RESUMO
Obesity-induced inflammation, triggered by lipid-mediated activation of the Nlrp3 inflammasome, results in glucose metabolism alterations and type 2 diabetes. This knowledge has been generated using animals deficient for any of the different components of this inflammasome (Caspase-1, Asc or Nlrp3) in the C57BL/6 background. Unlike C57BL/6 mice, which carry allele 2 of the Nlrp1b gene (Nlrp1b2), Balb/c mice that carry allele 1 (Nlrp1b1) are less prone to develop alterations in the glucose metabolism when fed with a high fat diet. However, the molecular bases for these metabolic differences are unknown. Here we show that the Nlrp1b1 allele down regulates the adipose tissue inflammatory response attenuating glucose intolerance and insulin resistance in obese C57BL/mice. Our results indicate that the positive effects of the Nlrp1b1 inflammasome on glucose tolerance and insulin sensitivity involve IL-18-mediated effects on lipolysis, pointing out that differential expression of allelic variants of genes coding for inflammasome components might control susceptibility or resistance to develop diabetes in obese individuals.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Intolerância à Glucose/genética , Resistência à Insulina/genética , Interleucina-18/metabolismo , Obesidade/genética , Células 3T3-L1 , Alelos , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Intolerância à Glucose/imunologia , Resistência à Insulina/imunologia , Lipólise , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/induzido quimicamente , Obesidade/complicaçõesRESUMO
Overweight and obesity have become epidemic worldwide and are linked to sedentary lifestyle and the consumption of processed foods and drinks. Citrate is a metabolite that plays central roles in carbohydrate and lipid metabolism. In addition, citrate is the additive most commonly used by the food industry, and therefore is highly consumed. Extracellular citrate can freely enter the cells via the constitutively expressed plasma membrane citrate transporter. Within the cytosol, citrate is readily metabolised by ATP-citrate lyase into acetyl-CoA - the metabolic precursor of endogenously produced lipids and cholesterol. We therefore hypothesised that the citrate ingested from processed foods and drinks could contribute to increased postprandial fat production and weight gain. To test our hypothesis, we administered citrate to mice through their drinking water with or without sucrose and monitored their weight gain and other metabolic parameters. Our results showed that mice receiving citrate or citrate+sucrose did not show increased weight gain or an increase in the weight of the liver, skeletal muscles or adipose tissues (AT). Moreover, the plasma lipid profiles (TAG, total cholesterol, LDL and HDL) were similar across all groups. However, the group receiving citrate+sucrose showed augmented fasting glycaemia, glucose intolerance and the expression of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6 and IL-10) in their AT. Therefore, our results suggest that citrate consumption contributes to increased AT inflammation and altered glucose metabolism, which is indicative of initial insulin resistance. Thus, citrate consumption could be a previously unknown causative agent for the complications associated with obesity.
Assuntos
Ácido Cítrico/efeitos adversos , Sacarose Alimentar/efeitos adversos , Aditivos Alimentares/efeitos adversos , Intolerância à Glucose/etiologia , Resistência à Insulina , Gordura Intra-Abdominal/imunologia , Paniculite/etiologia , Animais , Citocinas/sangue , Dieta Ocidental/efeitos adversos , Intolerância à Glucose/imunologia , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Lipídeos/sangue , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Músculo Esquelético/imunologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Tamanho do Órgão , Paniculite/imunologia , Paniculite/metabolismo , Paniculite/patologia , Distribuição AleatóriaRESUMO
AIMS: To define if there is an imbalance in plasma levels of proinflammatory, fibrogenic and antifibrogenic cytokines in patients with liver cirrhosis (LC) and impaired glucose tolerance (IGT) or diabetes mellitus (DM). MATERIAL AND METHODS: We randomly selected 54 out of 100 patients with LC who had normal fasting plasma glucose (FPG) levels. Three groups were formed based on an oral glucose tolerance test (OGTT) results: 18 patients were normal, 18 had IGT, and 18 had DM. Plasma levels of cytokines were measured: TNF- α, soluble tumor necrosis factor receptor 1 (sTNF-R1), leptin, TGF-ß1, and hepatocyte growth factor (HGF). Also, fasting plasma insulin (FPI) levels were determined and HOMA2-IR was calculated. Results were compared with those of a control group of 18 patients without liver disease nor DM. Intergroup comparison was performed using non parametric tests. RESULTS: Significantly higher sTNF-R1 and lower TGF-ß1 were found in patients with IGT and DM compared to controls. Leptin, HGF, and TNF-α levels showed no significant differences. According to Child-Pugh classification all cytokines levels were impaired in groups B or C as compared to group A. Positive correlations between sTNF-R1 and HOMA2-IR and between leptin and HOMA2-IR were found. CONCLUSIONS: IGT and DM were associated with abnormalities of sTNF-R1 and TGF-ß1 compared to non cirrhotic controls. Among cirrhotic patients impairment of all cytokines were more marked in advanced liver disease. Finally, sTNF-R1 and leptin correlated with IR. These findings suggest that IGT and DM may be causally implicated with liver inflammation process.
Assuntos
Citocinas/imunologia , Diabetes Mellitus Tipo 2/imunologia , Intolerância à Glucose/imunologia , Insulina/sangue , Cirrose Hepática/imunologia , Adulto , Idoso , Glicemia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/complicações , Teste de Tolerância a Glucose , Fator de Crescimento de Hepatócito/imunologia , Humanos , Resistência à Insulina , Leptina/imunologia , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Fator de Crescimento Transformador beta1/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto JovemRESUMO
BACKGROUND: Inflammation has been associated with insulin resistance, type 2 diabetes mellitus (T2DM), and atherothrombosis. AIM: To determine differences in levels of proinflammatory and prothrombotic markers such as high sensitivity C-reactive protein (hs-CRP) and fibrinogen in subjects with normal glucose tolerance (NGT), prediabetes, and T2DM and to establish their relationship with other cardiovascular risk factors before clinical manifestations of cardiovascular disease. METHODS: We conducted a nonrandomized, cross-sectional assay in a hospital at México City. The levels of hs-CRP and fibrinogen were measured and compared according to glucose tolerance status. RESULTS: We enrolled 1047 individuals and they were distributed into NGT n = 473, pre-DM n = 250, and T2DM n = 216. There was a statistical difference between NGT and T2DM groups for fibrinogen (P = 0.01) and hs-CRP (P = 0.05). Fibrinogen and hs-CRP showed a significant positive correlation coefficient (r = 0.53, P<0.0001). In a multiple stepwise regression analysis, the variability in fibrinogen levels was explained by age, HbA1c, and hs-CRP (adjusted R² = 0.31, P<0.0001), and for hs-CRP it was explained by BMI and fibrinogen (adjusted R² = 0.33, P<0.0001). CONCLUSION: Inflammation and prothrombotic state are present in people with T2DM lacking cardiovascular disease. Fibrinogen and Hs-CRP are positively correlated. Fibrinogen and hs-CRP concentrations are predominantly determined by BMI rather than glucose levels.
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Intolerância à Glucose/fisiopatologia , Estado Pré-Diabético/fisiopatologia , Trombose/etiologia , Vasculite/etiologia , Adulto , Idoso , Biomarcadores/metabolismo , Índice de Massa Corporal , Proteína C-Reativa/análise , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/imunologia , Diagnóstico Precoce , Feminino , Fibrinogênio/análise , Intolerância à Glucose/sangue , Intolerância à Glucose/complicações , Intolerância à Glucose/imunologia , Hemoglobinas Glicadas/análise , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Sobrepeso/complicações , Estado Pré-Diabético/sangue , Estado Pré-Diabético/complicações , Estado Pré-Diabético/imunologia , Fatores de Risco , Trombose/complicações , Trombose/diagnóstico , Vasculite/complicações , Vasculite/diagnósticoRESUMO
Maternal consumption of a high-fat diet (HFD) during pregnancy and lactation is closely related to hepatic lipid accumulation, insulin resistance and increased serum cytokine levels in offspring and into their adulthood. MicroRNA (miRNA) have been implicated in cholesterol biosynthesis and fatty acid metabolism. We evaluated the modulation of hepatic fatty acid synthesis (de novo), ß-oxidation pathways, and miRNA-122 (miR-122) and miRNA-370 (miR-370) expression in recently weaned offspring (day 28) of mouse dams fed a HFD (HFD-O) or a standard chow (SC-O) during pregnancy and lactation. Compared with SC-O mice, HFD-O mice weighed more, had a larger adipose tissue mass and were more intolerant to glucose and insulin (P< 0·05). HFD-O mice also presented more levels of serum cholesterol, TAG, NEFA and hepatic IκB kinase and c-Jun N-terminal kinase phosphorylation compared with SC-O mice (P< 0·05). Protein levels of fatty acid synthase, acetyl-CoA carboxylase and 3-hydroxy-3-methylglutaryl-CoA reductase were similar in HFD-O and SC-O mice, whereas expression levels of SCD1 mRNA and protein were more abundant in HFD-O mice than in SC-O mice (P< 0·05). Interestingly, mRNA expression levels of the ß-oxidation-related genes ACADVL and CPT1 were decreased in HFD-O mice (P< 0·05). Furthermore, the expression of miR-122 was reduced but that of miR-370 was increased in HFD-O mice compared with that in SC-O mice (P< 0·05). Changes in hepatic lipid metabolism were accompanied by increased mRNA content of AGPAT1 and TAG deposition in HFD-O mice (P< 0·05). Taken together, the present results strongly suggest that maternal consumption of a HFD affects the early lipid metabolism of offspring by modulating the expression of hepatic ß-oxidation-related genes and miRNA that can contribute to metabolic disturbances in adult life.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Lactação , Metabolismo dos Lipídeos , Fígado/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , MicroRNAs/biossíntese , Adiposidade , Animais , Feminino , Desenvolvimento Fetal , Regulação da Expressão Gênica no Desenvolvimento , Intolerância à Glucose/etiologia , Intolerância à Glucose/imunologia , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Fígado/enzimologia , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos , Obesidade/fisiopatologia , Gravidez , Complicações na Gravidez/fisiopatologia , Distribuição Aleatória , Organismos Livres de Patógenos Específicos , Desmame , Aumento de PesoRESUMO
Diet-induced overweight rats exhibit delayed cutaneous healing; however, when receiving an obesogenic diet, some rats are susceptible to developing the overweight phenotype, whereas others are resistant. We investigated cutaneous healing in diet-induced obesity (DIO)-prone and diet-resistant (DR) rats. Male rats were fed with a standard (control) or a high-saturated fat (30 % fat, w/w) diet for 20 weeks. Then, the experimental group was subdivided into DIO (n 17) and DR (n 16) groups. An excision lesion was made, and the animals were killed 7 or 14 d later. The average body weight was 29 and 25 % higher in the DIO group compared with the C and DR groups. Retroperitoneal fat was higher in the DIO group than in the control and DR groups (518 and 92 %) and was higher in the DR group than in the control group (223 %). The DIO group presented glucose intolerance, and both the DIO and DR groups presented delayed wound contraction (50 %) and re-epithelialisation (20 %). Compared with the DR group, the DIO group displayed higher amounts of inflammatory cells as well as higher levels of lipid peroxidation (P < 0·05). Myofibroblastic differentiation and vessel remodelling were delayed in both the DIO and DR groups. Nitrite levels were lower in the DIO group (340 % less) than in the DR group. TNF-α expression was increased in the DIO group (130 %) compared with the DR group. Our results showed that DIO as well as DR rats present delays in cutaneous wound healing, even though the DR group does not have an overweight phenotype.