were associated with PM2.5 during pregnancy (two at p<0.05), suggesting results vary by time of exposure.ConclusionIn this pilot study, we found that PM2.5 exposure during the first year postpartum was associated with altered fatty acid metabolism in plasma from mothers at 48 months postpartum. The postpartum period may be a susceptibility window for PM2.5 exposure with regard to metabolic dysregulation, particularly lipids. We plan to replicate these findings in the full sample and in independent cohorts.

Graphene oxide nano-bio interaction induces inhibition of spermatogenesis and disturbance of fatty acid metabolism in the nematode Caenorhabditis elegans

Graphene oxide (GO) has the potential for wide applications, which necessitates an intensive investigation of its potential hazard on human and environmental health. Even if previous studies show reproductive toxicity in the nematode Caenorhabditis elegans, the mechanisms of reproductive toxicity by GO are poorly understood. To understand the underlying mechanisms of GO-induced reproductive toxicity, we investigated the interaction between GO and C. elegans using Raman spectroscopy, sperm counts produced by spermatogenesis, progeny and analyzed the fatty acid metabolism using molecular techniques. GO-characteristic Raman spectral bands measured throughout C. elegans, brood size and Hoecst staining of dissected gonads clearly showed GO accumulation in the reproductive organs, reduced progeny and low sperm counts, which are possibly direct results of the reproductive toxicity from GO exposure. Interestingly, reduced fatty acid metabolites, such as stearic, oleic, palmitoleic, and palmitic acids, were found with GO exposure. We found that GO increased intestinal fat accumulation in wild type N2, fat-5(tm420), and fat-7(wa36) mutants, whereas it decreased fat storage in the fat-6(tm331) and nhr-49(nr2041) mutants. GO exposure affected C. elegans fat accumulation and consumption, which was possibly regulated by daf-16 and nhr-80 gene activity. Also, GO exposure suppressed the survival of long-lived fat-5(tm420) mutants, whereas it increased the survival of short-lived nhr-49(nr2041) mutants. Hence, our studies collectively indicated that GO accumulation in reproductive organs, suppression of spermatogenesis, and the alteration of fatty acid metabolism play critical roles in understanding mechanisms of toxicity in C. elegans.

Porphyromonas gingivalis Promotes 4-Nitroquinoline-1-Oxide-Induced Oral Carcinogenesis With an Alteration of Fatty Acid Metabolism.

Microbiota has been widely considered to play a critical role in human carcinogenesis. Human papilloma virus, hepatitis B and C virus, and Helicobacter pylori are implicated in the pathogenesis of cancer of uterine cervix, liver, and stomach, respectively. However, whether Porphyromonas gingivalis (P. gingivalis), a common Gram negative oral bacteria, is associated with oral carcinogenesis still remains unclear and its underlying mechanism needs to be addressed. Here, we established a combined experimental system of 4NQO-induced oral carcinoma model and chronic periodontitis model and investigated the effects of P. gingivalis infection on oral carcinogenesis and fatty acid metabolism during oral carcinogenesis. The data showed that in this animal model, P. gingivalis infection induced mice periodontitis, increased the tongue lesion size and multiplicity of each mouse and promoted oral cancer development. P. gingivalis treatment significantly increased the level of free fatty acids and altered the fatty acid profile in tongue tissues and the serum of mice. And P. gingivalis induced the formation of fatty liver of the mice. Besides, immunohistochemical analysis and qRT-PCR showed that the expression of fatty-acid synthase and acetyl-CoA carboxylase 1 were increased in the tongue and liver tissues of 4NQO-treated mice infected with P. gingivalis. These results showed that P. gingivalis promoted oral carcinogenesis and aggravated disturbance of fatty acid metabolism, indicating a close association among P. gingivalis, lipid metabolic and oral carcinogenesis.

FoxK1/K2 Are New, Important Components of IR and IGF1R Signaling and Control of Cell Proliferation and Metabolism

Insulin and IGF-1 are regulators of cell growth and metabolism. Despite considerable progress in understanding the molecular mechanisms underlying these effects, except for members of the FoxO family, many regulators of the transcriptional effects of these hormones remain poorly understood. To identify new components of IR/IGF1R signaling, we created brown preadipocyte lines in which both endogenous IR and IGF1R genes had been deleted and then reconstituted these cells with normal IR, IGF1R or chimeric receptors containing the extracellular domain of IR fused to intracellular domain of IGF1R and vice versa. Mass spectroscopic proteomic analysis revealed a number of proteins co-precipitated with each receptor construct, in both ligand stimulation-dependent and -independent manners. Among the proteins that associated with both receptors and chimeric receptors in a ligand-dependent manner was FoxK1. In contrast to FoxO1, the transcription factor FoxK1 was translocated from the cytoplasm to the nucleus after insulin stimulation, a pattern that is reciprocal to that of FoxO1 after insulin stimulation. We show that FoxK1 and FoxK2 are phosphorylated in two major domains and that translocation to the nucleus is dependent on the Akt-mTOR mediated phosphorylation, while their localization to the cytoplasm in the basal state is dependent on GSK3 phosphorylation. Knockdown of FoxK1 and FoxK2 in a mouse hepatocyte cell line causes marked alteration of the transcription of genes associated with apoptotic pathway and down-regulation of genes involved in control of cell cycle and metabolism. This resulted in decreased cell proliferation and altered mitochondrial fatty acid metabolism in these cells. Thus, insulin stimulates the reciprocal translocation of FoxKs and FoxO1 between the cytoplasm and nucleus turning off FoxO1-regulated genes and turning on FoxK-regulated genes resulting in an elaborate balance in insulin regulation of metabolism, growth and cell survival. Disclosure M. Sakaguchi: None. W. Cai: None. C. Wang: None. T.M. Batista: None. E. Araki: Speaker's Bureau; Self; Astellas Pharma US, Inc., MSD K.K., Kowa Pharmaceuticals America, Inc., Sanofi, Novo Nordisk Inc.. Research Support; Self; Astellas Pharma US, Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Takeda Pharmaceuticals U.S.A., Inc., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Sanofi, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.

A Reversible Epigenetic Link between Obesity and Cancer Risk

In a recent Cell Reports article, Li et al. report that obesity is associated with altered fatty acid metabolism and DNA methylation in the colonic epithelium, which precede a tumor-prone gene-expression profile. Interestingly, obesity-associated methylation and transcriptome changes were reversed by weight loss, and the duration of weight loss correlated with the extent of restored gene expression. These findings have implications that are encouraging for weight loss and cancer prevention.

Septic Shock Nonsurvivors Have Persistently Elevated Acylcarnitines Following Carnitine Supplementation.

Sepsis-induced metabolic disturbances include hyperlactatemia, disruption of glycolysis, protein catabolism, and altered fatty acid metabolism. It may also lower serum L-carnitine that supports the use of L-carnitine supplementation as a treatment to ameliorate several of these metabolic consequences. To further understand the association between L-carnitine-induced changes in serum acylcarnitines, fatty acid metabolism and survival, serum samples from (T0), 12 hfollowing completion (T24) of L-carnitine (n = 16) or placebo (n = 15) administration, and 48 h (T48) after enrollment from patients with septic shock enrolled in a randomized control trial were assayed for acylcarnitines, free fatty acids, and insulin. Data were analyzed comparing 1-year survivors and nonsurvivors within treatment groups. Mortality was 8 of 16 (50%) and 12 of 15 (80%) at 1 year for L-carnitine and placebo-treated patients, respectively. Free carnitine, C2, C3, and C8 acylcarnitines were higher among nonsurvivors at enrollment. L-Carnitine treatment increased levels of all measured acylcarnitines; an effect that was sustained for at least 36 h following completion of the infusion and was more prominent among nonsurvivors. Several fatty acids followed a similar, though less consistent pattern. Glucose, lactate, and insulin levels did not differ based on survival or treatment arm. In human patients with septic shock, L-Carnitine supplementation increases a broad range of acylcarnitine concentrations that persist after cessation of infusion, demonstrating both immediate and sustained effects on the serum metabolome. Nonsurvivors demonstrate a distinct metabolic response to L-carnitine compared with survivors, which may indicate preexisting or more profound metabolic derangement that constrains any beneficial response to treatment.

HIV latency is reversed by ACSS2-driven histone crotonylation.

Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2). This reprogrammed the local chromatin at the HIV LTR through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminished histone crotonylation-induced HIV replication and reactivation. ACSS2 induction was highly synergistic in combination with either a protein kinase C agonist (PEP005) or a histone deacetylase inhibitor (vorinostat) in reactivating latent HIV. In the SIV-infected nonhuman primate model of AIDS, the expression of ACSS2 was significantly induced in intestinal mucosa in vivo, which correlated with altered fatty acid metabolism. Our study links the HIV/SIV infection-induced fatty acid enzyme ACSS2 to HIV latency and identifies histone lysine crotonylation as a novel epigenetic regulator for HIV transcription that can be targeted for HIV eradication.

Influences of Physalis peruviana L. and Lupinus albus L. fruits extracts on the levels of some biochemical parameters in brain and muscle tissues of type II diabetic rats

New functional foods are increasingly sought to improve the treatment of diseases related to glucose and lipid metabolism. The present study was designed to investigate the possible antidiabetic and antioxidant effects of goldenberry and lupin on brain and muscle tissues of streptozotocin-induced type II diabetic rats. Type II diabetes was produced in albino rats by the streptozotocin injection. Wistar albino rats were divided into four groups, each one containing 10 rats: non-diabetic control group, STZ- type II Diabetes group, STZ- type II Diabetes+goldenberry group, and STZ- type II Diabetes+lupin group. After one week from the injection, goldenberry and lupin were injected to rats for 2 months. Malondialdehyde, glutathione, cholesterol, and fatty acid levels, which are signs of lipid peroxidation, were measured in brain and muscle tissues. In type II diabetes, malondialdehyde increased compared to the control group. Glutathione decreased in the both tissues and all of the streptozotocin-induced diabetic groups. In type II diabetes, brain cholesterol levels decreased. Treatment with similar doses of goldenberry and lupin significantly reduced oxidative stress, augments antioxidant system and altered fatty acid metabolism in these tissues, thereby maintaining favourable fatty acid distribution affected by diabetic complications. These results validate the use of goldenberry and lupin fruits as a treatment against diabetes mellitus and its complications and suggest it is suitable to continue studies for its safe therapeutic use.

Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart.

Nutrients are transported through endothelial cells before being metabolized in muscle cells. However, little is known about the regulation of endothelial transport processes. Notch signaling is a critical regulator of metabolism and angiogenesis during development. Here, we studied how genetic and pharmacological manipulation of endothelial Notch signaling in adult mice affects endothelial fatty acid transport, cardiac angiogenesis, and heart function. Endothelial-specific Notch inhibition was achieved by conditional genetic inactivation of Rbp-jκ in adult mice to analyze fatty acid metabolism and heart function. Wild-type mice were treated with neutralizing antibodies against the Notch ligand Delta-like 4. Fatty acid transport was studied in cultured endothelial cells and transgenic mice. Treatment of wild-type mice with Delta-like 4 neutralizing antibodies for 8 weeks impaired fractional shortening and ejection fraction in the majority of mice. Inhibition of Notch signaling specifically in the endothelium of adult mice by genetic ablation of Rbp-jκ caused heart hypertrophy and failure. Impaired heart function was preceded by alterations in fatty acid metabolism and an increase in cardiac blood vessel density. Endothelial Notch signaling controlled the expression of endothelial lipase, Angptl4, CD36, and Fabp4, which are all needed for fatty acid transport across the vessel wall. In endothelial-specific Rbp-jκ-mutant mice, lipase activity and transendothelial transport of long-chain fatty acids to muscle cells were impaired. In turn, lipids accumulated in the plasma and liver. The attenuated supply of cardiomyocytes with long-chain fatty acids was accompanied by higher glucose uptake, increased concentration of glycolysis intermediates, and mTOR-S6K signaling. Treatment with the mTOR inhibitor rapamycin or displacing glucose as cardiac substrate by feeding a ketogenic diet prolonged the survival of endothelial-specific Rbp-jκ-deficient mice. This study identifies Notch signaling as a novel regulator of fatty acid transport across the endothelium and as an essential repressor of angiogenesis in the adult heart. The data imply that the endothelium controls cardiomyocyte metabolism and function.

Docosahexaenoic Acid in Combination with Dietary Energy Restriction for Reducing the Risk of Obesity Related Breast Cancer.

There is strong evidence that obesity poses a significant risk factor for postmenopausal breast cancer. There are multiple mechanisms by which obesity can predispose to breast cancer, prominent among which is the creation of a pro-inflammatory milieu systemically in the visceral and subcutaneous tissue, as well as locally in the breast. Although dietary intervention studies have shown in general a favorable effect on biomarkers of breast cancer risk, it is still unclear whether losing excess weight will lower the risk. In this manuscript, we will review the evidence that omega-3 fatty acids, and among them docosahexaenoic acid (DHA) in particular, may reduce the risk of obesity related breast cancer primarily because of their pleotropic effects which target many of the systemic and local oncogenic pathways activated by excess weight. We will also review the evidence indicating that intentional weight loss (IWL) induced by dietary energy restriction (DER) will augment the tumor protective effect of DHA because of its complementary mechanisms of action and its ability to reverse the obesity-induced alterations in fatty acid metabolism predisposing to carcinogenesis. We believe that the combination of DER and DHA is a promising safe and effective intervention for reducing obesity-related breast cancer risk which needs to be validated in appropriately designed prospective, randomized clinical trials.

Alterations in fatty acid metabolism in response to obesity surgery combined with dietary counseling

Background:The effects of obesity surgery on serum and adipose tissue fatty acid (FA) profile and FA metabolism may modify the risk of obesity-related diseases.Methods:We measured serum (n=122) and adipose tissue (n=24) FA composition and adipose tissue mRNA expression of genes regulating FA metabolism (n=100) in participants of the Kuopio Obesity Surgery Study (KOBS, age 47.2±8.7 years, BMI 44.6±6.0, 40 men, 82 women) before and one year after obesity surgery. As part of the surgery protocol, all the subjects were instructed to add sources of unsaturated fatty acids, such as rapeseed oil and fatty fish, into their diet. The results were compared with changes in serum FA composition in 122 subjects from the Finnish Diabetes Prevention study (DPS) (age 54.3±7.1 years, BMI 32.2±4.6, 28 men, 94 women).Results:The proportion of saturated FAs decreased and the proportion of n-3 and n-6 FAs increased in serum triglycerides after obesity surgery (all P<0.002). Weight loss predicted changes in quantitative amounts of saturated FAs, monounsaturated FAs, n-3 and n-6 FAs in triglycerides (P<0.002 for all). Moreover, the changes in adipose tissue FAs reflected the changes in serum FAs, and some of the changes were associated with mRNA expression of elongases and desaturases in adipose tissue (all P<0.05). In line with this the estimated activity of elongase (18:1 n-7/16:1 n-7) increased significantly after obesity surgery in all lipid fractions (all P<4 × 10−7) and the increase in the estimated activity of D5D in triglycerides was associated with higher weight loss (r=0.415, P<2 × 10−6). Changes in serum FA profile were similar after obesity surgery and lifestyle intervention, except for the change in the absolute amounts of n-3 FAs between the two studies (P=0.044).Conclusions:Beneficial changes in serum and adipose tissue FAs after obesity surgery could be associated with changes in endogenous metabolism and diet.

Evaluation of fatty acid metabolism and innate immunity interactions between commercial broiler, F1 layer \xd7 broiler cross and commercial layer strains selected for different growth potentials

BackgroundThe broiler industry has undergone intense genetic selection over the past 50 yr. resulting in improvements for growth and feed efficiency, however, significant variation remains for performance and growth traits. Production improvements have been coupled with unfavourable metabolic consequences, including immunological trade-offs for growth, and excess fat deposition. To determine whether interactions between fatty acid (FA) metabolism and innate immunity may be associated with performance variations commonly seen within commercial broiler flocks, total carcass lipid %, carcass and blood FA composition, as well as genes involved with FA metabolism, immunity and cellular stress were investigated in male birds of a broiler strain, layer strain and F1 layer × broiler cross at d 14 post hatch. Heterophil: lymphocyte ratios, relative organ weights and bodyweight data were also compared.ResultsBroiler bodyweight (n = 12) was four times that of layers (n = 12) by d 14 and had significantly higher carcass fat percentage compared to the cross (n = 6; P = 0.002) and layers (P = 0.017) which were not significantly different from each other (P = 0.523). The carcass and whole blood FA analysis revealed differences in the FA composition between the three groups indicating altered FA metabolism, despite all being raised on the same diet. Genes associated with FA synthesis and β-oxidation were upregulated in the broilers compared to the layers indicating a net overall increase in FA metabolism, which may be driven by the larger relative liver size as a percentage of bodyweight in the broilers. Genes involved in innate immunity such as TLR2 and TLR4, as well as organelle stress indicators ERN1 and XBP1 were found to be non-significant, with the exception of high expression levels of XBP1 in layers compared to the cross and broilers. Additionally there was no difference in heterophil: lymphocytes between any of the birds.ConclusionsThe results provide evidence that genetic selection may be associated with altered metabolic processes between broilers, layers and their F1 cross. Whilst there is no evidence of interactions between FA metabolism, innate immunity or cellular stress, further investigations at later time points as growth and fat deposition increase would provide useful information as to the effects of divergent selection on key metabolic and immunological processes.

Maternal obesity alters fatty acid oxidation, AMPK activity, and associated DNA methylation in mesenchymal stem cells from human infants

ObjectiveInfants born to mothers with obesity have greater adiposity, ectopic fat storage, and are at increased risk for childhood obesity and metabolic disease compared with infants of normal weight mothers, though the cellular mechanisms mediating these effects are unclear. MethodsWe tested the hypothesis that human, umbilical cord-derived mesenchymal stem cells (MSCs) from infants born to obese (Ob-MSC) versus normal weight (NW-MSC) mothers demonstrate altered fatty acid metabolism consistent with adult obesity. In infant MSCs undergoing myogenesis in vitro, we measured cellular lipid metabolism and AMPK activity, AMPK activation in response to cellular nutrient stress, and MSC DNA methylation and mRNA content of genes related to oxidative metabolism. ResultsWe found that Ob-MSCs exhibit greater lipid accumulation, lower fatty acid oxidation (FAO), and dysregulation of AMPK activity when undergoing myogenesis in vitro. Further experiments revealed a clear phenotype distinction within the Ob-MSC group where more severe MSC metabolic perturbation corresponded to greater neonatal adiposity and umbilical cord blood insulin levels. Targeted analysis of DNA methylation array revealed Ob-MSC hypermethylation in genes regulating FAO (PRKAG2, ACC2, CPT1A, SDHC) and corresponding lower mRNA content of these genes. Moreover, MSC methylation was positively correlated with infant adiposity. ConclusionsThese data suggest that greater infant adiposity is associated with suppressed AMPK activity and reduced lipid oxidation in MSCs from infants born to mothers with obesity and may be an important, early marker of underlying obesity risk.

Differential effects of late gestation maternal overnutrition on the regulation of surfactant maturation in fetal and postnatal life.

Offspring of overweight and obese women are at greater risk for respiratory complications at birth. We determined the effect of late gestation maternal overnutrition (LGON) in sheep on surfactant maturation, glucose transport and fatty acid metabolism in the lung in fetal and postnatal life. There were significant decreases in surfactant components and numerical density of surfactant producing cells in the alveolar epithelium due to LGON in the fetal lung. However, there were no differences in the levels of these surfactant components between control and LGON lambs at 30days of age. The reduced capacity for surfactant production in fetuses as a result of LGON may affect the transition to air breathing at birth. There was altered glucose transport and fatty acid metabolism in the lung as a result of LGON in postnatal life. However, there is a normalisation of surfactant components that suggests accelerated maturation in the lungs after birth. With the increasing incidence of obesity worldwide, the proportion of women entering pregnancy overweight or obese has increased dramatically. The fetus of an overnourished mother experiences numerous metabolic changes that may modulate lung development and hence successful transition to air breathing at birth. We used a sheep model of maternal late gestation overnutrition (LGON; from 115days' gestation, term 147±3days) to determine the effect of exposure to an increased plane of nutrition in late gestation on lung development in the fetus (at 141days' gestation) and the lamb (30days after birth). We found a decrease in the numerical density of surfactant protein positive cells, as well as a reduction in mRNA expression of surfactant proteins (SFTP-A, -B and -C), a rate limiting enzyme in surfactant phospholipid synthesis (phosphate cytidylyltransferase 1, choline, α; PCYT1A), and glucose transporters (SLC2A1 and SLC2A4) in the fetal lung. In lambs at 30days after birth, there were no differences between Control and LGON groups in the surfactant components that were downregulated in the LGON fetuses. However, mRNA expression of SFTP-A, PCYT1A, peroxisome proliferator activated receptor-γ, fatty acid synthase and fatty acid transport protein were increased in LGON lambs compared to controls. These results indicate a reduced capacity for surfactant production in late gestation. While these deficits are normalised by 30days after birth, the lungs of LGON lambs exhibited altered glucose transport and fatty acid metabolism, which is consistent with an enhanced capacity for surfactant synthesis and restoration of surfactant maturity in these animals.

GPR55 receptor antagonist decreases glycolytic activity in PANC-1 pancreatic cancer cell line and tumor xenografts.

The Warburg effect is a predominant metabolic pathway in cancer cells characterized by enhanced glucose uptake and its conversion to l-lactate and is associated with upregulated expression of HIF-1α and activation of the EGFR-MEK-ERK, Wnt-β-catenin, and PI3K-AKT signaling pathways. (R,R')-4'-methoxy-1-naphthylfenoterol ((R,R')-MNF) significantly reduces proliferation, survival, and motility of PANC-1 pancreatic cancer cells through inhibition of the GPR55 receptor. We examined (R,R')-MNF's effect on glycolysis in PANC-1 cells and tumors. Global NMR metabolomics was used to elucidate differences in the metabolome between untreated and (R,R')-MNF-treated cells. LC/MS analysis was used to quantify intracellular concentrations of β-hydroxybutyrate, carnitine, and l-lactate. Changes in target protein expression were determined by Western blot analysis. Data was also obtained from mouse PANC-1 tumor xenografts after administration of (R,R')-MNF. Metabolomics data indicate that (R,R')-MNF altered fatty acid metabolism, energy metabolism, and amino acid metabolism and increased intracellular concentrations of β-hydroxybutyrate and carnitine while reducing l-lactate content. The cellular content of phosphoinositide-dependent kinase-1 and hexokinase 2 was reduced consistent with diminished PI3K-AKT signaling and glucose metabolism. The presence of the GLUT8 transporter was established and found to be attenuated by (R,R')-MNF. Mice treated with (R,R')-MNF had significant accumulation of l-lactate in tumor tissue relative to vehicle-treated mice, together with reduced levels of the selective l-lactate transporter MCT4. Lower intratumoral levels of EGFR, pyruvate kinase M2, β-catenin, hexokinase 2, and p-glycoprotein were also observed. The data suggest that (R,R')-MNF reduces glycolysis in PANC-1 cells and tumors through reduced expression and function at multiple controlling sites in the glycolytic pathway.

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats.

Despite the fact that skeletal muscle insulin resistance is the hallmark of type‐2 diabetes mellitus (T2DM), inflexibility in substrate energy metabolism has been observed in other tissues such as liver, adipose tissue, and heart. In the heart, structural and functional changes ultimately lead to diabetic cardiomyopathy. However, little is known about the early biochemical changes that cause cardiac metabolic dysregulation and dysfunction. We used a dietary model of fructose‐induced T2DM (10% fructose in drinking water for 6 weeks) to study cardiac fatty acid metabolism in early T2DM and related signaling events in order to better understand mechanisms of disease. In early type‐2 diabetic hearts, flux through the fatty acid oxidation pathway was increased as a result of increased cellular uptake (CD36), mitochondrial uptake (CPT1B), as well as increased β‐hydroxyacyl‐CoA dehydrogenase and medium‐chain acyl‐CoA dehydrogenase activities, despite reduced mitochondrial mass. Long‐chain acyl‐CoA dehydrogenase activity was slightly decreased, resulting in the accumulation of long‐chain acylcarnitine species. Cardiac function and overall mitochondrial respiration were unaffected. However, evidence of oxidative stress and subtle changes in cardiolipin content and composition were found in early type‐2 diabetic mitochondria. Finally, we observed decreased activity of SIRT1, a pivotal regulator of fatty acid metabolism, despite increased protein levels. This indicates that the heart is no longer capable of further increasing its capacity for fatty acid oxidation. Along with increased oxidative stress, this may represent one of the earliest signs of dysfunction that will ultimately lead to inflammation and remodeling in the diabetic heart.

Circulating acylcarnitine profile in human heart failure: a surrogate of fatty acid metabolic dysregulation in mitochondria and beyond.

Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FAs), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely, acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 control subjects and 68 HF patients exhibiting depressed left ventricular ejection fraction (25.9 ± 6.9%) and mostly of ischemic etiology with ≥2 comorbidities. HF patients displayed marginal changes in plasma levels of tricarboxylic acid cycle-related metabolites or indexes of mitochondrial or cytosolic redox status. They had, however, 22-79% higher circulating ACs, irrespective of chain length (P < 0.0001, adjusted for sex, age, renal function, and insulin resistance, determined by shotgun MS/MS), which reflects defective mitochondrial β-oxidation, and were significantly associated with levels of NH2-terminal pro-B-type natriuretic peptide levels, a disease severity marker. Subsequent extended liquid chromatography-tandem MS analysis of 53 plasma ACs in a subset group from the primary cohort confirmed and further substantiated with a comprehensive lipidomic analysis in a validation cohort revealed in HF patients a more complex circulating AC profile. The latter included dicarboxylic-ACs and dihydroxy-ACs as well as very long chain (VLC) ACs or sphingolipids with VLCFAs (>20 carbons), which are proxies of dysregulated FA metabolism in peroxisomes. Our study identified alterations in circulating ACs in HF patients that are independent of biological traits and associated with disease severity markers. These alterations reflect dysfunctional FA metabolism in mitochondria but also beyond, namely, in peroxisomes, suggesting a novel mechanism contributing to global lipid perturbations in human HF.NEW & NOTEWORTHY Mass spectrometry-based profiling of circulating energy metabolites, including acylcarnitines, in two cohorts of heart failure versus control subjects revealed multiple alterations in fatty acid metabolism in peroxisomes in addition to mitochondria, thereby highlighting a novel mechanism contributing to global lipid perturbations in heart failure.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/acylcarnitines-in-human-heart-failure/.

Significance of Microbiota in Obesity and Metabolic Diseases and the Modulatory Potential by Medicinal Plant and Food Ingredients.

Metabolic syndrome is a cluster of three or more metabolic disorders including insulin resistance, obesity, and hyperlipidemia. Obesity has become the epidemic of the twenty-first century with more than 1.6 billion overweight adults. Due to the strong connection between obesity and type 2 diabetes, obesity has received wide attention with subsequent coining of the term “diabesity.” Recent studies have identified unique contributions of the immensely diverse gut microbiota in the pathogenesis of obesity and diabetes. Several mechanisms have been proposed including altered glucose and fatty acid metabolism, hepatic fatty acid storage, and modulation of glucagon-like peptide (GLP)-1. Importantly, the relationship between unhealthy diet and a modified gut microbiota composition observed in diabetic or obese subjects has been recognized. Similarly, the role of diet rich in polyphenols and plant polysaccharides in modulating gut bacteria and its impact on diabetes and obesity have been the subject of investigation by several research groups. Gut microbiota are also responsible for the extensive metabolism of polyphenols thus modulating their biological activities. The aim of this review is to shed light on the composition of gut microbes, their health importance and how they can contribute to diseases as well as their modulation by polyphenols and polysaccharides to control obesity and diabetes. In addition, the role of microbiota in improving the oral bioavailability of polyphenols and hence in shaping their antidiabetic and antiobesity activities will be discussed.

Serum metabolomic response to exercise training in spontaneously hypertensive rats

Chronic aerobic exercise training exhibits blood pressure protective effects, but the mechanism in metabolic level remains largely unclear. This study aims to investigate the effect of exercise training from serum metabolic profiles on the development of hypertension in spontaneously hypertensive rats (SHRs). Exercise training was performed, and the serum metabolites were measured by integrating gas chromatography–mass spectrometer and correlation-based network analysis. After a period of 6 weeks of chronic aerobic exercise training, systolic blood pressure was significant lower in the exercise training group (SHR + EX) rats than the control group (SHR). Principal component analysis indicated a clearly separation of metabolomic profiles between SHR + EX and SHR. Nineteen of 63 metabolites in serum were identified (P < .05, variable importance in projections > 1, false discovery rate < 0.1), including fatty acids, amino acids, and others. Lower levels of six fatty acids were observed in SHR + EX. Besides, pathway analysis indicated a significant alteration of fatty acid metabolism. The correlation-based (Pearson correlation coefficient > 0.83) network of serum metabolites revealed a decreased correlation linkage of SHR + EX than SHR rats. Higher activities of hexokinase, citrate synthase, aspartate aminotransferase, and alanine aminotransferase were detected in liver, left ventricle, and skeletal muscle of SHR + EX groups. In summary, these findings provided essential biochemistry information about the metabolic alteration to exercise training in SHR, which may in part explain the protective effect of exercise in hypertensive individuals.