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1.
J Biol Chem ; 289(23): 16032-45, 2014 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-24742673

RESUMO

Chronic low grade inflammation is closely linked to obesity-associated insulin resistance. To examine how administration of the anti-inflammatory compound indomethacin, a general cyclooxygenase inhibitor, affected obesity development and insulin sensitivity, we fed obesity-prone male C57BL/6J mice a high fat/high sucrose (HF/HS) diet or a regular diet supplemented or not with indomethacin (±INDO) for 7 weeks. Development of obesity, insulin resistance, and glucose intolerance was monitored, and the effect of indomethacin on glucose-stimulated insulin secretion (GSIS) was measured in vivo and in vitro using MIN6 ß-cells. We found that supplementation with indomethacin prevented HF/HS-induced obesity and diet-induced changes in systemic insulin sensitivity. Thus, HF/HS+INDO-fed mice remained insulin-sensitive. However, mice fed HF/HS+INDO exhibited pronounced glucose intolerance. Hepatic glucose output was significantly increased. Indomethacin had no effect on adipose tissue mass, glucose tolerance, or GSIS when included in a regular diet. Indomethacin administration to obese mice did not reduce adipose tissue mass, and the compensatory increase in GSIS observed in obese mice was not affected by treatment with indomethacin. We demonstrate that indomethacin did not inhibit GSIS per se, but activation of GPR40 in the presence of indomethacin inhibited glucose-dependent insulin secretion in MIN6 cells. We conclude that constitutive high hepatic glucose output combined with impaired GSIS in response to activation of GPR40-dependent signaling in the HF/HS+INDO-fed mice contributed to the impaired glucose clearance during a glucose challenge and that the resulting lower levels of plasma insulin prevented the obesogenic action of the HF/HS diet.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Dieta Hiperlipídica , Indometacina/farmacologia , Resistência à Insulina , Obesidade/prevenção & controle , Animais , Linhagem Celular , Ácidos Graxos não Esterificados/sangue , Teste de Tolerância a Glucose , Glicerol/sangue , Mediadores da Inflamação/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxilipinas/sangue , Reação em Cadeia da Polimerase em Tempo Real
2.
Biochim Biophys Acta ; 1831(2): 291-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23085008

RESUMO

Reduced mitochondrial fatty acid (FA) ß-oxidation can cause accumulation of triglyceride in liver, while intake of eicosapentaenoic acid (EPA) has been recommended as a promising novel therapy to decrease hepatic triglyceride content. However, reduced mitochondrial FA ß-oxidation also facilitates accumulation of EPA. To investigate the interplay between EPA administration, mitochondrial activity and hepatic triglyceride accumulation, we investigated the effects of EPA administration to carnitine-deficient mice with impaired mitochondrial FA ß-oxidation. C57BL/6J mice received a high-fat diet supplemented or not with 3% EPA in the presence or absence of 500 mg mildronate/kg/day for 10 days. Liver mitochondrial and peroxisomal oxidation, lipid classes and FA composition were determined. Histological staining was performed and mRNA level of genes related to lipid metabolism and inflammation in liver and adipose tissue was determined. Levels of pro-inflammatory eicosanoids and cytokines were measured in plasma. The results showed that mildronate treatment decreased hepatic carnitine concentration and mitochondrial FA ß-oxidation and induced severe triglyceride accumulation accompanied by elevated systemic inflammation. Surprisingly, inclusion of EPA in the diet exacerbated the mildronate-induced triglyceride accumulation. This was accompanied by a considerable increase of EPA accumulation while decreased total n-3/n-6 ratio in liver. However, inclusion of EPA in the diet attenuated the mildronate-induced mRNA expression of inflammatory genes in adipose tissue. Taken together, dietary supplementation with EPA exacerbated the triglyceride accumulation induced by impaired mitochondrial FA ß-oxidation. Thus, further thorough evaluation of the potential risk of EPA supplementation as a therapy for NAFLD associated with impaired mitochondrial FA oxidation is warranted.


Assuntos
Suplementos Nutricionais , Ácido Eicosapentaenoico/administração & dosagem , Ácidos Graxos/metabolismo , Fígado/metabolismo , Triglicerídeos/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução
3.
Amino Acids ; 46(7): 1659-71, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24658997

RESUMO

High-protein diets induce alterations in metabolism that may prevent diet-induced obesity. However, little is known as to whether different protein sources consumed at normal levels may affect diet-induced obesity and associated co-morbidities. We fed obesity-prone male C57BL/6J mice high-fat, high-sucrose diets with protein sources of increasing endogenous taurine content, i.e., chicken, cod, crab and scallop, for 6 weeks. The energy intake was lower in crab and scallop-fed mice than in chicken and cod-fed mice, but only scallop-fed mice gained less body and fat mass. Liver mass was reduced in scallop-fed mice, but otherwise no changes in lean body mass were observed between the groups. Feed efficiency and apparent nitrogen digestibility were reduced in scallop-fed mice suggesting alterations in energy utilization and metabolism. Overnight fasted plasma triacylglyceride, non-esterified fatty acids, glycerol and hydroxy-butyrate levels were significantly reduced, indicating reduced lipid mobilization in scallop-fed mice. The plasma HDL-to-total-cholesterol ratio was higher, suggesting increased reverse cholesterol transport or cholesterol clearance in scallop-fed mice in both fasted and non-fasted states. Dietary intake of taurine and glycine correlated negatively with body mass gain and total fat mass, while intake of all other amino acids correlated positively. Furthermore taurine and glycine intake correlated positively with improved plasma lipid profile, i.e., lower levels of plasma lipids and higher HDL-to-total-cholesterol ratio. In conclusion, dietary scallop protein completely prevents high-fat, high-sucrose-induced obesity whilst maintaining lean body mass and improving the plasma lipid profile in male C57BL/6J mice.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Proteínas Alimentares/química , Proteínas Alimentares/farmacologia , Lipídeos/sangue , Obesidade/prevenção & controle , Pectinidae/química , Tecido Adiposo/efeitos dos fármacos , Animais , Ingestão de Energia/efeitos dos fármacos , Glicina/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Nitrogênio/farmacocinética , Obesidade/etiologia , Obesidade/metabolismo , Sacarose/efeitos adversos , Taurina/farmacologia , Aumento de Peso/efeitos dos fármacos
4.
J Lipid Res ; 53(8): 1662-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22628615

RESUMO

A subject's baseline FA composition may influence the ability of dietary highly unsaturated omega-3 FAs (n3-HUFA) to change circulating profiles of esterified FAs and their oxygenated metabolites. This study evaluates the influence of basal n3-HUFA and n3-oxylipin status on the magnitude of response to n3-HUFA consumption. Blood was collected from fasting subjects (n = 30) before and after treatment (4 weeks; 11 ± 2 mg/kg/day n3-HUFA ethyl esters). Esterified FAs were quantified in erythrocytes, platelets, and plasma by GC-MS. Esterified oxylipins were quantified in plasma by LC-MS/MS. Treatment with n3-HUFAs increased n3-HUFAs and decreased n6-HUFAs in all reservoirs and increased plasma n3-oxylipins without significantly changing n6-oxylipin concentrations. As subject basal n3-HUFAs increased, treatment-associated changes decreased, and this behavior was reflected in the percentage of 20:5n3 + 22:6n3 in red blood cell membrane FAs (i.e., the omega-3 index). To maintain an omega-3 index of 8% and thus reduce cardiovascular disease risk, our analyses suggest a maintenance dose of 7 mg/kg/day n3-HUFA ethyl esters for a 70-kg individual. These results suggest that the basal n3 index may have clinical utility to establish efficacious therapeutic experimental feeding regimens and to evaluate the USDA Dietary Guidelines recommendations for n3-HUFA consumption.


Assuntos
Metabolismo Basal , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-3/farmacologia , Saúde , Oxilipinas/sangue , Adulto , Metabolismo Basal/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Relação Dose-Resposta a Droga , Prescrições de Medicamentos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Esterificação/efeitos dos fármacos , Ácidos Graxos Ômega-3/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxilipinas/metabolismo , Adulto Jovem
5.
J Nutr ; 142(10): 1896-902, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22933750

RESUMO

We assessed the effect of daily consumption of orange-fleshed sweet potatoes (OFSP), with or without added fat, on the vitamin A (VA) status of Bangladeshi women with low initial VA status. Women (n = 30/group) received one of the following for 6 d/wk over 10 wk: 1) 0 µg retinol activity equivalents (RAE)/d as boiled white-fleshed sweet potatoes (WFSP) and a corn oil capsule, 2) 600 µg RAE/d as boiled OFSP and a corn oil capsule, 3) fried OFSP and a corn oil capsule, or 4) boiled WFSP and a retinyl palmitate capsule in addition to their home diets. Plasma concentrations of retinol and ß-carotene and total body VA pool size were assessed before and after the 60-d intervention. Initial and final plasma retinol concentrations (mean ± SD) were 0.75 ± 0.18 µmol/L and 0.84 ± 0.19 µmol/L, respectively (P = 0.31); final means did not differ by group. Initial and final plasma ß-carotene concentrations were 0.10 ± 00 µmol/L and 0.18 ± 0.09 µmol/L, respectively (P < 0.0001); final mean plasma ß-carotene concentrations were higher in groups that received OFSP (P < 0.0001), and final mean plasma ß-carotene was marginally higher in the group that received fried OFSP compared with boiled OFSP (P = 0.07). Initial and final total body VA pool sizes were 0.060 ± 0.047 mmol and 0.091 ± 0.070 mmol, respectively (P = 0.05, n = 110) and did not differ by group. Despite an increase in plasma ß-carotene concentration, the impact of OFSP on VA status appears to be limited in Bangladeshi women residing in a resource-poor community.


Assuntos
Dieta , Ipomoea batatas/química , Deficiência de Vitamina A/epidemiologia , Vitamina A/sangue , beta Caroteno/sangue , Adolescente , Adulto , Antropometria , Bangladesh/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Deficiência de Vitamina A/sangue , Adulto Jovem , beta Caroteno/administração & dosagem
6.
Artigo em Inglês | MEDLINE | ID: mdl-26029731

RESUMO

OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disease of aging with unknown causative factors. Accumulating evidence suggests that inflammation and neurovascular dysfunction play important roles in AD. The postprandial period following a moderately high-fat meal is associated with vascular inflammation in young, healthy individuals; however, this relationship has not been investigated in Alzheimer's patients despite their exaggerated inflammatory state. METHODS: Patients with AD and age-matched control subjects were recruited through the UC Davis Alzheimer's Disease Center. All subjects consumed a moderately high-fat breakfast meal. Fasting and postprandial blood samples were collected for lipid, lipoprotein, and oxylipin analyses, as well as assays for cytokine levels and monocyte activation. RESULTS: The plasma lipid analyses revealed similar levels of triglycerides and esterified oxylipins between groups, but there was an interaction between postprandial non-esterified fatty acid (NEFA) levels and body mass index in the AD group compared to the control subjects. The AD group also had increased behenic acid and decreased linoleic and oleic acids in the postprandial period; however, these were not significantly different. Inflammatory assays revealed elevated fasting levels of interleukin (IL)-10 and IL-12 p70, but no change in monocyte activation in the AD group. CONCLUSION: The postprandial period following a moderately high-fat meal is not associated with an exaggerated inflammatory state in Alzheimer's patients, and basal esterified oxylipin profiles do not indicate elevated oxidative stress. However, the baseline inflammatory state during fasting in AD patients includes elevated levels of plasma IL-10 and IL-12 p70, which may indicate a balance between immune responses mediated by these interleukins.

7.
Nutr Metab (Lond) ; 11: 24, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24963334

RESUMO

BACKGROUND: Diets rich in dairy and/or calcium (Ca) have been associated with reductions in adiposity and inflammation, but the mechanisms underlying this remain to be fully elucidated. Oxylipins and endocannabinoids are bioactive lipids, which influence energy homeostasis, adipose function, insulin signaling, and inflammation. Our objective was to determine if these metabolites associate with metabolic and inflammatory phenotypes stemming from dietary Ca and dairy in diet induced obese mice. METHODS: In one study, C57BL6/J mice were fed high fat diets (45% energy) with varying dietary matrices for 12 weeks: soy protein and Ca adequate (0.5%; CONTROL), soy protein and high Ca (1.5%; HighCa), or nonfat-dry-milk based high Ca (NFDM). In a second study, mice were pre-fattened for 12 weeks on the CONTROL high fat diet, and then fed one of three high fat diets for an additional 8 weeks: CONTROL, HighCa, or NFDM. In both studies, adiposity and associated metabolic and inflammatory outcomes were measured and a targeted lipidomics analysis was performed on plasma collected during the post-absorptive condition. RESULTS: As reported previously, mice fed NFDM had less body fat and reduced mRNA markers of adipose inflammation (p < 0.05) than CONTROL mice despite greater cumulative energy intake. Moreover, NFDM fed mice lipid mediator profiles were distinct from CONTROL and HighCa mice. NFDM fed mice showed elevated plasma monoacylglycerols (6 - 46% increase from CONTROL), including 2-arachidonoylglycerol (2-AG), and reduced fatty acid diols (8-75% decrease from CONTROL). CONCLUSIONS: Differences in specific plasma lipid mediator profiles reflect the metabolic and inflammatory phenotypes seen in NFDM feeding.

8.
Toxicol Sci ; 133(1): 90-100, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23377617

RESUMO

A deficit in zinc (Zn) availability can increase cell oxidant production, affect the antioxidant defense system, and trigger oxidant-sensitive signals in neuronal cells. This work tested the hypothesis that a decreased Zn availability can affect glutathione (GSH) metabolism in the developing rat brain and in neuronal cells in culture, as well as the capacity of human neuroblastoma IMR-32 cells to upregulate GSH when challenged with dopamine (DA). GSH levels were low in the brain of gestation day 19 (GD19) fetuses from dams fed marginal Zn diets throughout gestation and in Zn-deficient IMR-32 cells. γ-Glutamylcysteine synthetase (GCL), the first enzyme in the GSH synthetic pathway, was altered by Zn deficiency (ZD). The protein and mRNA levels of the GCL modifier (GCLM) and catalytic (GCLC) subunits were lower in the Zn-deficient GD19 fetal brain and in IMR-32 cells compared with controls. The nuclear translocation of transcription factor nuclear factor (erythroid-derived 2)-like 2, which controls GCL transcription, was impaired by ZD. Posttranslationally, the caspase-3-dependent GCLC cleavage was high in Zn-deficient IMR-32 cells. Cells challenged with DA showed an increase in GCLM and GCLC protein and mRNA levels and a consequent increase in GSH concentration. Although Zn-deficient cells partially upregulated GCL subunits after exposure to DA, GSH content remained low. In summary, results show that a low Zn availability affects the GSH synthetic pathway in neuronal cells and fetal brain both at transcriptional and posttranslational levels. This can in part underlie the GSH depletion associated with ZD and the high sensitivity of Zn-deficient neurons to pro-oxidative stressors.


Assuntos
Encéfalo/embriologia , Glutationa/metabolismo , Neurônios/metabolismo , Organogênese , Zinco/deficiência , Animais , Western Blotting , Encéfalo/metabolismo , Caspase 3/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/genética , Organogênese/fisiologia , Gravidez , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Processamento de Proteína Pós-Traducional , Subunidades Proteicas , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Zinco/metabolismo
9.
J Nutr Biochem ; 21(11): 1069-75, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20092996

RESUMO

Transcription factors AP-1, nuclear factor κB (NF-κB) and NFAT are central to brain development by regulating the expression of genes that modulate cell proliferation, differentiation, apoptosis and synaptic plasticity. This work investigated the consequences of feeding zinc-deficient and marginal zinc diets to rat dams during gestation on the modulation of AP-1, NF-κB and NFAT in fetal brain. Sprague-Dawley rats were fed from gestation day (GD) 0 a control diet ad libitum (25 µg zinc/g diet, C), a zinc-deficient diet ad libitum (0.5 µg zinc/g diet, ZD), the control diet in the amounts eaten by the ZD rats (restrict fed, RF) or a diet containing a marginal zinc concentration ad libitum (10 µg zinc/g diet, MZD) until GD 19. AP-1-DNA binding was higher (50-190%) in nuclear fraction isolated from ZD, RF and MZD fetal brains compared to controls. In MZD fetal brain, high levels of activation of the upstream mitogen-activated protein kinases JNK and p38 and low levels of ERK phosphorylation were observed. Total levels of NF-κB and NFAT activation were higher or similar in the ZD and MZD groups than in controls, respectively. However, NF-κB- and NFAT-DNA binding in nuclear fractions was markedly lower in ZD and MZD fetal brain than in controls (50-80%). The latter could be related to zinc deficiency-associated alterations of the cytoskeleton, which is required for NF-κB and NFAT nuclear transport. In summary, suboptimal zinc nutrition during gestation could cause long-term effects on brain function, partially through a deregulation of transcription factors AP-1, NF-κB and NFAT.


Assuntos
Encéfalo/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , NF-kappa B/metabolismo , Fator de Transcrição AP-1/metabolismo , Zinco/deficiência , Zinco/metabolismo , Animais , Western Blotting , Encéfalo/embriologia , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Feto/embriologia , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Gravidez , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Fator de Transcrição AP-1/genética
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