Increased Carnitine Palmitoyltransferase Research Articles

Alkaline Mineral Complex Water Attenuates Transportation-Induced Hepatic Lipid Metabolism Dysregulation by AMPKα-SREBP-1c/PPARα Pathways.

Transportation, an unavoidable process in livestock farming, causes metabolic disorders in the body, which then lead to endocrine disruption, being immunocompromised, and growth suppression. Lipid metabolism dysregulation is a critical phenotype induced by transportation. The liver is a vital organ in lipid metabolism, with a role in both lipid synthesis and lipolysis. However, the specific mechanisms by which transportation affects hepatic lipid metabolism remain unclear. This study employed rats as a model to investigate the effects of transportation on hepatic lipid metabolism. Rats subjected to transportation showed altered serum lipid profiles, including decreased serum triglyceride (TG), low-density lipoprotein cholesterol (VLDL-C), and non-esterified fatty acid (NEFA) immediately after transportation (IAT) and serum total cholesterol (TC) on day 3, and increasing serum TG, TC, and low-density lipoprotein cholesterol (LDL-C) on day 10. Meanwhile, fatty droplets in the liver were also reduced at IAT and increased on days 3 and 10. Notably, transportation also affected hepatic-lipid-metabolism-related enzyme activities and signaling pathways, such as increased AMP-activated protein kinase alpha (AMPKα) phosphorylation and modulations in key proteins and genes related to lipid metabolism, decreased hepatic acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) activities at IAT, and increased carnitine palmitoyl transferase 1 alpha (CPT-1α) at IAT and ACC and CPT-1α activities on days 3 and 10. Supplementation with alkaline mineral complex water (AMC) before and after transportation mitigated the adverse effects on hepatic lipid metabolism by modulating the AMPKα-SREBP-1c/PPARα pathway, enhancing lipid synthesis, and reducing the oxidative catabolism of fatty acids. AMC inhibited the transportation-induced activation of AMPKα and restored the balance of lipid-metabolism-related enzymes and pathways. These findings highlight AMC's potential as a therapeutic intervention to alleviate transportation-induced lipid metabolism disorders, offering significant implications for improving animal welfare and reducing economic losses in livestock farming.

Identification of Whey Protein-Derived Anti-Obesity Peptides Through 3T3-L1 Adipocyte Differentiation Assay.

Whey proteins are a rich source of bioactive peptides. Whey protein hydrolysate (WPH) can effectively improve metabolic syndrome and reduce the risk of obesity. Bioactive peptides isolated from various food sources exhibit anti-obesity effects. However, few reports are available on the identification of anti-obesity peptides from whey protein. In this study, we aimed to identify anti-obesitypeptides from whey protein. Our findings revealed that WPH suppressed the accumulation of lipid droplets in 3T3-L1 adipocytes. Anti-obesity peptides in WPH were identified using amino acid sequencing and LC-MS analysis. Then, the inhibitory effects of the synthetic peptides on adipogenesis were assessed through Oil Red O staining. Two peptides were identified as anti-adipogenic: LDQW and LKPTPEGDLEIL. Subsequently, real-time PCR analysis found that several adipogenesis-related genes, such as peroxisome proliferator-activated receptor γ, were downregulated in the treatment with these peptides. Furthermore, LDQW and LKPTPEGDLEIL decreased the mRNA expression levels of stearoyl-coenzyme A desaturase 1 and increased carnitine palmitoyl transferase 1α expression in 3T3-L1 adipocytes. These findings indicate that LDQW and LKPTPEGDLEIL have anti-obesity properties and may be beneficial for treating metabolic diseases. This study provides a reference basis for developing new techniques to prevent obesity and related diseases.

Alleviating effects of guar gum on high-fat diet-induced liver injury in common carp (Cyprinus carpio)

This research aimed to determine the effect of dietary guar gum inclusion in high-lipid diets on the liver health of common carp (Cyprinus carpio). Four high-fat diets (10 % crude lipid) containing 0 % (HF), 0.3 % (HFG0.3), 1 % (HFG1), and 3 % (HFG3) of guar gum and a normal-lipid diet (5 % crude lipid; Control) were formulated. The tested diets were evenly and randomly distributed to fifteen tanks, with each tank containing thirty fish (4.53 ± 0.05 g). Fish were fed until apparent satiation for eight weeks. Compared to HF, diets HFG0.3, HFG1, and HFG3 significantly improved feed efficiency, with the HFG0.3 diet enhancing weight gain rate and specific growth rate. The results indicated that HF induced gut dysbiosis, hepatic lipid accumulation, oxidative stress, inflammation, and disturbance in hepatic lipid and cholesterol metabolism. Compared to the HF diet, diets HFG0.3, HFG1, and HFG3 substantially decreased hepatic lipid accumulation and malonaldehyde content, increased catalase activity and the expression of AMP-activated protein kinase (AMPKα2), peroxisomal proliferator-activated receptor alpha (PPARα), cholesterol 7alpha-hydroxylase, and decreased the expression of interleukin-1β (IL-1β). Moreover, the HFG0.3 and HFG1 diets dramatically increased nuclear factor erythroid 2-related factor 2 and liver X receptor expression and decreased protein carbonyl contents and expression of IL-8, nuclear factor kappa B (NF-κB p65), and tumor necrosis factor α. Furthermore, the HFG1 diet significantly increased carnitine palmitoyltransferase 1 and peroxisomal proliferator-activated receptor gamma coactivator 1 expression and reduced expression levels of fibroblast growth factor 19, farnesoid X receptor, and sterol regulatory element-binding protein type 1. The linear discriminant analysis effect size (LEfSe) analysis showed that HFG 0.3 and HFG1 substantially increased the enrichment of beneficial microbiota (e.g., lactic acid bacteria, Cetobacterium, and Fusobacterial) and decreased the enrichment of harmful microbiota (e.g., Proteobacteria, Acinetobacter, and Pseudomonas) compared to HF. These results suggested that guar gum can mitigate high-fat diet-induced liver damage in fish.

Paeonol ameliorates hyperlipidemia and autophagy in mice by regulating Nrf2 and AMPK/mTOR pathways

BackgroundHyperlipidemia, inadequate diet, and excessive medication increase the risk of cardiovascular disease. Paeonl (Pae), a phenolic compound found in Peony and Angelica dahurica, can alleviate lipid metabolism disorders and lipotoxicity. However, the molecular mechanism of Pae alleviating hyperlipidemia remains unclear and needs to be further explored. PurposeIn this study, we explored whether Pae can prevent hyperlipidemia and investigated the molecular mechanisms. MethodsThe effects of Pae (30, 45, 60mg·kg−1) on hyperlipidemia in Tyloapol-induced WT mice and Nrf2 knockout mice (Pae: 60mg·kg−1) were detected by oil red O staining, HE staining, TG, TC and other indexes. The expression levels of proinflammatory mediators, key lipid proteins and autophagy signaling pathway proteins were analyzed by enzyme-linked immunosorbent assay, western blot and immunofluorescence. The molecular mechanism of Pae alleviating hyperlipidemia was explored through molecular docking technique and in vivo and in vitro experiments. ResultsSeveral studies indicated that Pae effectively improved tyloxapol (Ty)-induced lipid metabolism disorder, as evidenced by decreased triglyceride content, increased carnitine palmitoyltransferase 1 (CPT1), and Sirtuin 1 (Sirt1) protein expression. In addition, Pae ameliorated hyperlipidemia by activating the AMPK/ACC and PI3K/mTOR pathways. Interestingly, the therapeutic effect of Pae on hyperlipidemia was markedly reduced in Nrf2−/− mice. Molecular docking results indicated that Pae and Nrf2 exhibited good binding ability, suggesting that Nrf2 is a core target mediating the effects of Pae in the treatment of hyperlipidemia. Taken together, Pae alleviated hyperlipidemia in vivo and ameliorated lipid accumulation in vitro by activating AMPK/ACC and PI3K/mTOR signaling pathways via Nrf2 binding. ConclusionOur data suggest that paeonol can ameliorate hyperlipidemia and autophagy in mice by regulating Nrf2 and AMPK/mTOR pathways, and it has potential therapeutic value in the occurrence and development of hyperlipidemia.

Effects of dietary melatonin on growth performance, nutrient composition, and lipid metabolism of Pacific white shrimp (Penaeus vannamei)

The goal of this study was to investigate the effects of dietary melatonin (MT) on the growth physiology and lipid metabolism of Penaeus vannamei (P. vannamei). We prepared six experimental diets with varying MT levels (0 (control), 22.5, 41.2, 82.7, 165.1, 329.2 mg/kg) and fed six groups of shrimp with these diets for 2 months. The highest survival, body length growth rate, weight gain, and specific growth rates occurred in shrimp that were fed the diet containing 82.7 mg/kg MT, and the highest levels of docosahexaenoic acid (DHA) and arachidonic acid (ARA) were also found in this treatment group. Compared with the control group, there were no significant differences in moisture, crude protein, and ash contents in shrimp fed with MT, but the crude lipid content was significantly decreased in the high concentration MT supplemented group. Compared to the control group, shrimp fed 82.7 mg/kg MT had better morphology and structure of the hepatopancreas, whereas the hepatopancreas tissues were damaged in shrimp from the high dose MT groups. Analysis of lipid metabolism-related enzymes and genes in the hepatopancreas showed that dietary MT greatly decreased fatty acid synthase and acetyl-CoA carboxylase activities but increased carnitine palmitoyltransferase 1 activity. At the transcriptional level, dietary MT reduced hepatopancreas fat accumulation by upregulating lipid oxidation genes and downregulating lipid synthesis genes. A broken-line model revealed that the ideal MT concentration was in the range of 59.59–71.97 mg/kg. We found that MT supplementation improved P. vannamei growth performance, enhanced fatty acid β oxidation, and prevented fat deposition in the hepatopancreas.

Changes within Liver Accounts for Fatty Acids Decrease in the Blood of Rats with Adjuvant‐Induced Arthritis

AbstractThis study characterizes rheumatoid arthritis‐related free fatty acids (FFAs) changes using adjuvant‐induced arthritis (AIA) model. Blood FFAs of healthy and AIA rats are periodically determined. During acute inflammation, FFAs levels are analyzed under both fasting and non‐fasting conditions. Oral intake capacities are compared by everted intestinal sac experiment. Tissue distribution of FFAs in the rats fed with/without linolenic acid is also investigated. AIA decreases FFAs in rats. Saturated FFAs are gradually recovered, but unsaturated FFAs are further reduced till the secondary inflammation. FFAs level gap remains unchanged regardless of feeding/fasting, and intestinal intake capacities of the rats are similar. FFAs levels in liver fluctuate in accordance with blood levels. Increased carnitine palmitoyltransferase 1 (CPT‐1) reveals the accelerated FFAs utilization in AIA rats, resulting in the accumulation of acetoacetic acid and 2‐hydroxybutyrate. Hepatocytes incubated with AIA serum take in more FFAs than normal controls when supply is sufficient. To the opposite, intracellular FFAs are reduced after AIA serum stimulus without additional supply. Besides, AIA serum‐challenged cells produce more CPT‐1. Hence, the reduced circulating FFAs in AIA rats should be attributed to the accelerated utilization in liver.Practical Applications: This study provides additional possible therapeutic approaches for the treatment of RA by focusing on the changes of blood FFAs. Obtained clues demonstrate that liver will be a key in the elucidation of RA‐related lipid paradox, and diet supplement of the unsaturated FFAs will be beneficial in treating RA.

Quinizarin suppresses the differentiation of adipocytes and lipogenesis in vitro and in vivo via downregulation of C/EBP-beta/SREBP pathway

AimsPotential anti-obesity effects of quinizarin, a plant anthraquinone, were investigated using 3 T3-L1 preadipocyte cells and high-fat diet (HD)-induced obese mice. Main methodCell viability was determined using the MTT assay. Triglyceride (TG) and lipid accumulation were determined using a TG assay kit and Oil Red O staining, respectively. Adipogenic, lipogenic, and lipolytic gene and protein expression was measured by RT–PCR or Western blot. Serum biochemical indices, including cholesterol and blood glucose, in HD-fed obese mice were determined using corresponding assay kits. Histological analysis was performed with haematoxylin and eosin (H&E) staining. ResultsQuinizarin (0–10 μM) significantly reduced intracellular TG and lipid droplets during the differentiation of preadipocytes. Quinizarin significantly suppressed the expression of adipocyte differentiation marker proteins, such as CCAAT/enhancer-binding protein β (C/EBP-β), C/EBP-α, PPAR-γ, and aP2, and lipogenic marker proteins, including SREBP1c, SREBP2, fatty acid synthase (FAS), and acetyl-CoA carboxylase 1 (ACC1), reduced ACC2 expression and increased carnitine palmitoyltransferase 1 (CPT1) expression. Oral administration of quinizarin (15–30 mg/kg/day) to HD-fed mice for 6 weeks reduced the body weight gain and size of liver adipocytes and epididymal fat tissues, with significant reductions in liver TG and serum total cholesterol, blood glucose, LDL, and HDL levels. SignificanceThe results of this study indicated that quinizarin exerts anti-obesity effects by inhibiting both adipogenesis and lipogenesis and stimulating lipolysis in vitro and in vivo mainly by downregulating the SREBP signalling pathway; thus, it might be a potent candidate as a health-beneficial food or therapeutic agent to prevent or treat obesity.

Reduced mitochondrial respiration in T cells of patients with major depressive disorder

SummaryConverging evidence indicates that major depressive disorder (MDD) and metabolic disorders might be mediated by shared (patho)biological pathways. However, the converging cellular and molecular signatures remain unknown. Here, we investigated metabolic dysfunction on a systemic, cellular, and molecular level in unmedicated patients with MDD compared with matched healthy controls (HC). Despite comparable BMI scores and absence of cardiometabolic disease, patients with MDD presented with significant dyslipidemia. On a cellular level, T cells obtained from patients with MDD exhibited reduced respiratory and glycolytic capacity. Gene expression analysis revealed increased carnitine palmitoyltransferase IA (CPT1a) levels in T cells, the rate-limiting enzyme for mitochondrial long-chain fatty acid oxidation. Together, our results indicate metabolic dysfunction in unmedicated, non-overweight patients with MDD on a systemic, cellular, and molecular level. This evidence for reduced mitochondrial respiration in T cells of patients with MDD provides translation of previous animal studies regarding a putative role of altered immunometabolism in depression pathobiology.

Garlic Scape (Allium sativum L.) Extract Decreases Adipogenesis by Activating AMK-Activated Protein Kinase During the Differentiation in 3T3-L1 Adipocytes.

Regulating adipogenesis and lipogenesis in white adipose tissue (WAT) is an efficient strategy to reduce obesity. This study investigates whether garlic scape extract (GSE) has anti-adipogenic and anti-lipogenic effects and which stage of adipogenesis is critical for its effect using 3T3-L1 cells. 3T3-L1 cells that were treated with GSE during adipogenesis and differentiation exhibited reduced peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein a (Cebpa) and Cebpb, acetyl-CoA carboxylase, fatty acid synthase, sterol regulatory element binding protein 1c, diacylglycerol acyltransferase 1, and perilipin 1 genes. When the cells were treated with GSE during postdifferentiation or during preadipocytes, they showed less reduction and no change, respectively. Consistent with this, lipid accumulation was strongly reduced in the cells that were treated during adipogenesis and differentiation and to a lesser extent in the cells that were treated during preadipocytes and postdifferentiation. Phosphorylation on AMP-activated protein kinase (AMPK) and its downstream proteins was increased together with increased carnitine palmitoyl transferase 1α and phosphorylation on hormone-sensitive lipase in the cells that were treated with GSE during differentiation. In summary, GSE reduced intracellular lipid accumulation by suppressing adipogenic and lipogenic genes and proteins by possibly the activation of AMPK signaling pathway during adipocyte differentiation. This result indicates that garlic scape may have the potential to prevent obesity by regulating lipid metabolism in WAT.

β-elemene blocks lipid-induced inflammatory pathways via PPARβ activation in heart failure

This study aims to investigate the effects of β-elemene on a mouse model of heart failure (HF) and to elucidate the underlying mechanisms in vitro approaches. In this study, left anterior descending (LAD)-induced HF mouse model and oxygen-glucose deprivation/recovery (OGD/R)-induced H9C2 model were leveraged to assess the therapeutic effects of β-elemene. Histological examination, western blot and quantitative real-time PCR analysis (RT-qPCR) and immunofluorescence staining was utilized to elucidate mechanism of β-elemene in lipid-induced inflammation. Results showed that β-elemene improved heart function in HF mice evidenced by the increase of cardiac ejection fraction (EF) and fractional shortening (FS) values. Furthermore, β-elemene administration rescued ventricular dilation, lipid accumulation, and inflammatory infiltration in arginal areas of mice myocardial infarction. At transcription level, β-elemene augmented the mRNA expression of fatty acid oxidation-associated genes, such as peroxisome proliferator-activated receptor-β (PPARβ). In vitro, treatment of β-elemene increased carnitine palmitoyltransferase 1A (CPT1A) and sirtuin 3 (SIRT3). Hallmarks of inflammation including the nuclear translocation of nuclear factor κB (NF-κB) and the degradation of inhibitory κBα (IκBα) were significantly suppressed. Consistently, we observed down-regulation of interleukin-6 (IL-6) and pro-inflammatory cytokines (such as TNFα) in β-elemene treated H9C2 cells. Finally, molecular docking model predicted an interaction between β-elemene and PPARβ protein. Furthermore, β-elemene increased the expression of PPARβ, which was validated by antagonist of PPARβ and siRNA for PPARβ.

Structural analysis and anti‐obesity effect of Polygonatum cyrtonema polysaccharide against obesity induced by high‐fat diet in mice

AbstractThis study aimed to analyse the physicochemical properties of Polygonatum cyrtonema polysaccharide (PCP) and evaluated its effects in a high‐fat diet (HFD)‐induced obese mice. Experimentally, PCP was established as a homogeneous heteropolysaccharide with both α‐ and β‐configurations, and its estimated average molecular weight was ˜5.1 kDa. Besides, we discovered its major monosaccharides, including galactose, mannose, rhamnose, galacturonic acid and glucose. PCP markedly decreased obesity‐related parameters, improved serum lipid profile, fasting blood glucose, and leptin levels and reversed insulin resistance. It also reduced the hepatic infiltration of lipid droplets and the size of adipocytes in adipose tissues. Finally, PCP simulation significantly downregulated the mRNA expression of CCAAT/enhancer‐binding protein‐α (C/EBPα), peroxisome proliferator‐activated receptor‐γ (PPARγ), sterol regulatory element‐binding protein‐1c (SREBP‐1c) and fatty acid synthase (FAS). On the contrary, it increased carnitine palmitoyltransferase (CPT1) and uncoupling protein 2 (UCP2) levels closely related to thermogenesis and glucolipid metabolism. Taken together, these findings have provided evidence that PCP could be a potential anti‐obesity ingredient in preventing diet‐induced obesity.

Short-Chain Fatty Acids (Except Hexanoic Acid) Lower NF-kB Transactivation, Which Rescues Inflammation-Induced Decreased Apolipoprotein A-I Transcription in HepG2 Cells.

Concentrations of apolipoprotein A-I (ApoA-I) decrease during inflammation, which may lead to dysfunctional ApoA-I-poor high-density lipoprotein (HDL) particles, and as such, elevate cardiovascular risk. Therefore, rescuing ApoA-I concentrations, especially during inflammation, seems beneficial. Recently, short-chain fatty acids (SCFAs) have received more attention as a strategy in reversing atherosclerosis. We here evaluated the effects of SCFAs on inflammatory pathways in relation to ApoA-I transcription. SCFAs dose–response studies were performed in the presence and absence of inflammatory cytokines. ApoA-I and interleukin 8 (IL-8) mRNA expression were analyzed using qPCR and ELISA, respectively. To study underlying mechanisms, nuclear factor kappa B (NF-κB) transactivation and changes in mRNA expressions of the genes targets of bromodomain and extra-terminal (BET) inhibition, peroxisome proliferator-activated receptor-alpha (PPARα) transactivation and activator protein 1 (AP-1) pathway were analyzed. SCFAs (except hexanoic acid) increased ApoA-I mRNA transcription in both normal and inflammatory conditions and lowered IL-8 mRNA expression. This anti-inflammatory effect of SCFAs was confirmed by inhibition of NF-κB transactivation. Moreover, butyric acid increased carnitine palmitoyltransferase 1 (CPT1), PPARα target gene, mRNA transcription in both conditions, and there was a negative correlation between CPT1 and NF-κB. Therefore, PPARα transactivation is probably involved in the anti-inflammatory effects of SCFAs, which rescues ApoA-I transcription. In conclusion, propionate, butyrate and valerate elicit anti-inflammatory effects which might rescue ApoA-I transcription in inflammatory conditions via PPARα transactivation mediated NF-κB inhibition.

Nitrate And Nitrite Treatment Modulate Performance And Available Fuel Sources In Zebrafish Muscle And Liver

Treatment with nitrate, but not nitrite, improves exercise performance, in part, by increasing availability of metabolic fuels that require less oxygen for energy production. However, the mechanisms by which these inorganic anions produce performance effects is not well understood. PURPOSE: The purpose of this study is to quantify changes in the metabolic state in zebrafish muscle and liver with nitrate and nitrite treatment during exercise using gene expression and metabolomic methods. METHODS: Liver and muscle were collected from adult zebrafish fish exposed to sodium nitrate (606.9 mg NaNO3/L water), sodium nitrite (19.5 mg NaNO2/L of water), or control water for 21 days (n= 128-130). Tissues were analyzed by quantitative real-time PCR and 1H-NMR untargeted metabolomics. RESULTS: Nitrate treatment significantly increased expression of peroxisome proliferator activated receptor-γ (pparg), a gene involved in regulation of lipid and glucose metabolism. In contrast, acetyl-CoA carboxylase (acaca), a gene that inhibits fatty acid oxidation, significantly decreased in the skeletal muscle of fish treated with nitrate or nitrite as compared to control skeletal muscle tissue. Nitrite treatment also significantly increased carnitine palmitoyl transferase 1b (cpt1b) expression in the liver, which is a primary regulator involved in long-chain fatty acid transport into the mitochondria. Preliminary NMR results show that, relative to control skeletal muscle, nitrate treatment in unexercised fish at rest induces significant increases in metabolic fuels, such as ATP and creatine phosphate, and fuel sources including β-hydroxybutyrate and glycolytic intermediates. After a graded exercise test, the same metabolites increased in control but were decreased in skeletal muscle of nitrate-treated, exercised fish. CONCLUSIONS: Our data are consistent with the hypothesis that nitrate treatment may alter lipid and carbohydrate metabolism of zebrafish, in part, through a PPAR-γ mediated mechanism in the liver, and may improve exercise performance through utilization of fuel sources that require less oxygen during exercise. In contrast, our data indicate that nitrite may increase oxygen cost of exercise, in part, by promoting dependence on fatty acid oxidation in the liver of zebrafish.

Nitrate and Nitrite Treatment Modulate Performance and Available Fuel Sources In Zebrafish Muscle and Liver

Abstract Objectives Treatment with nitrate, but not nitrite, improves exercise performance but the mechanisms responsible are not fully understood. Thus, we tested the hypothesis that nitrate and nitrite treatment alter exercise performance through regulation of genes related to glucose and lipid metabolism in skeletal muscle and liver. Furthermore, we tested the hypothesis that nitrate treatment caused increased abundance and utilization of metabolic fuels in muscle that require less oxygen for energy production. Methods Adult zebrafish fish were exposed to sodium nitrate (606.9 mg NaNO3/L water), sodium nitrite (19.5 mg NaNO2/L of water), or control water for 21 days (n = 9–12/treatment). Liver and muscle gene expression were analyzed by quantitative real-time PCR and liver and muscle metabolomes were assessed by 1H-NMR untargeted metabolomics. Results Nitrite treatment significantly increased carnitine palmitoyl transferase 1b (cpt1b) expression in the liver and significantly decreased acetyl-CoA carboxylase (acaca) expression in skeletal muscle. Nitrate treatment significantly increased expression of peroxisome proliferator activated receptor-γ (pparg) muscle while acaca significantly decreased in skeletal muscle. Nitrate treatment also induced significant increases in metabolic fuels, such as ATP and creatine phosphate, and fuel sources including β-hydroxybutyrate and glycolytic intermediates in rested skeletal muscle. After a graded exercise test, these metabolites decreased in skeletal muscle of nitrate-treated fish while they increased with exercise in the skeletal muscle of control-treated zebrafish. Conclusions Our data are consistent with the hypothesis that nitrate treatment altered lipid and carbohydrate metabolism of zebrafish, in part, through a pparg mediated mechanism in the liver, and may improve exercise performance through utilization of fuel sources that require less oxygen during exercise. In contrast, our data indicate that nitrite may attenuate exercise performance, in part, by promoting dependence on fatty acid oxidation in the liver of zebrafish. These mechanisms may mediate improved exercise tolerance in populations with cardiovascular disease. Funding Sources Celia Strickland and G. Kenneth Austin III Endowment and National Institutes of Health.

Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition–resistant triple-negative breast cancer cells

Triple-negative breast cancers (TNBCs) lack progesterone and estrogen receptors and do not have amplified human epidermal growth factor receptor 2, the main therapeutic targets for managing breast cancer. TNBCs have an altered metabolism, including an increased Warburg effect and glutamine dependence, making the glutaminase inhibitor CB-839 therapeutically promising for this tumor type. Accordingly, CB-839 is currently in phase I/II clinical trials. However, not all TNBCs respond to CB-839 treatment, and the tumor resistance mechanism is not yet fully understood. Here we classified cell lines as CB-839-sensitive or -resistant according to their growth responses to CB-839. Compared with sensitive cells, resistant cells were less glutaminolytic and, upon CB-839 treatment, exhibited a smaller decrease in ATP content and less mitochondrial fragmentation, an indicator of poor mitochondrial health. Transcriptional analyses revealed that the expression levels of genes linked to lipid metabolism were altered between sensitive and resistant cells and between breast cancer tissues (available from The Cancer Genome Atlas project) with low versus high glutaminase (GLS) gene expression. Of note, CB-839-resistant TNBC cells had increased carnitine palmitoyltransferase 2 (CPT2) protein and CPT1 activity levels. In agreement, CB-839-resistant TNBC cells mobilized more fatty acids into mitochondria for oxidation, which responded to AMP-activated protein kinase and acetyl-CoA carboxylase signaling. Moreover, chemical inhibition of both glutaminase and CPT1 decreased cell proliferation and migration of CB-839-resistant cells compared with single inhibition of each enzyme. We propose that dual targeting of glutaminase and CPT1 activities may have therapeutic relevance for managing CB-839-resistant tumors.

Potential role of ALDH3A2 on the lipid and glucose metabolism regulated by (-)-hydroxycitric acid in chicken embryos.

This study aimed to investigate the effect of (-)-hydroxycitric acid ((-)-HCA) on lipid and glucose metabolism, and further analyzed these actions whether associated with modulation of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) expression in chicken embryos. Results showed that (-)-HCA decreased triglyceride content and lipid droplet counts, while these effects induced by (-)-HCA were reversed in chicken embryos pre-transfected with sh4-ALDH3A2. (-)-HCA decreased malic enzyme, acetyl-CoA carboxylase, fatty acid synthase, and sterol regulatory element binding protein-1c mRNA level, while increased carnitine palmitoyl transferase 1A (CPT1A) and peroxisome proliferators-activated receptor α (PPARα) mRNA level; and the action of (-)-HCA on lipid metabolism factors had completely eliminated in embryos pre-transfected with sh4-ALDH3A2. Chicken embryos pre-transfected with sh4-ALDH3A2 had eliminated the increasing of serum glucose and hepatic glycogen content induced by (-)-HCA. (-)-HCA decreased phosphofructokinase-1 and increased G6P, fructose-1,6-bisphosphatase, phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate carboxylase mRNA level in chicken embryos. Similarly, the effect of (-)-HCA on these key enzyme mRNA level was reversed in embryos pre-transfected with sh4-ALDH3A2. Furthermore, (-)-HCA increased PPAR-γ-coactivator-1α (PGC-1α), PPARα, hepatic nuclear factor-4A, PEPCK, and CPT1A protein level, and these actions of (-)-HCA disappeared in embryos pre-transfected with sh4-ALDH3A2. These results indicated that (-)-HCA reduced fat accumulation and accelerated gluconeogenesis via activation of PGC-1α signaling pathway, and these effects of (-)-HCA might associate with the increasing of ALDH3A2 expression level in chicken embryos.

Dietary supplement of Smilax china L. ethanol extract alleviates the lipid accumulation by activating AMPK pathways in high-fat diet fed mice

BackgroundObesity has become a public health concern worldwide because it is linked to numerous metabolic disorders, such as hyperlipidemia, hypertension and cardiovascular disease. Therefore, there is an urgent need to develop new therapeutic strategies that are efficacious and have minimal side effects in obesity treatment. This study examined the effect of dietary supplement of Smilax china L. ethanol extract (SCLE) on high-fat diet (HFD) induced obesity.MethodsFifty ICR mice were fed a normal diet, high-fat diet (HFD) or HFD supplemented with 0.25, 0.5% or 1% SCLE for 8 weeks. Body weight, intraperitioneal adipose tissue (IPAT) weight, serum biochemical parameters, and liver lipids were measured. Activity, mRNA and protein expressions of lipid metabolism-related enzymes were analyzed.ResultsOver 0.5% SCLE had reduced cholesterol biosynthesis by the activation of AMP-activated protein kinase (AMPK), which subsequently suppressed the mRNA expression of both sterol regulatory element binding protein-2 and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Thus, the plasma and liver cholesterol concentrations in the HFD-fed mice were decreased. AMPK activation caused by SCLE also significantly upregulated lipolysis by enhancing adipose triglyceride lipase and hormone-sensitive lipase activities. This accelerated triglyceride hydrolysis and fatty acid release. Finally, SCLE increased carnitine palmitoyltransferase 1 and acyl-CoA oxidase activities, which further promoted fatty acid β-oxidation.ConclusionSCLE could lead to a decrease in body weight gain and fat mass by inhibiting the lipid synthesis and promoting lipolysis and β-oxidation in HFD fed mice. The underlying mechanism is probably associated with regulating AMPK pathway.

Chronic Exercise Improves Mitochondrial Function and Insulin Sensitivity in Brown Adipose Tissue.

The aim of the present work was to study the consequences of chronic exercise training on factors involved in the regulation of mitochondrial remodeling and biogenesis, as well as the ability to produce energy and improve insulin sensitivity and glucose uptake in rat brown adipose tissue (BAT). Male Wistar rats were divided into two groups: (1) control group (C; n = 10) and (2) exercise-trained rats (ET; n = 10) for 8 weeks on a motor treadmill (five times per week for 50 min). Exercise training reduced body weight, plasma insulin, and oxidized LDL concentrations. Protein expression of ATP-independent metalloprotease (OMA1), short optic atrophy 1 (S-OPA1), and dynamin-related protein 1 (DRP1) in BAT increased in trained rats, and long optic atrophy 1 (L-OPA1) and mitofusin 1 (MFN1) expression decreased. BAT expression of nuclear respiratory factor type 1 (NRF1) and mitochondrial transcription factor A (TFAM), the main factors involved in mitochondrial biogenesis, was higher in trained rats compared to controls. Exercise training increased protein expression of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and AMP-activated protein kinase (pAMPK/AMPK ratio) in BAT. In addition, training increased carnitine palmitoyltransferase II (CPT II), mitochondrial F1 ATP synthase α-chain, mitochondrial malate dehydrogenase 2 (mMDH) and uncoupling protein (UCP) 1,2,3 expression in BAT. Moreover, exercise increased insulin receptor (IR) ratio (IRA/IRB ratio), IRA-insulin-like growth factor 1 receptor (IGF-1R) hybrids and p42/44 activation, and decreased IGF-1R expression and IR substrate 1 (p-IRS-1) (S307) indicating higher insulin sensitivity and favoring glucose uptake in BAT in response to chronic exercise training. In summary, the present study indicates that chronic exercise is able to improve the energetic profile of BAT in terms of increased mitochondrial function and insulin sensitivity.

Beneficial Effects of Common Bean on Adiposity and Lipid Metabolism.

In developed countries which are at the epicenter of the obesity pandemic, pulse crop consumption is well below recommended levels. In a recent systematic review and meta-analysis of 21 randomized controlled clinical trials, pulse consumption was associated with improved weight control and reduced adiposity, although the underlying mechanisms were a matter of speculation. Common bean (Phaseolus vulgaris L.) is the most widely consumed pulse crop and was the focus of this investigation. Using outbred genetic models of dietary induced obesity resistance and of dietary induced obesity sensitivity in the rat, the impact of bean consumption was investigated on the efficiency with which consumed food was converted to body mass (food efficiency ratio), body fat accumulation, adipocyte morphometrics, and patterns of protein expression associated with lipid metabolism. Cooked whole bean as well as a commercially prepared cooked bean powders were evaluated. While bean consumption did not affect food efficiency ratio, bean reduced visceral adiposity and adipocyte size in both obesity sensitive and resistant rats. In liver, bean consumption increased carnitine palmitoyl transferase 1, which is the rate limiting step in long chain fatty acid oxidation and also resulted in lower levels of circulating triglycerides. Collectively, our results are consistent with the clinical finding that pulse consumption is anti-obesogenic and indicate that one mechanism by which cooked bean exerts its bioactivity is oxidation of long chain fatty acids.

Multiphasic Regulation of Systemic and Peripheral Organ Metabolic Responses to Cardiac Hypertrophy.

Reduced fat oxidation in hypertrophied hearts coincides with a shift of carnitine palmitoyl transferase I from muscle to increased liver isoforms. Acutely increased carnitine palmitoyl transferase I in normal rodent hearts has been shown to recapitulate the reduced fat oxidation and elevated atrial natriuretic peptide message of cardiac hypertrophy. Because of the potential for reduced fat oxidation to affect cardiac atrial natriuretic peptide, and thus, induce adipose lipolysis, we studied peripheral and systemic metabolism in male C57BL/6 mice model of transverse aortic constriction in which left ventricular hypertrophy occurred by 2 weeks without functional decline until 16 weeks (ejection fraction, -45.6%; fractional shortening, -22.6%). We report the first evidence for initially improved glucose tolerance and insulin sensitivity in response to 2 weeks transverse aortic constriction versus sham, linked to enhanced insulin signaling in liver and visceral adipose tissue (epididymal white adipose tissue [WAT]), reduced WAT inflammation, elevated adiponectin, mulitilocular subcutaneous adipose tissue (inguinal WAT) with upregulated oxidative/thermogenic gene expression, and downregulated lipolysis and lipogenesis genes in epididymal WAT. By 6 weeks transverse aortic constriction, the metabolic profile reversed with impaired insulin sensitivity and glucose tolerance, reduced insulin signaling in liver, epididymal WAT and heart, and downregulation of oxidative enzymes in brown adipose tissue and oxidative and lipogenic genes in inguinal WAT. Changes in insulin signaling, circulating natriuretic peptides and adipokines, and varied expression of adipose genes associated with altered insulin response/glucose handling and thermogenesis occurred prior to any functional decline in transverse aortic constriction hearts. The findings demonstrate multiphasic responses in extracardiac metabolism to pathogenic cardiac stress, with early iWAT browning providing potential metabolic benefits.