RESUMO
Obesity is associated with an increased incidence of high-grade prostate cancer (PC) and worse prognosis for PC patients. Recently, we showed in men that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures, was associated with high-grade PC. Possibly, interventions that suppress periprostatic WAT inflammation will improve outcomes for men with PC. Here, we tested the hypothesis that supplemental 17ß-estradiol (E2) could decrease periprostatic WAT inflammation in obese male mice. Mice were fed a high-fat diet to induce periprostatic WAT inflammation before being treated with supplemental E2. E2 supplementation suppressed caloric intake, induced weight loss, decreased periprostatic WAT inflammation and downregulated the expression of genes linked to inflammation including Cd68, Mcp1 and Tnf. Similar to the effects of E2 supplementation, treatment with diethylstilbestrol, a synthetic estrogen, also suppressed caloric intake and reduced periprostatic WAT inflammation. To determine whether the observed effects of supplemental estrogen could be reproduced by caloric restriction (CR) alone, obese mice were put on a 30% CR diet. Like estrogen treatment, CR was effective in reducing body weight, periprostatic WAT inflammation and the expression of pro-inflammatory genes. Transcriptomic analyses of periprostatic fat showed that obesity was associated with enrichment in inflammatory response pathways, which were normalized by both supplemental E2 and CR. Taken together, these findings strengthen the rationale for future efforts to determine whether either CR or supplemental estrogen will decrease periprostatic WAT inflammation and thereby improve outcomes for men with PC.
Assuntos
Restrição Calórica , Estradiol/administração & dosagem , Estrogênios/administração & dosagem , Inflamação/terapia , Gordura Intra-Abdominal/efeitos dos fármacos , Obesidade/complicações , Adipócitos/imunologia , Adipócitos/patologia , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Inflamação/imunologia , Inflamação/patologia , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/patologia , Masculino , Camundongos , Obesidade/imunologia , Obesidade/terapia , Próstata/efeitos dos fármacos , Próstata/imunologia , Próstata/patologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Resultado do Tratamento , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Loss of white adipose tissue (WAT), associated with type 1 diabetes (DM1), contributes to increased chronic systemic inflammation. AIM: The aim of this study was to investigate the effects of leucine supplementation and resistance training (RT) in attenuating WAT loss and improving inflammatory parameters and glucose metabolism in DM1 rats. METHODS: Thirty-two male Wistar rats were distributed into four groups: DA (sedentary and supplemented with non-essential amino acids (NEAA)), DL (sedentary and supplemented with leucine), DTA (submitted to RT and supplemented with NEAA) and DTL (submitted to RT and supplemented with leucine). DM1 was induced by streptozotocin (STZ). An 8-week period of RT consisted of climbing a ladder with a progressively increased load, and supplementation was offered in the feed. RESULTS: Glycemia, polyphagia and polydipsia were lower in DL, DTA and DTL groups compared with the DA group by approximately 20% ( p<.0001), 28% ( p=.004) and 64% ( p<.0001), respectively. Weight of total WAT and retroperitoneal adipose tissue (RPAT) were higher by approximately 21% ( p=.01) and 54% ( p=.0004), respectively, in DL, DTA and DTL groups compared with DA. However, gene expression of adiponectin and leptin in RPAT was only increased by RT (DTA and DTL) compared with DA and DL by approximately 93% ( p<.0001) and 78% ( p=.0002), respectively. Similarly, the levels of adiponectin in the serum, tissue IL-10 (RPAT) and serum IL-10 were only increased in DTA and DTL compared with DA and DL by approximately 31% ( p=.03), 45% ( p=.0009) and 35% ( p=.003), respectively. CONCLUSIONS: Both interventions, isolated or together, reduced hyperglycemia and excessive loss of WAT, but RT was the main factor responsible for attenuating inflammation.
Assuntos
Tecido Adiposo Branco/patologia , Adiposidade , Diabetes Mellitus Tipo 1/terapia , Suplementos Nutricionais , Hiperglicemia/prevenção & controle , Leucina/uso terapêutico , Treinamento Resistido , Adiponectina/sangue , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Terapia Combinada , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Regulação da Expressão Gênica , Mediadores da Inflamação/sangue , Resistência à Insulina , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Leptina/sangue , Leptina/genética , Leptina/metabolismo , Masculino , Distribuição Aleatória , Ratos Wistar , Redução de PesoRESUMO
SCOPE: Beta-carotene-15,15'-oxygenase (BCO1) and beta-carotene-9',10'-oxygenase (BCO2) metabolize lycopene to biologically active metabolites, which can ameliorate nonalcoholic fatty liver disease (NAFLD). We investigate the effects of tomato powder (TP containing substantial lycopene (2.3 mg/g)) on NAFLD development and gut microbiome in the absence of both BCO1 and BCO2 in mice. METHOD AND RESULTS: BCO1-/- /BCO2-/- double knockout mice were fed a high fat diet (HFD) alone (n = 9) or with TP feeding (n = 9) for 24 weeks. TP feeding significantly reduced pathological severity of steatosis and hepatic triglyceride levels in BCO1-/- /BCO2-/- mice (p < 0.04 vs HFD alone). This was associated with increased SIRT1 activity, nicotinamide phosphoribosyltransferase expression and AMP-activated protein kinase phosphorylation, and subsequently decreased lipogenesis, hepatic fatty acid uptake, and increasing fatty acid ß-oxidation (p < 0.05). TP feeding significantly decreased mRNA expression of proinflammatory genes (tnf-α, il-1ß, and il-6) in both liver and mesenteric adipose tissue, which were associated with increased plasma adiponectin and hepatic adiponectin receptor-2. Multiplexed 16S rRNA gene sequencing was performed using DNA extracted from cecum fecal samples. TP feeding increased microbial richness and decreased relative abundance of the genus Clostridium. CONCLUSION: Dietary TP can inhibit NAFLD independent of carotenoid cleavage enzymes, potentially through increasing SIRT1 activity and adiponectin production and decreasing Clostridium abundance.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Suplementos Nutricionais , Dioxigenases/metabolismo , Frutas/química , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Solanum lycopersicum/química , beta-Caroteno 15,15'-Mono-Oxigenase/metabolismo , Adiponectina/agonistas , Adiponectina/sangue , Adiponectina/genética , Adiponectina/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Dioxigenases/genética , Disbiose/imunologia , Disbiose/metabolismo , Disbiose/microbiologia , Disbiose/prevenção & controle , Fezes/microbiologia , Microbioma Gastrointestinal , Regulação da Expressão Gênica , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Metabolismo dos Lipídeos , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Licopeno/uso terapêutico , Masculino , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Sirtuína 1/química , Sirtuína 1/metabolismo , beta-Caroteno 15,15'-Mono-Oxigenase/genéticaRESUMO
PURPOSE: Obesity is usually associated with low-grade inflammation, which impairs insulin action. The amino acid, taurine (TAU), regulates glucose homeostasis and lipid metabolism and presents anti-inflammatory actions. Here, we evaluated whether inflammatory markers are altered in the serum and retroperitoneal adipose tissue of monosodium glutamate (MSG) obese rats, supplemented or not with TAU. METHODS: Male Wistar rats received subcutaneous injections of MSG (4 mg/kg body weight/day, MSG group) or hypertonic saline (CTL) during the first 5 days of life. From 21 to 120 days of age, half of each of the MSG and CTL groups received 2.5 % TAU in their drinking water (CTAU and MTAU). RESULTS: At 120 days of age, MSG rats were obese and hyperinsulinemic. TAU supplementation reduced fat deposition without affecting insulinemia in MTAU rats. MSG rats presented increased pIκ-Bα/Iκ-Bα protein expression in the retroperitoneal adipose tissue. TAU supplementation decreased the ratio of pIκ-Bα/Iκ-Bα protein, possibly contributing to the increased Iκ-Bα content in MTAU adipose tissue. Furthermore, MSG obesity or supplementation did not alter TNF-α, IL-1ß or IL-6 content in adipose tissue. In contrast, MSG rats presented lower serum TNF-α, IL-4 and IL-10 concentrations, and these alterations were prevented by TAU treatment. CONCLUSION: MSG obesity in rats was not associated with alterations in pro-inflammatory markers in retroperitoneal fat stores; however, reductions in the serum concentrations of anti-inflammatory cytokines and of TNF-α were observed. TAU treatment decreased adiposity, and this effect was associated with the normalization of circulating TNF-α and IL-4 concentrations in MTAU rats.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Suplementos Nutricionais , Regulação da Expressão Gênica , Gordura Intra-Abdominal/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Obesidade/dietoterapia , Taurina/uso terapêutico , Adiposidade , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/sangue , Biomarcadores/metabolismo , Hiperinsulinismo/dietoterapia , Hiperinsulinismo/etiologia , Hiperinsulinismo/imunologia , Hiperinsulinismo/metabolismo , Proteínas I-kappa B/agonistas , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Injeções Subcutâneas , Interleucina-4/antagonistas & inibidores , Interleucina-4/sangue , Interleucina-4/metabolismo , Gordura Intra-Abdominal/imunologia , Masculino , Inibidor de NF-kappaB alfa/agonistas , Inibidor de NF-kappaB alfa/genética , Obesidade/etiologia , Obesidade/imunologia , Obesidade/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Ratos Wistar , Glutamato de Sódio/administração & dosagem , Glutamato de Sódio/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
It is now broadly accepted that the nutritional environment in early life is a key factor in susceptibility to metabolic diseases. In this study, we evaluated the effects of maternal chromium restriction in vivo on the modulation of lipid metabolism and the mechanisms involved in this process. Sixteen pregnant C57BL mice were randomly divided into two dietary treatments: a control (C) diet group and a low chromium (L) diet group. The diet treatment was maintained through gestation and lactation period. After weaning, some of the pups continued with either the control diet or low chromium diet (CC or LL), whereas other pups switched to another diet (CL or LC). At 32 weeks of age, serum lipid metabolism, proinflammatory indexes, oxidative stress and anti-oxidant markers, and DNA methylation status in adipose tissue were measured. The results indicated that the maternal low chromium diet increased body weight, fat pad weight, serum triglyceride (TG), low-density lipoprotein cholesterol (LDL), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), and oxidized glutathione (GSSG). There was a decrease in serum reduced/oxidized glutathione (GSH/GSSG) ratio at 32 weeks of age in female offspring. From adipose tissue, we identified 1214 individual hypomethylated CpG sites and 411 individual hypermethylated CpG sites in the LC group when compared to the CC group. Pathway analysis of the differential methylation genes revealed a significant increase in hypomethylated genes in the mitogen-activated protein kinase (MAPK) signaling pathway in the LC group. Our study highlights the importance of the MAPK signaling pathway in epigenetic changes involved in the lipid metabolism of the offspring from chromium-restricted dams.
Assuntos
Cromo/deficiência , Deficiências Nutricionais/metabolismo , Desenvolvimento Fetal , Gordura Intra-Abdominal/metabolismo , Metabolismo dos Lipídeos , Sistema de Sinalização das MAP Quinases , Fenômenos Fisiológicos da Nutrição Materna , Adiposidade , Animais , Biomarcadores/sangue , Cromo/uso terapêutico , Ilhas de CpG , Metilação de DNA , Deficiências Nutricionais/dietoterapia , Deficiências Nutricionais/imunologia , Deficiências Nutricionais/fisiopatologia , Suplementos Nutricionais , Feminino , Gordura Intra-Abdominal/imunologia , Lactação , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/prevenção & controle , Estresse Oxidativo , Gravidez , Distribuição Aleatória , Desmame , Aumento de PesoRESUMO
We evaluated maternal flaxseed oil intake during lactation on body composition, lipid profile, glucose homeostasis and adipose tissue inflammation in male and female progeny at adulthood. Lactating rats were divided into the following: control 7% soybean oil (C), hyper 19% soybean oil (HS) and hyper 17% flaxseed oil+2% soybean oil (HF). Weaned pups received a standard diet. Offspring were killed in PN180. Male HF presented higher visceral adipose tissue (VAT) and triacylglycerol, and female HF showed insulin resistance. Both male and female HF had hyperleptinemia, and only male HF had hyperprolactinemia. In VAT, male HF presented lower PPAR-γ expressions and higher TNF-α, IL-6, IL-1ß and IL-10 expressions; in subcutaneous adipose tissue (SAT), they presented lower PPAR-γ and TNF-α expressions. Female HF presented higher leptin, as well as lower adiponectin, TNF-α, IL-6 and IL-1ß expressions in VAT and lower TNF-α in SAT. Flaxseed oil during lactation leads to gender-specific effects with more adiposity and dyslipidemia in male and insulin resistance in female. Higher prolactin and inflammatory cytokines in male could play a role in these gender differences. We suggest that the use of flaxseed oil during lactation increases metabolic syndrome risk in the adult progeny.
Assuntos
Adiposidade , Dieta Hiperlipídica/efeitos adversos , Dislipidemias/etiologia , Resistência à Insulina , Lactação , Óleo de Semente do Linho/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Dislipidemias/imunologia , Dislipidemias/metabolismo , Dislipidemias/patologia , Feminino , Hiperprolactinemia/etiologia , Hiperprolactinemia/imunologia , Hiperprolactinemia/metabolismo , Hiperprolactinemia/patologia , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Leptina/sangue , Masculino , PPAR gama/metabolismo , Distribuição Aleatória , Ratos Wistar , Fatores Sexuais , Gordura Subcutânea/imunologia , Gordura Subcutânea/metabolismo , Gordura Subcutânea/patologiaRESUMO
Chronic intake of high sucrose (HS) diet exacerbates high-fat (HF) diet-induced obesity and its associated metabolic complications. Previously, we have demonstrated that ellagic acid (EA), an abundant polyphenol found in some fruits and nuts, exerts distinct lipid-lowering characteristics in hepatocytes and adipocytes. In this study, we hypothesized that EA supplementation inhibits HS diet-mediated hepatic toxicity and its accompanied metabolic dysregulation. To test this hypothesis, C57BL/6 male mice were randomly assigned to three isocaloric HF diets (41% calories from fat) containing either no-sucrose (HF), high-sucrose (HFHS), or high-sucrose plus EA (HFHS-R) from raspberry seed flour (RSF, equivalent to 0.03% of EA), and fed for 12weeks. The inclusion of EA from RSF significantly improved HFHS diet-mediated dyslipidemia and restored glucose homeostasis levels similar to the HF diet-fed mice. Despite marginal difference in hepatic triglyceride content, the addition of EA substantially reversed the activation of endoplasmic reticulum (ER) stress and oxidative damage triggered by HFHS diet in the liver. These effects of EA were further confirmed in human hepatoma cells by reducing ER stress and reactive oxygen species (ROS) production. Moreover, HFHS-R diet significantly decreased visceral adipocyte hypertrophy and adipose tissue inflammation evidenced by reduced proinflammatory gene expression and macrophage infiltration. In summary, EA supplementation from RSF was effective in reducing HFHS diet-mediated metabolic complication by attenuating hepatic ER and oxidative stresses as well as adipocyte inflammation. Our results suggest that the inclusion of EA in diets may normalize metabolic insults triggered by HS consumption.
Assuntos
Antioxidantes/uso terapêutico , Suplementos Nutricionais , Estresse do Retículo Endoplasmático , Fígado/metabolismo , Estresse Oxidativo , Paniculite/dietoterapia , Rubus/química , Adiposidade , Animais , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/análise , Antioxidantes/química , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Sacarose Alimentar/efeitos adversos , Suplementos Nutricionais/análise , Ácido Elágico/análise , Ácido Elágico/metabolismo , Ácido Elágico/uso terapêutico , Humanos , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/fisiopatologia , Paniculite/etiologia , Paniculite/imunologia , Paniculite/metabolismo , Distribuição Aleatória , Sementes/química , Organismos Livres de Patógenos EspecíficosRESUMO
Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea.
Assuntos
Fármacos Antiobesidade/farmacologia , Hipóxia/imunologia , Resistência à Insulina , Gordura Intra-Abdominal/imunologia , Macrófagos/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Ingestão de Alimentos , Insulina/sangue , Leptina/sangue , Masculino , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Resveratrol , Aumento de PesoRESUMO
Prolonged niacin treatment elicits beneficial effects on the plasma lipid and lipoprotein profile that is associated with a protective CVD risk profile. Acute niacin treatment inhibits nonesterified fatty acid release from adipocytes and stimulates prostaglandin release from skin Langerhans cells, but the acute effects diminish upon prolonged treatment, while the beneficial effects remain. To gain insight in the prolonged effects of niacin on lipid metabolism in adipocytes, we used a mouse model with a human-like lipoprotein metabolism and drug response [female APOE*3-Leiden.CETP (apoE3 Leiden cholesteryl ester transfer protein) mice] treated with and without niacin for 15 weeks. The gene expression profile of gonadal white adipose tissue (gWAT) from niacin-treated mice showed an upregulation of the "biosynthesis of unsaturated fatty acids" pathway, which was corroborated by quantitative PCR and analysis of the FA ratios in gWAT. Also, adipocytes from niacin-treated mice secreted more of the PUFA DHA ex vivo. This resulted in an increased DHA/arachidonic acid (AA) ratio in the adipocyte FA secretion profile and in plasma of niacin-treated mice. Interestingly, the DHA metabolite 19,20-dihydroxy docosapentaenoic acid (19,20-diHDPA) was increased in plasma of niacin-treated mice. Both an increased DHA/AA ratio and increased 19,20-diHDPA are indicative for an anti-inflammatory profile and may indirectly contribute to the atheroprotective lipid and lipoprotein profile associated with prolonged niacin treatment.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Ácidos Graxos Ômega-3/sangue , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Gordura Intra-Abdominal/efeitos dos fármacos , Niacina/uso terapêutico , Oxilipinas/sangue , Algoritmos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Ácido Araquidônico/sangue , Ácido Araquidônico/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Dieta Ocidental/efeitos adversos , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Insaturados/sangue , Ácidos Graxos Insaturados/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroxilação , Hiperlipidemias/sangue , Hiperlipidemias/imunologia , Hiperlipidemias/metabolismo , Hipolipemiantes/farmacologia , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Camundongos Transgênicos , Niacina/farmacologia , Oxilipinas/metabolismo , Fatores de TempoRESUMO
BACKGROUND: Adverse fetal environments predispose offspring to pathologies associated with the metabolic syndrome. Previously we demonstrated that adult offspring of dexamethasone-treated mothers had elevated plasma insulin and pro-inflammatory cytokines, effects prevented by a postnatal diet enriched with omega (n)-3 fatty acids. Here we tested whether prenatal glucocorticoid excess also programmed the adipose tissue phenotype, and whether this outcome is rescued by dietary n-3 fatty acids. METHODS: Offspring of control and dexamethasone-treated mothers (0.75 µg/ml in drinking water, day 13 to term) were cross-fostered to mothers on a standard (Std) or high n-3 (Hn3) diet at birth. Offspring remained on these diets post-weaning, and serum and retroperitoneal fat were obtained at 6 months of age (n = 5-8 per group). Serum was analysed for blood lipids and fatty acid profiles, adipocyte cross sectional area was measured by unbiased stereological analysis and adipose expression of markers of inflammation, glucocorticoid sensitivity and lipid metabolism were determined by RT-qPCR analysis. RESULTS: Serum total fatty acid levels were elevated (P < 0.01) in male offspring of dexamethasone-treated mothers, an effect prevented by Hn3 consumption. Prenatal dexamethasone also programmed increased adipose expression of Il6, Il1b (both P < 0.05) and Tnfa (P < 0.001) mRNAs regardless of fetal sex, but again this effect was prevented (for Il6 and Il1b) by Hn3 consumption. Offspring of dexamethasone-treated mothers had increased adipose expression of Gr (P = 0.008) and Ppara (P < 0.05) regardless of sex or postnatal diet, while 11bHsd1 was upregulated in males only. The Hn3 diet increased Ppard expression and reduced adipocyte size in all offspring (both P < 0.05) irrespective of prenatal treatment. CONCLUSIONS: Prenatal glucocorticoid exposure programmed increased expression of inflammatory markers and enhanced glucocorticoid sensitivity of adipose tissue. Partial prevention of this phenotype by high n-3 consumption indicates that postnatal dietary manipulations can limit adverse fetal programming effects on adipose tissue.
Assuntos
Suplementos Nutricionais , Modelos Animais de Doenças , Ácidos Graxos Ômega-3/uso terapêutico , Gordura Intra-Abdominal/imunologia , Síndrome Metabólica/prevenção & controle , Complicações na Gravidez/fisiopatologia , Estresse Psicológico/fisiopatologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Dexametasona/análogos & derivados , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-3/metabolismo , Feminino , Desenvolvimento Fetal , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Lactação , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Síndrome Metabólica/imunologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Gravidez , Distribuição Aleatória , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Regulação para Cima , DesmameRESUMO
PURPOSE: The immune response is altered according to hormonal and metabolic status. Obesity increases the inflammatory and fever response, whereas loss of gonadal steroid decreases behavioral response to immune stress. However, the immune systems of ovariectomized animals exhibiting obesity and gonadal steroid deficiency, particularly under septic conditions, have not been fully examined. In the present study, we evaluated the ovariectomy-induced changes of central and peripheral immune responses to life-threatening septic stimulus. METHODS AND RESULTS: Ovariectomized rats showed heavier body weight and lighter uterine weight when compared with gonadally intact rats. Fever response to septic dose of lipopolysaccharide (LPS) in ovariectomized rats was less evident when compared with that in gonadally intact rats. In addition, under LPS-injected septic conditions, hypothalamic gene levels of Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and serum protein levels of IL-1ß and TNF-α in ovariectomized rats were lower than those in gonadally intact rats. On the other hand, IL-6 levels in visceral fat under septic conditions were higher in ovariectomized rats than in gonadally intact rats. CONCLUSIONS: These findings indicate that ovariectomy-induced site-specific changes in cytokine response under septic conditions. As hypothalamic, but not peripheral, pro-inflammatory cytokines are directly involved in the fever response, the attenuation of fever response observed in ovariectomized rats may be caused by a reduction in central cytokine responses.
Assuntos
Envelhecimento , Citocinas/metabolismo , Modelos Animais de Doenças , Hipotálamo/imunologia , Gordura Intra-Abdominal/imunologia , Obesidade/imunologia , Sepse/imunologia , Adiposidade , Animais , Anorexia/etiologia , Citocinas/sangue , Citocinas/genética , Feminino , Febre/etiologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Hipotálamo/metabolismo , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Lipopolissacarídeos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Obesidade/complicações , Tamanho do Órgão , Especificidade de Órgãos , Ovariectomia , Ratos Sprague-Dawley , Sepse/complicações , Sepse/metabolismo , Sepse/fisiopatologia , Útero/patologiaRESUMO
Obesity is considered to be accompanied by a chronic low-grade inflammatory state that contributes to the occurrence of many chronic diseases. Our previous study has demonstrated that histidine supplementation significantly ameliorates inflammation and oxidative stress in obese women. However, the in vivo potential mechanisms are not known. The present study was conducted to investigate the mechanisms underlying the effects of histidine on inflammation in a high-fat diet (HFD)-induced female obese rat model. An obese model was established in female Sprague-Dawley rats by HFD feeding for 8 weeks and followed by histidine supplementation for another 4 weeks. The results revealed that HFD-increased body weight and HFD-lowered serum histidine concentrations were significantly reversed by histidine supplementation (P< 0·05). In addition, the serum concentrations of TNF-α, IL-6, C-reactive protein (CRP) and malondialdehyde were significantly reduced and those of superoxide dismutase (SOD) were significantly increased by histidine supplementation when compared with those in obese rats (P< 0·05). Correspondingly, the mRNA expressions of TNF-α, IL-6 and CRP in the adipose tissue were significantly down-regulated and that of CuZnSOD was significantly up-regulated by histidine supplementation (P< 0·05). Histidine supplementation significantly reduced the HFD-induced translocation of NF-κB p65 into the nucleus (P= 0·032) by reducing the phosphorylation of the inhibitor of κBα in the adipose tissue. The results also revealed that the expression of adiponectin was markedly increased both in the serum and in the adipose tissue after histidine supplementation, accompanied by the activation of PPARγ (P= 0·021). These findings indicate that histidine is an effective candidate for ameliorating inflammation and oxidative stress in obese individuals via the NF-κB- and PPARγ-involved pathways.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Suplementos Nutricionais , Histidina/uso terapêutico , Gordura Intra-Abdominal/metabolismo , Obesidade/dietoterapia , PPAR gama/agonistas , Fator de Transcrição RelA/antagonistas & inibidores , Adiponectina/agonistas , Adiponectina/sangue , Adiponectina/genética , Adiponectina/metabolismo , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/sangue , Fármacos Antiobesidade/uso terapêutico , Proteína C-Reativa/análise , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Núcleo Celular/metabolismo , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Regulação da Expressão Gênica , Histidina/administração & dosagem , Histidina/sangue , Gordura Intra-Abdominal/enzimologia , Gordura Intra-Abdominal/imunologia , Obesidade/etiologia , Obesidade/imunologia , Obesidade/metabolismo , Estresse Oxidativo , PPAR gama/metabolismo , Transporte Proteico , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/química , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator de Transcrição RelA/metabolismoRESUMO
Inflammation of adipose tissue triggers the metabolic syndrome, atherosclerosis and CHD. In the present study, we investigated whether the milk casein-derived tripeptide valine-proline-proline (VPP) has an anti-inflammatory effect on the adipose tissue of high-fat diet (HFD)-fed mice. Male C57BL/6J mice (7 weeks of age) were fed ad libitum with either a HFD and plain tap water (HFD group) or a HFD and water containing 0·3 mg VPP/ml (HFD+VPP group) for 10 weeks. The results showed that the expression level of CD18 in the peripheral blood monocytes of the HFD+VPP group was significantly decreased compared with the level observed in those of the HFD group. Activated monocytes and pro-inflammatory macrophages were accumulated in the stromal vascular fractions of the adipose tissue from HFD-fed mice, which were significantly decreased in those supplemented with VPP. The formation of crown-like structures rich in pro-inflammatory macrophages was also significantly reduced in the adipose tissue of mice administered with VPP. Real-time PCR analysis revealed that the expression of monocyte chemoattractant protein-1 and that of the pro-inflammatory cytokine IL-6 in adipose tissue tend to be lower in the HFD+VPP group than in the HFD group. These observations indicate that oral administration of VPP exerts an anti-inflammatory effect on the adipose tissue of HFD-fed mice, which may eventually lead to the primary prevention of chronic inflammation-related diseases.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Caseínas/uso terapêutico , Suplementos Nutricionais , Gordura Intra-Abdominal/imunologia , Obesidade/dietoterapia , Oligopeptídeos/uso terapêutico , Paniculite/prevenção & controle , Animais , Antígenos CD18/sangue , Antígenos CD18/metabolismo , Caseínas/química , Bovinos , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Monócitos/metabolismo , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Paniculite/etiologia , Fragmentos de Peptídeos/uso terapêuticoRESUMO
The present study investigated the potential health-promoting effects of heat-inactivated Lactobacillus gasseri TMC0356 (TMC0356) on the metabolic syndrome (MS) and the probable mechanisms underlying these effects using an MS rat model. For the purpose of the study, sixty Sprague-Dawley rats were randomly divided into five groups: a control group fed a conventional diet, an MS model group fed a high-fat and high-salt (HFS) diet and three TMC0356 test groups (low-, medium- and high-dose groups) fed an HFS diet supplemented with TMC0356 at 41.8, 83.5 and 167.0 mg/kg body weight (BW) per d, respectively. Food intake and BW were measured weekly. Fasting blood glucose (FBG), lipid profiles and blood pressure (BP) were measured at 0, 5, 10 and 15 weeks. Organ coefficients, immune cell counts and serum insulin, adiponectin, C-reactive protein (CRP), IL-6, TNF-α, IgG and secretory IgA levels were measured at the 15th week after diet intervention. The HFS diet increased the BW, liver or fat:BW ratio, FBG, homeostatic model assessment of insulin resistance, adiponectin, serum LDL-cholesterol and total cholesterol levels and BP (P< 0.01). Average food and energy intakes in the three TMC0356 groups were significantly lower than those of the MS model group. All the metabolic indices, except BP, were markedly improved (P< 0.05) by oral administration of low and medium doses of TMC0356. The thymus index in the medium-dose group and lymphocyte, CRP, IL-6, TNF-α and IgG levels in all the three TMC0356 groups were significantly increased (P< 0.05 or P< 0.01) compared with those in the MS model group. These results suggest that TMC0356 can improve the metabolic characteristics of MS rats by suppressing appetite. Additionally, the enhancement of inflammatory immune response may be, at least in part, the mechanism underlying the health-promoting effects of TMC0356 on the MS.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Suplementos Nutricionais , Fatores Imunológicos/uso terapêutico , Lactobacillus/imunologia , Síndrome Metabólica/imunologia , Síndrome Metabólica/prevenção & controle , Obesidade/prevenção & controle , Adiposidade , Animais , Fármacos Antiobesidade/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Temperatura Alta , Fatores Imunológicos/administração & dosagem , Resistência à Insulina , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/patologia , Fígado/imunologia , Fígado/patologia , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/patologia , Viabilidade Microbiana , Obesidade/complicações , Tamanho do Órgão , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Timo/imunologia , Timo/patologiaRESUMO
Obesity is characterised by a state of chronic low-grade inflammation and the elevated circulating and tissue levels of inflammatory markers, including inflammation-related adipokines, released from white adipose tissue. The expression and release of these adipokines generally rises as the adipose tissue expands and hypoxic conditions start to develop within the tissue. Here, the effect of betaine, a trimethylglycine having a biological role as an osmolyte and a methyl donor, on the expression of inflammation-related markers was tested in human adipocytes under hypoxia. Differentiated adipocytes were cultivated under low (1 %) oxygen tension for 8-20 h. The expression of different adipokines, including IL-6, leptin, PPARγ, TNF-α and adiponectin, was measured by quantitative PCR by determining the relative mRNA level from the adipocytes. Hypoxia, in general, led to a decrease in the expression of PPARγ mRNA in human adipocytes, whereas the expression levels of leptin and IL-6 mRNA were substantially increased by hypoxia. The cultivation of adipocytes under hypoxia also led to a reduction in the expression of TNF-α mRNA. The results showed that hypoxia increased the relative quantification of leptin gene transcription, and that betaine (250 µmol/l) reduced this effect, caused by low oxygen conditions. Under hypoxia, betaine also reduced the mRNA level of the pro-inflammatory markers IL-6 and TNF-α. These results demonstrate that the extensive changes in the expression of inflammation-related adipokines in human adipocytes caused by hypoxia can be diminished by the presence of physiologically relevant concentrations of betaine.
Assuntos
Adipocinas/metabolismo , Anti-Inflamatórios não Esteroides/metabolismo , Betaína/metabolismo , Citocinas/metabolismo , Regulação para Baixo , Gordura Intra-Abdominal/metabolismo , Adipogenia , Adipocinas/genética , Adulto , Biomarcadores/metabolismo , Hipóxia Celular , Células Cultivadas , Citocinas/genética , Suplementos Nutricionais , Feminino , Humanos , Gordura Intra-Abdominal/citologia , Gordura Intra-Abdominal/imunologia , PPAR gama/genética , PPAR gama/metabolismo , RNA Mensageiro/metabolismo , Regulação para CimaRESUMO
PURPOSE: To examine the effect of different dietary fat types on osteopontin (OPN) expressions and inflammation of adipose tissues in diet-induced obese rats. METHODS: Male Sprague-Dawley rats were randomly assigned to one control group fed standard diet (LF, n = 10) and two high-fat diet groups fed isoenergy diet rich in lard or soybean oil (HL or HS, n = 45 each). Diet-induced obese rats in HL and HS group were then subdivided into two groups either continuously fed high-fat diet or switched to low-fat diet for 8 more weeks. Fasting serum glucose, insulin, and OPN concentrations were assayed and QUICKI was calculated; the expression of OPN, IL-6, IL-10, TNF-α, NF-κB, and F4/80 in adipose tissue was determined. RESULTS: Both high-fat diets lead to comparable development of obesity characterized by insulin resistance and adipose tissue inflammation. Obese rats continuously fed high-fat diet rich in lard oil exhibited the highest fasting serum insulin level and adipose tissue OPN, F4/80, TNF-α, and NF-κB expression level. In both high-fat diet groups, switching to low-fat diet resulted in less intra-abdominal fat mass, decreased expression of F4/80, TNF-α, and NF-κB, while decreased OPN expression was only observed in lard oil fed rats after switching to low-fat diet. CONCLUSIONS: Reducing diet fat or replacing lard oil with soybean oil in high-fat diet alleviates obesity-related inflammation and insulin resistance by attenuating the upregulation of OPN and macrophage infiltration into adipose tissue induced by high-fat diet.
Assuntos
Tecido Adiposo Branco/metabolismo , Dieta com Restrição de Gorduras , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/efeitos adversos , Obesidade/dietoterapia , Osteopontina/metabolismo , Óleo de Soja/uso terapêutico , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/patologia , Adiposidade , Animais , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Gorduras na Dieta/administração & dosagem , Regulação para Baixo , Hiperinsulinismo/etiologia , Hiperinsulinismo/prevenção & controle , Resistência à Insulina , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Ativação de Macrófagos , Masculino , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/patologia , Osteopontina/sangue , Osteopontina/genética , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Óleo de Soja/administração & dosagem , Óleo de Soja/efeitos adversos , Organismos Livres de Patógenos EspecíficosRESUMO
The present study aimed to characterize serum haptoglobin (Hp) concentrations throughout an entire lactation period in both primi- and multiparous cows and to compare them to the Hp mRNA expression in liver and - in view of Hp being potentially an adipokine - also in different subcutaneous (s.c.) and visceral fat depots. In addition, potential anti-inflammatory effects of long-term supplementation with conjugated linoleic acids (CLA) were evaluated by assessing Hp. Trial 1 comprised 33 cows and 16 Holstein heifers from day 21 ante partum until day 252 postpartum. The animals received 100 or 50 g/day CLA or a control fat supplement. Blood samples and biopsy (tail head fat and liver) samples were collected. Trial 2 included 25 Holstein heifers, 5 animals were slaughtered on the day of parturition, the remaining animals were allocated to either CLA (100 g/day, n=10) or control fat supplement (n=10) and slaughtered on days 42 and 105 postpartum, respectively. At slaughter, fat samples were collected from 3 different visceral depots, 3 s.c. depots and from liver tissue. Results indicated no effects of CLA on serum Hp and liver Hp mRNA for both trials and on Hp mRNA in biopsies from s.c. tail head fat. In omental and s.c. withers fat from trial 2, CLA reduced Hp mRNA on both day 42 and day 105. Hp mRNA was detectable in fat tissues from both trials with abundance values being significantly lower than in liver. The Hp mRNA abundance in the s.c. fat depots was generally higher than in the visceral depots. Haptoglobin mRNA abundance in the different tissues from trial 2 was correlated whereby all s.c. depots were interrelated. The evidence of Hp mRNA expression in adipose tissues and the presence of Hp-immune staining in histological fat sections confirm that Hp can be classified as a bovine adipokine. The lack of an evident relationship between circulating Hp concentrations and normal body fat portions in dairy cattle demonstrates that varying degrees of adiposity are not confounding factors when using Hp as inflammatory marker. The physiological changes in serum Hp concentration seem to be limited to parity and parturition. In view of the lack of effects of CLA on serum Hp concentrations, the observed reaction in two out of six different fat depots seems of marginal importance for the organisms as an entity.
Assuntos
Bovinos/imunologia , Haptoglobinas/imunologia , Gordura Intra-Abdominal/imunologia , Ácidos Linoleicos Conjugados/administração & dosagem , Fígado/imunologia , Gordura Subcutânea/imunologia , Ácido 3-Hidroxibutírico/sangue , Animais , Biópsia/veterinária , Ácidos Graxos não Esterificados/sangue , Feminino , Haptoglobinas/genética , Imuno-Histoquímica/veterinária , Gordura Intra-Abdominal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Período Pós-Parto , RNA Mensageiro/química , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária , Estatísticas não Paramétricas , Gordura Subcutânea/efeitos dos fármacosRESUMO
Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common liver disease in industrialised countries. Various mushrooms have been used in Eastern folk medicine for the treatment of lifestyle diseases. We previously found that the dietary intake of powdered whole Panellus serotinus (Mukitake) alleviates NAFLD in obese, diabetic db/db mice. In the present study, we investigated the influence of Mukitake fractional extracts on the development of NAFLD in db/db mice. A significant reduction in the hepatic TAG content, macrovesicular hepatocytes and activities of key enzymes for de novo synthesis of the fatty acid was observed in both the water-soluble Mukitake extract (WE) diet and the ethanol-soluble Mukitake extract (EE) diet groups compared with the control diet group of the db/db mice. The serum level of monocyte chemoattractant protein-1 (MCP-1), which is known to exacerbate insulin resistance, was significantly decreased in the WE group. On the other hand, the serum level of adiponectin, which plays a protective role against the metabolic syndrome, was significantly increased in the EE group. Additionally, differential analysis between Mukitake and Shiitake, mycelia from the same family, using liquid chromatography time-of-flight MS technology revealed that only seven and five compounds exist in WE and EE from Mukitake, respectively. In conclusion, the present study demonstrated that Mukitake displays at least two different physiological actions that alleviate NAFLD: one through the reduction in inflammatory damage by its suppression in MCP-1 production and the other through an increase in level of serum adiponectin and the prevention of visceral fat accumulation.
Assuntos
Agaricales/química , Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/prevenção & controle , Fígado Gorduroso/prevenção & controle , Hipoglicemiantes/uso terapêutico , Medicina Tradicional do Leste Asiático , Obesidade/prevenção & controle , Adiponectina/sangue , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Fármacos Antiobesidade/química , Quimiocina CCL2/sangue , Quimiocina CCL2/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/química , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Mutantes , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , RNA Mensageiro/metabolismo , Distribuição Aleatória , Solubilidade , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Visceral adipose inflammation mediated by innate and adaptive immune alterations plays a critical role in diet-induced obesity and insulin resistance (IR). The dietary supplement α-lipoic acid (αLA) has been shown to ameliorate inflammatory processes in macrophages, however the relative significance of these effects in the context of visceral adipose inflammation and IR remain unknown. In this study we investigated its effects via both intraperitoneal and oral administration in lean and obese transgenic mice expressing yellow fluorescent protein (YFP) under control of a monocyte specific promoter (c-fms(YFP+)). αLA significantly improved indices of insulin-resistance concomitant with a decrease in total (YFP(+)CD11b(+)) and activated (YFP(+)CD11b(+)CD11c(+)) visceral adipose tissue macrophages. Histologically, the visceral adipose tissue of obese mice receiving αLA had fewer "crown-like structures," a hallmark of adipose inflammation in murine obesity. Monocyte adhesion assessed by intravital microscopy of cremasteric venules was attenuated by αLA. In cultured WT and toll-like receptor 4 (TLR4) null primary mouse macrophages, αLA significantly decreased basal CCR-2, MCP-1 and TNF-α expression levels. LPS treatment resulted in increased TNFα, MCP-1, and IL-6 expression while αLA partially abrogated the LPS effect on MCP-1 and TNFα; Interestingly, CCR-2 was not coordinately regulated. AαLA prevented LPS-induced nuclear factor kappa B (NFκB) activation in the same cultured macrophages. These data suggest that αLA may modulate visceral adipose inflammation, a critical determinant of IR via TLR4 and NF-κB pathways.
Assuntos
Anti-Inflamatórios/farmacologia , Imunidade Inata/efeitos dos fármacos , Resistência à Insulina , Gordura Intra-Abdominal/patologia , Obesidade/tratamento farmacológico , Ácido Tióctico/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Glicemia , Vasos Sanguíneos/patologia , Peso Corporal , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Expressão Gênica , Injeções Intraperitoneais , Insulina/sangue , Gordura Intra-Abdominal/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Obesidade/imunologia , Obesidade/patologia , Distribuição Aleatória , Ácido Tióctico/administração & dosagem , Triglicerídeos/metabolismoRESUMO
Clinical evidence indicates that fat is inversely proportional to bone mass in elderly obese women. However, it remains unclear whether obesity accelerates bone loss. In this report we present evidence that increased visceral fat leads to inflammation and subsequent bone loss in 12-month-old C57BL/6J mice that were fed 10% corn oil (CO)-based diet and a control lab chow (LC) for 6 months. As expected from our previous work, CO-fed mice demonstrated increased visceral fat and enhanced total body fat mass compared to LC. The adipocyte-specific PPARγ and bone marrow (BM) adiposity were increased in CO-fed mice. In correlation with those modifications, inflammatory cytokines (IL-1ß, IL-6, TNF-α) were significantly elevated in CO-fed mice compared to LC-fed mice. This inflammatory BM microenvironment resulted in increased superoxide production in osteoclasts and undifferentiated BM cells. In CO-fed mice, the increased number of osteoclasts per trabecular bone length and the increased osteoclastogenesis assessed ex-vivo suggest that CO diet induces bone resorption. Additionally, the up-regulation of osteoclast-specific cathepsin k and RANKL expression and down-regulation of osteoblast-specific RUNX2/Cbfa1 supports this bone resorption in CO-fed mice. Also, CO-fed mice exhibited lower trabecular bone volume in the distal femoral metaphysis and had reduced OPG expression. Collectively, our results suggest that increased bone resorption in mice fed a CO-enriched diet is possibly due to increased inflammation mediated by the accumulation of adipocytes in the BM microenvironment. This inflammation may consequently increase osteoclastogenesis, while reducing osteoblast development in CO-fed mice.