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1.
Am J Physiol Cell Physiol ; 327(1): C74-C96, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38738303

RESUMO

Activation of incretin receptors by their cognate agonist augments sustained cAMP generation both from the plasma membrane as well as from the endosome. To address the functional outcome of this spatiotemporal signaling, we developed a nonacylated glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist I-M-150847 that reduced receptor internalization following activation of the incretin receptors. The incretin receptor dual agonist I-M-150847 was developed by replacing the tryptophan cage of exendin-4 tyrosine substituted at the amino terminus with the C-terminal undecapeptide sequence of oxyntomodulin that placed lysine 30 of I-M-150847 in frame with the corresponding lysine residue of GIP. The peptide I-M-150847 is a partial agonist of GLP-1R and GIPR; however, the receptors, upon activation by I-M-150847, undergo reduced internalization that promotes agonist-mediated iterative cAMP signaling and augments glucose-stimulated insulin exocytosis in pancreatic ß cells. Chronic administration of I-M-150847 improved glycemic control, enhanced insulin sensitivity, and provided profound weight loss in diet-induced obese (DIO) mice. Our results demonstrated that despite being a partial agonist, I-M-150847, by reducing the receptor internalization upon activation, enhanced the incretin effect and reversed obesity.NEW & NOTEWORTHY Replacement of the tryptophan cage (Trp-cage) with the C-terminal oxyntomodulin undecapeptide along with the tyrosine substitution at the amino terminus converts the selective glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 to a novel GLP-1R and GIPR dual agonist I-M-150847. Reduced internalization of incretin receptors upon activation by the GLP-1R and GIPR dual agonist I-M-150847 promotes iterative receptor signaling that enhances the incretin effect and reverses obesity.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1 , Incretinas , Camundongos Endogâmicos C57BL , Obesidade , Animais , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos , Masculino , Incretinas/farmacologia , Incretinas/metabolismo , Transporte Proteico/efeitos dos fármacos , Controle Glicêmico/métodos , Camundongos Obesos , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Humanos , Dieta Hiperlipídica/efeitos adversos , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Insulina/metabolismo , Exenatida/farmacologia , Transdução de Sinais/efeitos dos fármacos , AMP Cíclico/metabolismo
2.
Int J Mol Sci ; 24(4)2023 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-36835180

RESUMO

Daily exposure to bisphenols can affect reproductive functions due to their pseudo-estrogenic and/or anti-androgenic effects. Testicular lipids contain high levels of polyunsaturated fatty acids necessary for sperm maturity, motility, and spermatogenesis. Whether prenatal exposure to bisphenols alters testicular fatty acid metabolism in adult offspring is unknown. Pregnant Wistar rats were gavaged from gestational day 4 to 21 with BPA and BPS (0.0, 0.4, 4.0, 40.0 µg/kg bw/day). Despite increased body and testis weight, the total testicular cholesterol, triglyceride, and plasma fatty acids were unaffected in the offspring. Lipogenesis was upregulated by increased SCD-1, SCD-2, and expression of lipid storage (ADRP) and trafficking protein (FABP4). The arachidonic acid, 20:4 n-6 (ARA) and docosapentaenoic acid, 22:5 n-6 (DPA) levels were decreased in the BPA-exposed testis, while BPS exposure had no effects. The expression of PPARα, PPARγ proteins, and CATSPER2 mRNA were decreased, which are important for energy dissipation and the motility of the sperm in the testis. The endogenous conversion of linoleic acid,18:2 n-6 (LA), to ARA was impaired by a reduced ARA/LA ratio and decreased FADS1 expression in BPA-exposed testis. Collectively, fetal BPA exposure affected endogenous long-chain fatty acid metabolism and steroidogenesis in the adult testis, which might dysregulate sperm maturation and quality.


Assuntos
Compostos Benzidrílicos , Disruptores Endócrinos , Ácidos Graxos , Efeitos Tardios da Exposição Pré-Natal , Maturação do Esperma , Testículo , Animais , Feminino , Humanos , Masculino , Gravidez , Ratos , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/farmacologia , Canais de Cálcio/metabolismo , Disruptores Endócrinos/farmacologia , Ácidos Graxos/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Proteínas/metabolismo , Ratos Wistar , Sêmen/metabolismo , Proteínas de Plasma Seminal/metabolismo , Testículo/metabolismo
3.
Eur J Nutr ; 57(6): 2171-2187, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28676973

RESUMO

PURPOSE: Consumption of Western diet high in fat and fructose has been attributed to the recent epidemic of nonalcoholic fatty liver disease (NAFLD). However, the impact of specific fatty acids on the progression of NAFLD to nonalcoholic steatohepatitis (NASH) is poorly understood. In the present study, we investigated the chronic effects of consumption of fructose in combination with saturated fatty acids (SFA) or trans fatty acids (TFA) on the development of NAFLD. METHODS: Male Sprague-Dawley rats were randomly assigned to six isocaloric starch/high fructose (44% of calories), high fat (39% calories) diet containing either starch-peanut oil, fructose-peanut oil, fructose-palmolein, fructose-clarified butter, fructose-coconut oil or fructose-partially hydrogenated vegetable oil and fed for 24 weeks. Palmolein, clarified butter and coconut oil were used as the source of SFA whereas partially hydrogenated vegetable oil was used as the source of TFA. Peanut oil was used as the reference oil. RESULTS: Long-term feeding of fructose in combination with SFA or TFA induced hepatic steatosis of similar extent associated with upregulation of stearoyl CoA desaturase-1. In contrast, fructose in combination with TFA induced NASH with fibrosis as evidenced by upregulation of hepatic proinflammatory cytokine and fibrogenic gene expression, increased hepatic oxidative stress and adipocytokine imbalance. Histopathological analysis revealed the presence of NASH with fibrosis. Further, peanut oil prevented the development of NAFLD in fructose-fed rats. CONCLUSION: Fructose in combination with TFA caused NASH with fibrosis by inducing oxidative stress and inflammation, whereas, fructose in combination with SFA caused simple steatosis, suggesting that the type of fatty acid is more important for the progression of NAFLD.


Assuntos
Frutose/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/etiologia , Ácidos Graxos trans/efeitos adversos , Animais , Ácidos Graxos/administração & dosagem , Frutose/administração & dosagem , Índia , Fígado , Masculino , Ratos , Ratos Sprague-Dawley , Ácidos Graxos trans/administração & dosagem
4.
Artigo em Inglês | MEDLINE | ID: mdl-36924605

RESUMO

Maternal n-3 PUFA (omega-3) deficiency can affect brain development in utero and postnatally. Despite the evidence, the impacts of n-3 PUFA deficiency on the expression of neurogenesis genes in the postnatal hippocampus remained elusive. Since postnatal brain development requires PUFAs via breast milk, we examined the fatty acid composition of breast milk and hippocampal expression of neurogenesis genes in n-3 PUFA deficient 21d mice. In addition, the expression of fatty acid desaturases, elongases, free fatty acids signaling receptors, insulin and leptin, and glucose transporters were measured. Among the genes involved in neurogenesis, the expression of brain-specific tenascin-R (TNR) was downregulated to a greater extent (∼31 fold), followed by adenosine A2A receptor (A2AAR), dopamine receptor D2 (DRD2), glial cell line-derived neurotrophic factor (GDNF) expression in the n-3 PUFA deficient hippocampus. Increasing dietary LA to ALA (50:1) elevated the ARA to DHA ratio by ∼8 fold in the n-3 PUFA deficient breast milk, with an overall increase of total n-6/n-3 PUFAs by ∼15:1 (p<0.05) compared to n-3 PUFA sufficient (LA to ALA: 2:1) diet. The n-3 PUFA deficient mice exhibited upregulation of FADS1, FADS2, ELOVL2, ELOVL5, ELOVL6, GPR40, GPR120, LEPR, IGF1 and downregulation of GLUT1, GLUT3, and GLUT4 mRNA expression in hippocampus (p<0.05). Maternal n-3 PUFA deficiency affects the hippocampal expression of key neurogenesis genes in the offspring with concomitant expression of desaturase and elongase genes, suggesting the importance of dietary n-3 PUFA for neurodevelopment.


Assuntos
Ácidos Graxos Ômega-3 , Gravidez , Feminino , Animais , Camundongos , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Insaturados/metabolismo , Lactação , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Neurogênese , Hipocampo/metabolismo
5.
Sci Total Environ ; 904: 166775, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37660821

RESUMO

Prenatal exposure to endocrine-disrupting bisphenol A (BPA) shows a long-lasting programming effect on an organ's metabolic function and predisposes it to the risk of adult metabolic diseases. Although a reduced contaminant risk due to "BPA-free" exposure is proposed, limited data on a comparative assessment of gestational exposure to BPS and BPA and their effects on metaflammation in predisposing liver metabolic disease is reported. Pregnant Wistar rats were exposed to BPS and BPA (0.0, 0.4, 4.0 µg/kg bw) via gavage from gestational day 4 to 21, and effects were assessed in the 90 d male offspring. Prenatal BPS-exposed offspring showed a more obesogenic effect than BPA, including changes in body fat distribution, feed efficiency, and leptin signalling. The BPS exposure induced the adipocyte hypertrophy of visceral adipose to a greater extent than BPA. The adipose hypertrophy was augmented by tissue inflammation, endoplasmic reticulum (ER) stress, and apoptosis due to increased expression of pro-inflammatory (IL6, IL1ß, CRP, COX2) cytokines, ER stress modulator (CHOP), and apoptotic effector (Caspase 3). The enlarged, stressed, inflamed adipocytes triggered de novo lipogenesis in the bisphenol-exposed offspring liver due to increased expression of cholesterol and lipid biogenesis mediators (srebf1, fasn, acaca, PPARα) concomitant with elevated triacylglycerol (TG) and cholesterol (TC), resulted in impaired hepatic clearance of lipids. The lipogenic effects were also promoted by increased expression of HSD11ß1. BPS exposure increased absolute liver weight, discoloration, altered liver lobes more than in BPA. Liver histology showed numerous lipid droplets, and hepatocyte ballooning, upregulated ADRP expression, an increased expression of pro-inflammatory mediators (IL6, CRP, IL1ß, TNFα, COX2), enhanced lipid peroxidation in the BPS-exposed offspring's liver suggest altered metaflammation leads to microvesicular steatosis. Overall, gestational BPS exposure demonstrated a higher disruption in metabolic changes than BPA, involving excess adiposity, liver fat, inflammation, and predisposition to steatosis in the adult male offspring.


Assuntos
Fígado Gorduroso , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Feminino , Ratos , Masculino , Animais , Humanos , Ratos Wistar , Ciclo-Oxigenase 2 , Interleucina-6 , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Inflamação/induzido quimicamente , Colesterol , Hipertrofia , Compostos Benzidrílicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
6.
J Nutr Biochem ; 112: 109218, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36375730

RESUMO

Maternal omega-3 (n-3) polyunsaturated fatty acids (PUFAs) deficiency can affect offspring's adiposity and metabolism by modulating lipid and glucose metabolism. However, the impact of n-3 PUFA deficiency on the development of fetal thermogenesis and its consequences is not reported. Using an n-3 PUFA deficient mice, we assessed fetal interscapular brown adipose tissue (iBAT), body fat composition, insulin growth factor-1 (IGF-1), glucose transporters (GLUTs), and expression of lipid storage & metabolic proteins in the offspring. The n-3 PUFA deficiency did not change the pups' calorie intake, organ weight, and body weight. However, the offspring's skeletal growth was altered due to excess fat to lean mass, reduced tibia & femur elongation, dysregulated IGF-1 in the mother and pups (P< .05). Localization of uncoupling protein 1 (UCP1) in iBAT exhibited a reduced expression in the deficient fetus. Further, UCP1, GLUT1, GPR120 were downregulated while FABP3, ADRP, GLUT4 expressions were upregulated in the BAT of the deficient offspring (P< .05). The deficiency decreased endogenous conversion of the n-3 LCPUFAs from their precursors and upregulated SCD1, FASN, and MFSD2A mRNAs in the liver (P< .05). An altered musculoskeletal growth in the offspring is associated with impaired browning of the fetal adipose, dysregulated thermogenesis, growth hormone, and expression of glucose and fatty acid metabolic mediators due to maternal n-3 PUFA deficiency. BAT had higher metabolic sensitivity compared to WAT in n-3 PUFA deficiency. Maternal n-3 PUFA intake may prevent excess adiposity by modulating fetal development of thermogenesis and skeletal growth dynamics in the mice offspring.


Assuntos
Ácidos Graxos Ômega-3 , Camundongos , Animais , Ácidos Graxos Ômega-3/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Tecido Adiposo Marrom/metabolismo , Desenvolvimento Fetal , Obesidade/metabolismo , Termogênese , Glucose/metabolismo , Camundongos Endogâmicos C57BL
7.
Br J Nutr ; 108(9): 1612-22, 2012 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-22243775

RESUMO

Increasing prevalence of inflammatory bowel disease may be due to imbalance in the intake of n-6 and n-3 PUFA in the diet. This study investigates the impact of varying ratios of dietary linoleic acid (LA, 18 : 2n-6) to α-linolenic acid (ALA, 18 : 3n-3) on the inflammatory response in dextran sulphate sodium (DSS)-induced colitis. Weanling male Sprague-Dawley rats were divided into five groups: a non-colitic group with a LA:ALA ratio of 215 (CON-215), and colitic groups with LA:ALA ratios of 215 (DSS-215), 50 (DSS-50), 10 (DSS-10) and 2 (DSS-2). Blends of groundnut, palmolein and linseed oils were used to provide varying LA:ALA ratios. All the rats were fed the respective experimental isoenergetic diets containing 10 % fat for 90 d and DSS was administered during the last 11 d. Colonic inflammation was evaluated by clinical, biochemical and histological parameters. The results showed attenuation of colitis in the DSS-2 group as evidenced by significant reductions in disease activity index, mucosal myeloperoxidase activity (P < 0·05), alkaline phosphatase activity (P < 0·01) and increase in colon length (P < 0·01) compared to the groups fed with higher ratios (DSS-215). This was accompanied by significant reductions in mucosal proinflammatory cytokines TNF-α (P < 0·01) and IL-1ß (P < 0·01) and improvement in the histological score. Further, ALA supplementation increased long-chain (LC) n-3 PUFA and decreased LC n-6 PUFA in colon structural lipids. These data suggest that substitution of one-third of LA with ALA (LA:ALA ratio 2) mitigates experimental colitis by down-regulating proinflammatory mediators.


Assuntos
Colite/prevenção & controle , Colo/imunologia , Suplementos Nutricionais , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/prevenção & controle , Mucosa Intestinal/imunologia , Ácido alfa-Linolênico/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/metabolismo , Colite/imunologia , Colite/patologia , Colite/fisiopatologia , Colo/crescimento & desenvolvimento , Colo/metabolismo , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/fisiopatologia , Mucosa Intestinal/crescimento & desenvolvimento , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Ácido Linoleico/administração & dosagem , Masculino , Infiltração de Neutrófilos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Desmame , Ácido alfa-Linolênico/administração & dosagem
8.
Artigo em Inglês | MEDLINE | ID: mdl-35413515

RESUMO

In celebration of the centenary of the National Institute of Nutrition (NIN), Hyderabad, India (1918-2018), a symposium highlighted the progress in nutrition knowledge made over the century, as well as major gaps in implementation of that knowledge. Brain famine caused by a shortage of nutrients required for perinatal brain development has unfortunately become a global reality, even as protein-calorie famine was largely averted by the development of high yield crops. While malnutrition remains widespread, the neglect of global food policies that support brain development and maintenance are most alarming. Brain disorders now top the list of the global burden of disease, even with obesity rising throughout the world. Neurocognitive health, remarkably, is seldom listed among the non-communicable diseases (NCDs) and is therefore seldom considered as a component of food policy. Most notably, the health of mothers before conception and through pregnancy as mediated by proper nutrition has been neglected by the current focus on early death in non-neurocognitive NCDs, thereby compromising intellectual development of the ensuing generations. Foods with balanced essential fatty acids and ample absorbable micronutrients are plentiful for populations with access to shore-based foods, but deficient only a few kilometres away from the sea. Sustained access to brain supportive foods is a priority for India and throughout the world to enable each child to develop to their intellectual potential, and support a prosperous, just, and peaceful world. Nutrition education and food policy should place the nutritional requirements for the brain on top of the list of priorities.


Assuntos
Aniversários e Eventos Especiais , Desnutrição , Criança , Feminino , Humanos , Política Nutricional , Estado Nutricional , Gravidez , Estudos Retrospectivos
9.
J Nutr Biochem ; 96: 108784, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34062269

RESUMO

The maternal n-3 polyunsaturated fatty acid (PUFA) deficiency on decidual vascular structure and angiogenesis in mice placenta was investigated. Namely, we studied uterine artery remodeling, fatty acid metabolism, and placental epigenetic methylation in this animal model. Weanling female Swiss albino mice were fed either alpha-linolenic acid (18:3 n-3, ALA) deficient diets (0.13% energy from ALA) or a sufficient diet (2.26% energy from ALA) throughout the study. The dietary n-3 PUFA deficiency altered uteroplacental morphology and vasculature by reversing luminal to vessel area and increased luminal wall thickness at 8.5-12.5gD. Further, placentas (F0 and F1) showed a significant decrease in the expression of VCAM1, HLAG proteins and an increase in MMP9, KDR expression. The conversion of ALA to long-chain (LC) n-3 PUFAs was significantly decreased in plasma and placenta during the n-3 deficiency state. Reduced n-3 LCPUFAs increased the placental expression of intracellular proteins FABP3, FABP4, and ADRP to compensate decreased availability of these fatty acids in the n-3 deficient mice. The N-3 PUFA deficiency significantly increased the 5-methylcytosine levels in the placenta but not in the liver. The alteration in DNA methylation continued to the next generation in the placental epigenome with augmented expression of DNMT3A and DNMT3B. Our study showed that maternal n-3 PUFA deficiency alters placental vascular architecture and induces epigenetic changes suggesting the importance of n-3 PUFA intake during the development of the fetus. Moreover, the study shows that the placenta is the susceptible target for epigenetic alteration in maternal deficiency n-3 fatty acids.


Assuntos
Epigenoma , Ácidos Graxos Ômega-3/metabolismo , Placenta/irrigação sanguínea , Artéria Uterina/ultraestrutura , Animais , Metilação de DNA , Dieta , Feminino , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Placenta/fisiologia , Gravidez , Artéria Uterina/fisiologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-32169807

RESUMO

In the present study, we investigated the impact of substituting alpha-linolenic acid (ALA) or long-chain n-3 PUFA (eicosapentaenoic acid and docosahexaenoic acid) for linoleic acid and hence decreasing n-6:n-3 PUFA ratio on high-fructose diet-induced hypertriglyceridemia and associated hepatic changes. Weanling male Wistar rats were divided into four groups and fed with starch-diet (n-6:n-3 PUFA ratio 215:1) and high-fructose diets with different n-6:n-3 PUFA ratio (215:1, 2:1 with ALA and 5:1 with long-chain n-3 PUFA) for twenty-four weeks. Substitution of linoleic acid with ALA (n-6:n-3 PUFA ratio of 2) or long-chain n-3 PUFA (n-6:n-3 PUFA ratio of 5) protected the rats from fructose-induced dyslipidemia, hepatic oxidative stress and corrected lipogenic and proinflammatory gene expression. Both ALA and long-chain n-3 PUFA supplementation also reversed the fructose-induced upregulation of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) gene, which is involved in the generation of active glucocorticoids in tissues. Although both ALA and LC n-3 PUFA prevented fructose-induced dyslipidemia to a similar extent, compared to ALA, LC n-3 PUFA is more effective in preventing hepatic oxidative stress and inflammation.


Assuntos
Dieta/métodos , Dislipidemias/induzido quimicamente , Dislipidemias/dietoterapia , Frutose/efeitos adversos , Ácido Linoleico/administração & dosagem , Fígado/metabolismo , Ácido alfa-Linolênico/administração & dosagem , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Inflamação/prevenção & controle , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
11.
Elife ; 92020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33349332

RESUMO

Given its glycemic efficacy and ability to reduce the body weight, glucagon-like peptide 1 receptor (GLP-1R) agonism has emerged as a preferred treatment for diabetes associated with obesity. We here report that a small-molecule Class 1 histone deacetylase (HDAC) inhibitor Entinostat (MS-275) enhances GLP-1R agonism to potentiate glucose-stimulated insulin secretion and decrease body weight in diet-induced obese (DIO) mice. MS-275 is not an agonist or allosteric activator of GLP-1R but enhances the sustained receptor-mediated signaling through the modulation of the expression of proteins involved in the signaling pathway. MS-275 and liraglutide combined therapy improved fasting glycemia upon short-term treatment and a chronic administration causes a reduction of obesity in DIO mice. Overall, our results emphasize the therapeutic potential of MS-275 as an adjunct to GLP-1R therapy in the treatment of diabetes and obesity.


Assuntos
Benzamidas/farmacologia , Glicemia/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Controle Glicêmico/métodos , Inibidores de Histona Desacetilases/farmacologia , Obesidade , Piridinas/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
12.
Br J Nutr ; 102(2): 233-41, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19166630

RESUMO

In recent years the intake of n-6 PUFA and trans-fatty acids (TFA) has increased, whereas n-3 PUFA intake has decreased. The present study investigated the effects of maternal diet high in n-6 PUFA, n-3 PUFA or TFA on glucose metabolism, insulin sensitivity and fatty acid profile in male offspring. Female weanling Wistar/NIN rats were randomly assigned to receive either a diet high in linoleic acid (LA), or alpha-linolenic acid (ALA), or long-chain n-3 PUFA (fish oil; FO), or TFA, for 90 d, and mated. Upon weaning, pups were randomly divided into seven groups (mother's diet-pup's diet): LA-LA, LA-ALA, LA-FO, ALA-ALA, FO-FO, TFA-TFA and TFA-LA. At the age of 105 d, an oral glucose tolerance test, adipocyte glucose transport and muscle phospholipid fatty acid composition were measured in the pups. All animals displayed normal insulin sensitivity as evidenced by similar plasma insulin and area under the curve of insulin after an oral glucose load. Maternal intake of n-3 PUFA (ALA or FO) resulted in higher n-3 PUFA in the offspring. Plasma cholesterol and NEFA were significantly higher in the TFA-TFA group compared with the other groups. Adipocyte insulin-stimulated glucose transport and adiponectin mRNA expression were lower in TFA-TFA and TFA-LA offspring compared with the other groups. While most mother-pup fatty acid combinations did not influence the measured variables in the pups, these results indicate that maternal intake of TFA led to an unfavourable profile in the pups through to the age of 105 d, whether the pups consumed TFA, or not.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Glicemia/metabolismo , Metabolismo dos Lipídeos , Fenômenos Fisiológicos da Nutrição Materna , Ácidos Graxos trans/administração & dosagem , Adipócitos/metabolismo , Adiponectina/sangue , Adiponectina/genética , Animais , Transporte Biológico , Colesterol/sangue , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Expressão Gênica , Glucose/metabolismo , Teste de Tolerância a Glucose , Insulina/sangue , Insulina/farmacologia , Ácido Linoleico/administração & dosagem , Masculino , Fosfolipídeos/metabolismo , Gravidez , RNA Mensageiro/análise , Distribuição Aleatória , Ratos , Ratos Wistar , Ácido alfa-Linolênico/administração & dosagem
13.
Sci Rep ; 8(1): 10953, 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30026586

RESUMO

Imbalance in the n-6 polyunsaturated fatty acids (PUFA) and n-3 PUFA in the Western diet may increase the risk of nonalcoholic fatty liver disease (NAFLD). This study investigates the impact of substitution of linoleic acid with α-linolenic acid (ALA) or long chain (LC) n-3 PUFA and hence decreasing n-6:n-3 fatty acid ratio on high fat, high fructose (HFHF) diet induced nonalcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were divided into four groups and fed control diet, HFHF diet (n-6:n-3 ratio of 200), HFHF diet with ALA (n-6:n-3 ratio of 2) or HFHF diet with LC n-3 PUFA (n-6:n-3 ratio of 5) for 24 weeks. Rats fed HFHF diet with n-6:n-3 ratio of 200 resulted in hepatic steatosis, induced glucose intolerance, insulin resistance and oxidative stress accompanied by increase in markers of inflammation, plasma lipids and aminotransferase levels. Histopathological examination of liver further confirmed the establishment of NASH. ALA and LC n-3 PUFA supplementation prevented hepatic steatosis and dyslipidemia by inhibiting lipogenesis and increasing insulin sensitivity. Furthermore, n-3 PUFA supplementation attenuated hepatic oxidative stress by restoring antioxidant status, decreased inflammation and preserved hepatic architecture. These finding suggest that decreasing n-6:n-3 ratio prevented HFHF induced NASH by attenuating oxidative stress and inflammation.


Assuntos
Dieta Ocidental/efeitos adversos , Ácidos Graxos Ômega-3/administração & dosagem , Intolerância à Glucose/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Ácido alfa-Linolênico/administração & dosagem , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ácidos Graxos Ômega-3/farmacologia , Intolerância à Glucose/induzido quimicamente , Humanos , Resistência à Insulina , Lipídeos/sangue , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Transaminases/sangue , Ácido alfa-Linolênico/farmacologia
14.
Biochim Biophys Acta ; 1733(1): 67-75, 2005 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-15801047

RESUMO

This study describes the effect of substituting dietary linoleic acid (18:2 n-6) with alpha-linolenic acid (18:3 n-3) on sucrose-induced insulin resistance (IR). Wistar NIN male weanling rats were fed casein based diet containing 22 energy percent (en%) fat with approximately 6, 9 and 7 en% saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) respectively for 3 months. IR was induced by replacing starch (ST) with sucrose (SU). Blends of groundnut, palmolein, and linseed oil in different proportions furnished the following levels of 18:3 n-3 (g/100 g diet) and 18:2 n-6/18:3 n-3 ratios respectively: ST-220 (0.014, 220), SU-220 (0.014, 220), SU-50 (0.06, 50), SU-10 (0.27, 10) and SU-2 (1.1, 2). The results showed IR in the sucrose fed group (SU-220) as evidenced by increase in fasting plasma insulin and area under the curve (AUC) of insulin in response to oral glucose load. In SU-220, the increase in adipocyte plasma membrane cholesterol/phospholipid ratio was associated with a decrease in fluidity, insulin stimulated glucose transport, antilipolytic effect of insulin and increase in basal and norepinephrine stimulated lipolysis in adipocytes. In SU-50, sucrose induced alterations in adipocyte lipolysis and antilipolysis were normalized. However, in SU-2, partial corrections in plasma insulin, AUC of insulin and adipocyte insulin stimulated glucose transport were observed. Further, plasma triglycerides and cholesterol decreased in SU-2. In diaphragm phospholipids, the observed dose dependent increase in long chain (LC) n-3 PUFA was associated with a decrease in LC-n-6 PUFA but insulin stimulated glucose transport increased only in SU-2. Thus, this study shows that the substitution of one-third of dietary 18:2 n-6 with 18:3 n-3 (SU-2) results in lowered blood lipid levels and increases peripheral insulin sensitivity, possibly due to the resulting high LCn-3 PUFA levels in target tissues of insulin action. These findings suggest a role for 18:3 n-3 in the prevention of insulin resistant states. The current recommendation to increase 18:3 n-3 intake for reducing cardiovascular risk may also be beneficial for preventing IR in humans.


Assuntos
Gorduras na Dieta/metabolismo , Resistência à Insulina/fisiologia , Ácido alfa-Linolênico/administração & dosagem , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Transporte Biológico Ativo/fisiologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/fisiologia , Diafragma/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Insulina/farmacologia , Ácido Linoleico/administração & dosagem , Lipólise/efeitos dos fármacos , Lipólise/fisiologia , Masculino , Norepinefrina/farmacologia , Ratos , Ratos Wistar , Sacarose/metabolismo , Ácido alfa-Linolênico/metabolismo , Ácido alfa-Linolênico/farmacologia
15.
J Nutr Metab ; 2016: 7510840, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27818793

RESUMO

Background. Increased fructose consumption is linked to the development of metabolic syndrome (MS). Here we investigated the time course of development of MS features in high-fructose-fed Sprague Dawley rats along with circulatory testosterone and homocysteine levels. Methods. Rats were divided into control and experimental groups and fed with diets containing 54.5% starch and fructose, respectively, for 4, 12, and 24 weeks. Plasma testosterone and homocysteine levels were measured along with insulin, glucose, and lipids. Body composition, insulin resistance, and hepatic lipids were measured. Results. Increase in hepatic triglyceride content was first observed in metabolic disturbance followed by hypertriglyceridemia and systemic insulin resistance in fructose-fed rats. Hepatic lipids were increased in time-dependent manner by fructose-feeding starting from 4 weeks, but circulatory triglyceride levels were increased after 12 weeks. Fasting insulin and Homeostatis Model Assessment of Insulin Resistance (HOMA-IR) were increased after 12 weeks of fructose-feeding. Decreased visceral adiposity, circulatory testosterone, and homocysteine levels were observed after 4 weeks of fructose-feeding, which were normalized at 12 and 24 weeks. Conclusions. We conclude that transient decrease in circulatory testosterone and homocysteine levels and increased hepatic triglyceride content are the earliest metabolic disturbances that preceded hypertriglyceridemia and insulin resistance in fructose-fed SD rats.

16.
Metabolism ; 54(2): 240-6, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15789505

RESUMO

The present study was designed to investigate the effects of dietary trans-fatty acids (TFA) present in Indian vanaspati (partially hydrogenated vegetable oils) in comparison with saturated fatty acids (SFA) on adipocyte plasma membrane fatty acid composition, fluidity, and insulin action. The effects of 3% energy (% en) TFA was studied at 2% and 4% en of linoleic acid (18:2 n-6). WNIN male weanling rats were divided into 4 groups and fed casein-based diet containing 10% groundnut oil control (CON), palmolein (SFA), blend of vanaspati and safflower oil (3% en TFA and 2% en 18:2 n-6, TFA-1), or blend of vanaspati and safflower oil (3% en TFA and 4% en 18:2 n-6, TFA-2) for 12 weeks. Compared with CON, rats fed TFA and SFA diets had high levels of fasting plasma insulin and triglycerides. Both TFA- and SFA-fed groups had low levels of arachidonic acid (20:4 n-6) in adipocyte plasma membrane phospholipids. However, adipocyte plasma membrane fluidity decreased only in TFA-fed rats. Norepinephrine-stimulated lipolysis was high, whereas the antilipolytic effect of insulin and insulin-stimulated glucose transport were low in the adipocytes of SFA- and TFA-fed rats. However, the extent of decrease in the antilipolytic effect of insulin and insulin-stimulated glucose transport was greater in TFA-fed rats. These findings suggest that diet providing approximately 10% en SFA (PUFA/SFA [P/S] ratio 0.2) decreased adipocyte insulin sensitivity in rats. In these diets, replacement of approximately 2% en SFA (16:0) and approximately 1% en monounsaturated fatty acid (18:1 cis) with TFA decreased adipocyte insulin sensitivity to a greater extent. However, increasing dietary 18:2 n-6 did not prevent or reduce the TFA-induced adipocyte insulin resistance.


Assuntos
Adipócitos/metabolismo , Gorduras na Dieta/farmacologia , Resistência à Insulina/fisiologia , Óleos de Plantas/farmacologia , Ácidos Graxos trans/farmacologia , Adipócitos/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Glicemia/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Separação Celular , Dieta , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Lipólise/efeitos dos fármacos , Masculino , Fluidez de Membrana/efeitos dos fármacos , Norepinefrina/farmacologia , Fosfolipídeos/metabolismo , Óleos de Plantas/química , Ratos
17.
Artigo em Inglês | MEDLINE | ID: mdl-25451558

RESUMO

Imbalances in the dietary n-6 and n-3 polyunsaturated fatty acids have been implicated in the increased prevalence of inflammatory bowel disease. This study investigated the effects of substitution of linoleic acid with long chain n-3 polyunsaturated fatty acids and hence decreasing n-6:n-3 fatty acid ratio on inflammatory response in dextran sulfate sodium induced colitis. Male weanling Sprague Dawley rats were fed diets with n-6:n-3 fatty acid in the ratios of 215,50,10 or 5 for 3 months and colitis was induced by administration of dextran sulfate sodium in drinking water during last 11 days. Decreasing the dietary n-6:n-3 fatty acid ratio to 10 and 5 significantly attenuated the severity of colitis as evidenced by improvements in clinical symptoms, reversal of shortening of colon length, reduced severity of anemia, preservation of colonic architecture as well as reduced colonic mucosal myeloperoxidase activity. This protection was associated with suppression of colonic mucosal proinflammatory mediators such as TNFα, IL-1ß and nitric oxide. These findings suggest that long chain n-3 polyunsaturated fatty acids at a level of 3.0 g/kg diet (n-6:n-3 ratio of 10) prevents dextran sulfate sodium induced colitis by suppressing the proinflammatory mediators.


Assuntos
Colite/induzido quimicamente , Colite/prevenção & controle , Sulfato de Dextrana , Gorduras na Dieta/administração & dosagem , Ácidos Graxos Ômega-3/administração & dosagem , Ácido Linoleico/administração & dosagem , Animais , Colite/patologia , Colo/química , Colo/patologia , Modelos Animais de Doenças , Interleucina-1beta/análise , Mucosa Intestinal/química , Mucosa Intestinal/enzimologia , Masculino , Óxido Nítrico/análise , Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/análise
18.
Diabetes Technol Ther ; 13(6): 683-94, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21488798

RESUMO

India is undergoing rapid nutritional transition, resulting in excess consumption of calories, saturated fats, trans fatty acids, simple sugars, salt and low intake of fiber. Such dietary transition and a sedentary lifestyle have led to an increase in obesity and diet-related non-communicable diseases (type 2 diabetes mellitus [T2DM], cardiovascular disease [CVD], etc.) predominantly in urban, but also in rural areas. In comparison with the previous guidelines, these consensus dietary guidelines include reduction in the intake of carbohydrates, preferential intake of complex carbohydrates and low glycemic index foods, higher intake of fiber, lower intake of saturated fats, optimal ratio of essential fatty acids, reduction in trans fatty acids, slightly higher protein intake, lower intake of salt, and restricted intake of sugar. While these guidelines are applicable to Asian Indians in any geographical setting, they are particularly applicable to those residing in urban and in semi-urban areas. Proper application of these guidelines will help curb the rising "epidemics" of obesity, the metabolic syndrome, hypertension, T2DM, and CVD in Asian Indians.


Assuntos
Diabetes Mellitus/prevenção & controle , Dieta/etnologia , Síndrome Metabólica/prevenção & controle , Política Nutricional , Necessidades Nutricionais/etnologia , Obesidade/prevenção & controle , Adolescente , Adulto , Idoso , Conferências de Consenso como Assunto , Feminino , Promoção da Saúde/tendências , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Caracteres Sexuais , Adulto Jovem
19.
Br J Nutr ; 93(6): 829-33, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16079026

RESUMO

The present study evaluates the effect of dietary trans fatty acids on diaphragm phospholipid fatty acid composition, intramyocellular triacylglycerol content and insulin-stimulated glucose uptake in comparison with dietary saturated fatty acids. Male weanling WNIN rats were divided into three groups and fed for 3 months on one of the following diets containing 10 % oil differing in fatty acid composition: control diet, saturated fatty acid diet and trans fatty acid diet. Dietary trans fatty acids increased the intramyocellular triacylglycerols and decreased the ratio of 20 : 4n-6 to 18 : 2n-6 and long-chain PUFA levels (20 %) in diaphragm phospholipids, indicating inhibition of PUFA biosynthesis. However, saturated fatty acids decreased both 18 : 2n-6 and 20 : 4n-6 without change in the ratio. Trans fatty acid-induced alterations in diaphragm phospholipid fatty acid composition and intramyocellular triacylglycerol content were associated with decreased insulin-stimulated glucose transport in the diaphragm. These observations suggest that dietary trans fatty acids decrease diaphragm insulin sensitivity, possibly due to increased intramyocellular triacylglycerol accumulation and decreased long-chain PUFA in phospholipids.


Assuntos
Diafragma/metabolismo , Gorduras na Dieta/farmacologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , Fosfolipídeos/metabolismo , Ácidos Graxos trans/farmacologia , Triglicerídeos/metabolismo , Animais , Dieta , Gorduras na Dieta/administração & dosagem , Ácidos Graxos Insaturados/metabolismo , Masculino , Ratos , Ácidos Graxos trans/administração & dosagem
20.
J Nutr ; 135(11): 2634-8, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16253960

RESUMO

This study was designed to determine the effect of substituting (n-3) long-chain PUFAs (LCPUFAs) for linoleic acid and hence decreasing the (n-6):(n-3) fatty acid ratio on sucrose-induced insulin resistance in rats. Weanling male Wistar rats were fed casein-based diets containing 100 g/kg fat for 12 wk. Insulin resistance was induced by replacing starch (ST) with sucrose (SU). The dietary fats were formulated with groundnut oil, palmolein, and fish oil to provide the following ratios of (n-6):(n-3) fatty acids: 210 (ST-210, SU-210), 50 (SU-50), 10 (SU-10), and 5 (SU-5). Compared with starch (ST-210), sucrose feeding (SU-210) significantly increased the plasma insulin and triglyceride concentrations and the plasma insulin area under the curve (AUC) in response to an oral glucose load. Adipocytes isolated from rats fed SU-210 had greater lipolytic rate, lower insulin stimulated glucose transport, and lower insulin-mediated antilipolysis than those from rats fed ST-210. Decreasing the dietary (n-6):(n-3) ratio in sucrose-fed rats (SU-10 and SU-5) normalized the plasma insulin concentration and the AUC of insulin after a glucose load. The sucrose-induced increase in plasma triglyceride concentration was normalized in rats fed SU-50, SU-10 and SU-5. Further, sucrose-induced alterations in adipocyte lipolysis and antilipolysis were partially reversed and glucose transport improved in rats fed diets SU-5 and SU-10. In diaphragm phospholipids, decreasing the (n-6):(n-3) ratio in the diet increased the concentration of (n-3) LCPUFAs with concomitant decreases in the concentration of (n-6) LCPUFAs. These results suggest that (n-3) LCPUFAs at a level of 2.6 g/kg diet [0.56% energy (n-3) LCPUFAs, (n-6):(n-3) ratio = 10] may prevent sucrose-induced insulin resistance by improving peripheral insulin sensitivity.


Assuntos
Gorduras na Dieta/administração & dosagem , Sacarose Alimentar/administração & dosagem , Ácidos Graxos Ômega-3/administração & dosagem , Resistência à Insulina , Adipócitos/metabolismo , Tecido Adiposo/anatomia & histologia , Animais , Transporte Biológico , Caseínas/administração & dosagem , Diafragma/química , Dieta , Ingestão de Energia , Ácidos Graxos Ômega-6/administração & dosagem , Óleos de Peixe/administração & dosagem , Glucose/metabolismo , Insulina/sangue , Lipídeos/análise , Lipólise , Masculino , Tamanho do Órgão , Óleo de Palmeira , Óleo de Amendoim , Óleos de Plantas/administração & dosagem , Ratos , Ratos Wistar , Amido/administração & dosagem , Triglicerídeos/sangue
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