RESUMO
OBJECTIVE: Human brown adipose tissue (BAT) has gained considerable attention as a potential therapeutic target for obesity and its related cardiometabolic diseases; however, whether the gut microbiota might be an efficient stimulus to activate BAT metabolism remains to be ascertained. We aimed to investigate the association of fecal microbiota composition with BAT volume and activity and mean radiodensity in young adults. METHODS: 82 young adults (58 women, 21.8 ± 2.2 years old) participated in this cross-sectional study. DNA was extracted from fecal samples and 16S rRNA sequencing was performed to analyse the fecal microbiota composition. BAT was determined via a static 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography scan (PET/CT) after a 2 h personalized cooling protocol. 18F-FDG uptake was also quantified in white adipose tissue (WAT) and skeletal muscles. RESULTS: The relative abundance of Akkermansia, Lachnospiraceae sp. and Ruminococcus genera was negatively correlated with BAT volume, BAT SUVmean and BAT SUVpeak (all rho ≤ - 0.232, P ≤ 0.027), whereas the relative abundance of Bifidobacterium genus was positively correlated with BAT SUVmean and BAT SUVpeak (all rho ≥ 0.262, P ≤ 0.012). On the other hand, the relative abundance of Sutterellaceae and Bifidobacteriaceae families was positively correlated with 18F-FDG uptake by WAT and skeletal muscles (all rho ≥ 0.213, P ≤ 0.042). All the analyses were adjusted for the PET/CT scan date as a proxy of seasonality. CONCLUSION: Our results suggest that fecal microbiota composition is involved in the regulation of BAT and glucose uptake by other tissues in young adults. Further studies are needed to confirm these findings. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov no. NCT02365129 (registered 18 February 2015).
Assuntos
Microbiota , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adulto , Feminino , Humanos , Adulto Jovem , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/metabolismo , Estudos Transversais , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons , RNA Ribossômico 16S/genéticaRESUMO
BACKGROUND AND AIMS: Inflammation may underlie the association between obesity, atherosclerosis and cardiovascular disease. We investigated to what extent markers of inflammation mediate associations between overall and visceral body fat and subclinical atherosclerosis. METHODS AND RESULTS: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study we estimated total body fat (TBF) by bio-impedance analysis, carotid artery intima media thickness (cIMT) by ultrasound, C-reactive protein (hs-CRP) and glycoprotein acetyls (GlycA) concentrations in fasting blood samples (n = 5627), and visceral adipose tissue (VAT) by magnetic resonance imaging (n = 2247). We examined associations between TBF and VAT, and cIMT using linear regression, adjusted for potential confounding factors, and for mediators: cardiometabolic risk factors (blood pressure, glucose and low-density lipoprotein cholesterol), and inflammation using CRP and GlycA as proxies. Mean (SD) cIMT was 615 (90) µm. Per SD of TBF (8%), cIMT was 19 µm larger (95% confidence interval, CI: 10, 28). This association was 17 µm (95% CI: 8, 27) after adjustment for cardiometabolic risk factors, and did not change after adjustment for markers of inflammation. Per SD (56 cm2) VAT, cIMT was 9 µm larger (95% CI: 2, 16) which changed to 5 µm (95% CI: -3, 12) after adjustment for cardiometabolic risk factors, and did not change after adjustment for inflammatory markers. CONCLUSION: Our results suggest that associations between measures of overall and visceral body fat and subclinical atherosclerosis are not mediated by inflammation as measured by CRP and GlycA. Obesity may exert cardiovascular risk via other markers of systemic inflammation.
Assuntos
Adiposidade , Doenças das Artérias Carótidas/sangue , Mediadores da Inflamação/sangue , Inflamação/sangue , Gordura Intra-Abdominal/fisiopatologia , Obesidade/fisiopatologia , Doenças Assintomáticas , Biomarcadores/sangue , Proteína C-Reativa/análise , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/epidemiologia , Espessura Intima-Media Carotídea , Estudos Transversais , Impedância Elétrica , Feminino , Glicoproteínas/sangue , Humanos , Inflamação/diagnóstico , Inflamação/epidemiologia , Gordura Intra-Abdominal/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Obesidade/diagnóstico por imagem , Obesidade/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND/OBJECTIVES: In obesity, B cells accumulate in white adipose tissue (WAT) and produce IgG, which may contribute to the development of glucose intolerance. IgG signals by binding to Fcγ receptors (FcγR) and by activating the complement system. The aim of our study was to investigate whether activation of FcγR and/or complement C3 mediates the development of high-fat diet-induced glucose intolerance. METHODS: We studied mice lacking all four FcγRs (FcγRI/II/III/IV-/-), only the inhibitory FcγRIIb (FcγRIIb-/-), only the central component of the complement system C3 (C3-/-), and mice lacking both FcγRs and C3 (FcγRI/II/III/IV/C3-/-). All mouse models and wild-type controls were fed a high-fat diet (HFD) for 15 weeks to induce obesity. Glucose metabolism was assessed and adipose tissue was characterized for inflammation and adipocyte functionality. RESULTS: In obese WAT of wild-type mice, B cells (+142%, P<0.01) and IgG (+128% P<0.01) were increased compared to lean WAT. Macrophages of FcγRI/II/III/IV-/-mice released lower levels of cytokines compared to wild-type mice upon IgG stimulation. Only C3-/- mice showed reduced HFD-induced weight gain as compared to controls (-18%, P<0.01). Surprisingly, FcγRI/II/III/IV-/- mice had deteriorated glucose tolerance (AUC +125%, P<0.001) despite reduced leukocyte number (-30%, P<0.05) in gonadal WAT (gWAT), whereas glucose tolerance and leukocytes within gWAT in the other models were unaffected compared to controls. Although IgG in gWAT was increased (+44 to +174%, P<0.05) in all mouse models lacking FcγRIIb, only FcγRI/II/III/IV/C3-/- mice exhibited appreciable alterations in immune cells in gWAT, for example, increased macrophages (+36%, P<0.001). CONCLUSIONS: Lack of FcγRs reduces the activity of macrophages upon IgG stimulation, but neither FcγR nor C3 deficiency protects against HFD-induced glucose intolerance or reduces adipose tissue inflammation. This indicates that if obesity-induced IgG contributes to the development of glucose intolerance, this is not mediated by FcγR or complement activation.
Assuntos
Tecido Adiposo Branco/metabolismo , Complemento C3/metabolismo , Intolerância à Glucose/metabolismo , Inflamação/metabolismo , Obesidade/metabolismo , Receptores de IgG/metabolismo , Animais , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Obesidade/fisiopatologiaRESUMO
BACKGROUND: The fat mass and obesity-associated (FTO) gene harbors the strongest common genetic variant associated with obesity. Recently, rs1421085-T to -C substitution mapped in FTO was shown to induce a developmental shift of human adipocytes from an energy-combusting beige to an energy-storing white phenotype in vitro. As browning of adipocytes selectively enhances fat oxidation (FatOx), we hypothesized that rs1421085-C in FTO is associated with deceased FatOx compared with carbohydrate oxidation (CarbOx) and an increased respiratory quotient (RQ). METHODS: In the Netherlands Epidemiology of Obesity study, a population-based cohort study of middle-aged individuals (45-65 years), anthropometry and genotyping was performed (n=5744), in addition to indirect calorimetry (n=1246). With linear regression analyses, we examined associations of rs1421085 genotype with FatOx, CarbOx and RQ. RESULTS: In the total study population, 36.7% carried the rs1421085-TT genotype, 47.6% rs1421085-CT and 15.7% rs1421085-CC. Mean (s.d.) age was 56 (6) years, mean (s.d.), body mass index (BMI) was 26.3 (4.4) kg m-2 and 56% of the total population were women. Measures of adiposity (difference, 95% confidence interval) were higher in CC carriers compared with that in rs1421085-TT carriers: BMI +0.56 (0.15, 0.98) kg m-2, waist circumference +1.25 (0.02, 2.49) cm and total body fat mass +1.21 (0.28, 2.14) kg. However, no differences in mean FatOx (+2.5 (-2.4, 7.4) mg min-1), CarbOx (-6.1 (-17.4, 5.2) mg min-1) or RQ (-0.01 (-0.02, 0.01)) were observed between the two genotypes. CONCLUSIONS: We observed no evidence for associations of rs1421085 in FTO with FatOx and RQ. This indicates that the rs1421085-C allele in FTO induces obesity likely via other pathways than via reduced FatOx.
Assuntos
Adipócitos/metabolismo , Adiposidade/fisiologia , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Variação Genética , Obesidade/genética , Adiposidade/genética , Índice de Massa Corporal , Calorimetria Indireta , Estudos de Coortes , Metabolismo Energético/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Obesidade/epidemiologia , Oxirredução , Circunferência da CinturaRESUMO
BACKGROUND AND AIMS: South Asians have an exceptionally high risk of developing cardiovascular disease compared to white Caucasians. A contributing factor might be dysfunction of high density lipoprotein (HDL). We aimed to compare HDL function in different age groups of both ethnicities. METHODS AND RESULTS: HDL functionality with respect to cholesterol efflux, anti-oxidation and anti-inflammation was determined using fasting, apoB-depleted, plasma samples from South Asian and white Caucasian neonates (n = 14 each), adolescent healthy men (n = 12 each, 18-25 y), and adult overweight men (n = 12 each, 40-50 y). Adolescents were subjected to a 5-day high fat high calorie diet (HCD) and adults to an 8-day very low calorie diet (LCD). Additionally, HDL composition was measured in adolescents and adults using (1)H-NMR spectroscopy. Anti-oxidative capacity was lower in South Asian adults before LCD (19.4 ± 2.1 vs. 25.8 ± 1.2%, p = 0.045, 95%-CI = [0.1; 12.7]) and after LCD (16.4 ± 2.4 vs. 27.6 ± 2.7%, p = 0.001, 95%-CI = [4.9; 17.5]). Anti-inflammatory capacity was reduced in South Asian neonates (23.8 ± 1.2 vs. 34.9 ± 1.3%, p = 0.000001, 95%-CI = [-14.6; -7.5]), and was negatively affected by an 8-day LCD only in South Asian adults (-12.2 ± 4.3%, p = 0.005, 95%-CI = [-5.9; -1.2]). Cholesterol efflux capacity was increased in response to HCD in adolescents (South Asians: +6.3 ± 2.9%, p = 0.073, 95%-CI = [-0.02; 0.46], Caucasians: +11.8 ± 3.4%, p = 0.002, 95%-CI = [0.17;0.65]) and decreased after LCD in adults (South Asians: -10.3 ± 2.4%, p < 0.001, 95%-CI = [-0.57; -0.20], Caucasians: -13.7 ± 1.9%, p < 0.00001, 95%-CI = [-0.67; -0.33]). Although subclass analyses of HDL showed no differences between ethnicities, cholesterol efflux correlated best with cholesterol and phospholipid within small HDL compared to other HDL subclasses and constituents. CONCLUSION: Impaired HDL functionality in South Asians may be a contributing factor to their high CVD risk. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/).
Assuntos
Povo Asiático , Restrição Calórica , Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/sangue , Dieta Hiperlipídica , Obesidade/dietoterapia , Adolescente , Adulto , Distribuição por Idade , Antioxidantes/metabolismo , Apolipoproteína B-100/sangue , Ásia/etnologia , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etnologia , Dieta Hiperlipídica/efeitos adversos , Humanos , Lactente , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Ressonância Magnética Nuclear Biomolecular , Obesidade/sangue , Obesidade/diagnóstico , Obesidade/etnologia , Fosfolipídeos/sangue , Medição de Risco , Fatores de Risco , Fatores de Tempo , População Branca , Adulto JovemRESUMO
The increased prevalence of metabolic disorders and obesity in modern society, together with the widespread use of artificial light at night, have led researchers to investigate whether altered patterns of light exposure contribute to metabolic disorders. This article discusses the experimental evidence that perturbed environmental cycles induce rhythm disorders in the circadian system, thus leading to metabolic disorders. This notion is generally supported by animal studies. Distorted environmental cycles, including continuous exposure to light, affect the neuronal organization of the central circadian pacemaker in the suprachiasmatic nucleus (SCN), its waveform and amplitude of the rhythm in electrical activity. Moreover, repeated exposure to a shifted light cycle or the application of dim light at night are environmental cues that cause a change in SCN function. The effects on the SCN waveform are the result of changes in synchronization among the SCN's neuronal cell population, which lead consistently to metabolic disturbances. Furthermore, we discuss the effects of sleep deprivation and the time of feeding on metabolism, as these factors are associated with exposure to disturbed environmental cycles. Finally, we suggest that these experimental studies reveal a causal relationship between the rhythm disorders and the metabolic disorders observed in epidemiological studies performed in humans.
Assuntos
Transtornos Cronobiológicos/complicações , Relógios Circadianos/fisiologia , Metabolismo Energético , Iluminação/efeitos adversos , Doenças Metabólicas/etiologia , Fotoperíodo , Núcleo Supraquiasmático/fisiopatologia , Animais , Plasticidade Celular , Ingestão de Alimentos/fisiologia , Humanos , Privação do Sono/metabolismoRESUMO
BACKGROUND: The autonomic nervous system attenuates inflammation through activation of the α7 nicotinic acetylcholine receptor (α7nAChR), a pathway termed the cholinergic anti-inflammatory reflex. Interestingly, α7nAChR is expressed on immune cells and platelets, both of which play a crucial role in the development of atherosclerosis. OBJECTIVE: To investigate the role of hematopoietic α7nAChR in inflammation and platelet function in atherosclerotic ldlr(-/-) mice and to identify its consequences for atherosclerotic lesion development. METHODS: Bone marrow from α7nAChR(-/-) mice or wild-type littermates was transplanted into irradiated ldlr(-/-) mice. After a recovery period of 8 weeks, the mice were fed an atherogenic Western-type diet for 7 weeks. RESULTS: Hematopoietic α7nAChR deficiency clearly increased the number of leukocytes in the peritoneum (2.6-fold, P < 0.001), blood (2.9-fold; P < 0.01), mesenteric lymph nodes (2.0-fold; P < 0.001) and spleen (2.2-fold; P < 0.01), indicative of an increased inflammatory status. Additionally, expression of inflammatory mediators was increased in peritoneal leukocytes (TNFα, 1.6-fold, P < 0.01; CRP, 1.8-fold, P < 0.01) as well as in the spleen (TNFα, 1.6-fold, P < 0.01). The lack of α7nAChR on platelets from these mice increased the expression of active integrin αIIb ß3 upon stimulation by ADP (1.9-fold, P < 0.01), indicating increased activation status, while incubation of human platelets with an α7nAChR agonist decreased aggregation (-35%, P < 0.05). Despite the large effects of hematopoietic α7nAChR deficiency on inflammatory status and platelet function, it did not affect atherosclerosis development or composition of lesions. CONCLUSIONS: Hematopoietic α7nAChR is important for attenuation of inflammatory responses and maintaining normal platelet reactivity, but loss of hematopoietic α7nAChR does not aggravate development of atherosclerosis.
Assuntos
Doenças da Aorta/etiologia , Aterosclerose/etiologia , Plaquetas/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Inflamação/etiologia , Fator de Ativação de Plaquetas , Receptor Nicotínico de Acetilcolina alfa7/deficiência , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Transplante de Medula Óssea , Dieta Ocidental , Modelos Animais de Doenças , Feminino , Genótipo , Transplante de Células-Tronco Hematopoéticas , Inflamação/sangue , Inflamação/genética , Mediadores da Inflamação/sangue , Leucócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Placa Aterosclerótica , Receptores de LDL/deficiência , Receptores de LDL/genética , Fatores de Tempo , Receptor Nicotínico de Acetilcolina alfa7/genéticaRESUMO
BACKGROUND: Toll-like receptor-4 (TLR4), a receptor of the innate immune system, is suggested to have detrimental effects on cardiac function after myocardial infarction (MI). RP105 (CD180) is a TLR4 homolog lacking the intracellular signaling domain that competitively inhibits TLR4-signaling. Thus, we hypothesized that RP105 deficiency, by amplifying TLR4 signaling, would lead to aggravated cardiac dysfunction after MI. METHODS AND RESULTS: First, whole blood from RP105-/- and wild-type (WT) male C57Bl/6N mice was stimulated with LPS, which induced a strong inflammatory TNFα response in RP105-/- mice. Then, baseline heart function was assessed by left ventricular pressure-volume relationships which were not different between RP105-/- and WT mice. Permanent ligation of the left anterior descending coronary artery was performed to induce MI. Infarct sizes were analyzed by (immuno)histology and did not differ. Fifteen days post MI heart function was assessed and RP105-/- mice had significantly higher heart rate (+21%, P<0.01), end systolic volume index (+57%, P<0.05), end systolic pressure (+22%, P<0.05) and lower relaxation time constant tau (-12%, P<0.05), and a tendency for increased end diastolic volume index (+42%, P<0.06), compared to WT mice. In the area adjacent to the infarct zone, compared to the healthy myocardium, levels of RP105, TLR4 and the endogenous TLR4 ligand fibronectin-EDA were increased as well as the number of macrophages, however this was not different between both groups. CONCLUSION: Deficiency of the endogenous TLR4 inhibitor RP105 leads to an enhanced inflammatory status and more pronounced cardiac dilatation after induction of MI, underscoring the role of the TLR4 pathway in post-infarction remodeling.
Assuntos
Antígenos CD/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Receptor 4 Toll-Like/biossíntese , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 4 Toll-Like/antagonistas & inibidores , Remodelação Ventricular/fisiologiaRESUMO
BACKGROUND AND PURPOSE: The aetiology of inflammation in the liver and vessel wall, leading to non-alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored. Here, we tested the hypothesis that exendin-4 reduces inflammation in both the liver and vessel wall, and investigated the common underlying mechanism. EXPERIMENTAL APPROACH: Female APOE*3-Leiden.CETP mice, a model with human-like lipoprotein metabolism, were fed a cholesterol-containing Western-type diet for 5 weeks to induce atherosclerosis and subsequently treated for 4 weeks with exendin-4. KEY RESULTS: Exendin-4 modestly improved dyslipidaemia, but markedly decreased atherosclerotic lesion severity and area (-33%), accompanied by a reduction in monocyte adhesion to the vessel wall (-42%) and macrophage content in the plaque (-44%). Furthermore, exendin-4 reduced hepatic lipid content and inflammation as well as hepatic CD68⺠(-18%) and F4/80⺠(-25%) macrophage content. This was accompanied by less monocyte recruitment from the circulation as the Mac-1⺠macrophage content was decreased (-36%). Finally, exendin-4 reduced hepatic chemokine expression in vivo and suppressed oxidized low-density lipoprotein accumulation in peritoneal macrophages in vitro, effects dependent on the GLP-1 receptor. CONCLUSIONS AND IMPLICATIONS: Exendin-4 reduces inflammation in both the liver and vessel wall by reducing macrophage recruitment and activation. These data suggest that exendin-4 could be a valuable strategy to treat NASH and atherosclerosis simultaneously.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aterosclerose/prevenção & controle , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Fígado Gorduroso/prevenção & controle , Fígado/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Aterosclerose/etiologia , Aterosclerose/imunologia , Aterosclerose/patologia , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Dieta Aterogênica/efeitos adversos , Implantes de Medicamento , Dislipidemias/etiologia , Dislipidemias/imunologia , Dislipidemias/patologia , Dislipidemias/prevenção & controle , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Exenatida , Fígado Gorduroso/etiologia , Fígado Gorduroso/imunologia , Fígado Gorduroso/patologia , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipolipemiantes/administração & dosagem , Hipolipemiantes/uso terapêutico , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Transgênicos , Hepatopatia Gordurosa não Alcoólica , Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Distribuição Aleatória , Receptores de Glucagon/antagonistas & inibidores , Receptores de Glucagon/metabolismo , Peçonhas/administração & dosagem , Peçonhas/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: Topiramate improves insulin sensitivity, in addition to its antiepileptic action. However, the underlying mechanism is unknown. Therefore, the present study was aimed at investigating the mechanism of the insulin-sensitizing effect of topiramate both in vivo and in vitro. EXPERIMENTAL APPROACH: Male C57Bl/6J mice were fed a run-in high-fat diet for 6 weeks, before receiving topiramate or vehicle mixed in high-fat diet for an additional 6 weeks. Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp. The extent to which the insulin sensitizing effects of topiramate were mediated through the CNS were determined by concomitant i.c.v. infusion of vehicle or tolbutamide, an inhibitor of ATP-sensitive potassium channels in neurons. The direct effects of topiramate on insulin signalling and glucose uptake were assessed in vivo and in cultured muscle cells. KEY RESULTS: In hyperinsulinaemic-euglycaemic clamp conditions, therapeutic plasma concentrations of topiramate (â¼4 µg·mL(-1) ) improved insulin sensitivity (glucose infusion rate + 58%). Using 2-deoxy-D-[(3) H]glucose, we established that topiramate improved the insulin-mediated glucose uptake by heart (+92%), muscle (+116%) and adipose tissue (+586%). Upon i.c.v. tolbutamide, the insulin-sensitizing effect of topiramate was completely abrogated. Topiramate did not directly affect glucose uptake or insulin signalling neither in vivo nor in cultured muscle cells. CONCLUSION AND IMPLICATIONS: In conclusion, topiramate stimulates insulin-mediated glucose uptake in vivo through the CNS. These observations illustrate the possibility of pharmacological modulation of peripheral insulin resistance through a target in the CNS.
Assuntos
Anticonvulsivantes/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Frutose/análogos & derivados , Resistência à Insulina , Canais KATP/antagonistas & inibidores , Fibras Musculares Esqueléticas/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Anticonvulsivantes/administração & dosagem , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Linhagem Celular , Sistema Nervoso Central/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Frutose/administração & dosagem , Frutose/farmacologia , Infusões Intraventriculares , Insulina/sangue , Canais KATP/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Bloqueadores dos Canais de Potássio/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , TopiramatoRESUMO
Hypothalamus-pituitary-adrenal-axis activity is suggested to be involved in the pathophysiology of the metabolic syndrome. In diet-induced obesity mouse models, features of the metabolic syndrome are induced by feeding high fat diet. However, the models reveal conflicting results with respect to the hypothalamus-pituitary-adrenal-axis activation. The aim of this review was to assess the effects of high fat feeding on the activity of the hypothalamus-pituitary-adrenal-axis in mice. PubMed, EMBASE, Web of Science, the Cochrane database, and Science Direct were electronically searched and reviewed by 2 individual researchers. We included only original mouse studies reporting parameters of the hypothalamus-pituitary-adrenal-axis after high fat feeding, and at least 1 basal corticosterone level with a proper control group. Studies with adrenalectomized mice, transgenic animals only, high fat diet for less than 2 weeks, or other interventions besides high fat diet, were excluded. 20 studies were included. The hypothalamus-pituitary-adrenal-axis evaluation was the primary research question in only 5 studies. Plasma corticosterone levels were unchanged in 40%, elevated in 30%, and decreased in 20% of the studies. The effects in the peripheral tissues and the central nervous system were also inconsistent. However, major differences were found between mouse strains, experimental conditions, and the content and duration of the diets. This systematic review demonstrates that the effects of high fat feeding on the basal activity of the hypothalamus-pituitary-adrenal-axis in mice are limited and inconclusive. Differences in experimental conditions hamper comparisons and accentuate the need for standardized evaluations to discern the effects of diet-induced obesity on the hypothalamus-pituitary-adrenal-axis.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/metabolismo , Modelos Animais de Doenças , Hipotálamo/metabolismo , Síndrome Metabólica/metabolismo , Camundongos/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Animais , Gorduras na Dieta/efeitos adversos , HumanosRESUMO
BACKGROUND AND PURPOSE: We have evaluated the effects of a peroxisome proliferator-activated receptor (PPAR)alpha/gamma agonist on the progression of pre-existing atherosclerotic lesions in APOE*3Leiden.cholesteryl ester transfer protein (E3L.CETP) transgenic mice. EXPERIMENTAL APPROACH: E3L.CETP mice were fed a high-cholesterol diet for 11 weeks to induce atherosclerosis, followed by a low-cholesterol diet for 4 weeks to obtain a lower plasma total cholesterol level of approximately 10 mmol.L(-1). Mice were divided into three groups, which were either killed before (baseline) or after an 8 week treatment period with low-cholesterol diet without (control) or with the PPARalpha/gamma agonist tesaglitazar (10 microg.kg(-1).day(-1)). Atherosclerosis was assessed in the aortic root. KEY RESULTS: Treatment with tesaglitazar significantly reduced plasma triglycerides, total cholesterol, CETP mass and CETP activity, and increased high-density lipoprotein-cholesterol. At baseline, substantial atherosclerosis had developed. During the 8 week low-cholesterol diet, atherosclerosis progressed in the control group with respect to lesion area and severity, whereas tesaglitazar inhibited lesion progression during this period. Tesaglitazar reduced vessel wall inflammation, as reflected by decreased monocyte adhesion and macrophage area, and modified lesions to a more stabilized phenotype, with increased smooth muscle cell content in the cap and collagen content. CONCLUSIONS AND IMPLICATIONS: Dual PPARalpha/gamma agonism with tesaglitazar markedly improved the atherogenic triad by reducing triglycerides and very low-density lipoprotein-cholesterol and increasing high-density lipoprotein-cholesterol and additionally reduced cholesterol-induced vessel wall activation. These actions resulted in complete inhibition of progression and stabilization of pre-existing atherosclerotic lesions in E3L.CETP mice.
Assuntos
Alcanossulfonatos/farmacologia , Apolipoproteína E3/genética , Aterosclerose/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/genética , PPAR alfa/agonistas , PPAR gama/agonistas , Fenilpropionatos/farmacologia , Animais , Valva Aórtica/patologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Proteínas de Transferência de Ésteres de Colesterol/biossíntese , HDL-Colesterol/sangue , VLDL-Colesterol/sangue , Feminino , Humanos , Inflamação/prevenção & controle , Camundongos , Camundongos Transgênicos , MutaçãoRESUMO
Apolipoprotein AV (apoAV) overexpression causes a decrease in plasma triglyceride (TG) levels, while deficiency of apoAV causes hypertriglyceridemia in both men and mice. However, contrary to what would be expected, plasma apoAV and TG levels in humans are positively correlated. To address this apparent paradox, we determined plasma apoAV levels in various mouse models with median TG levels ranging from 30 mg/dl in wild-type mice to 2089 mg/dl in glycosylphosphatidylinositol-anchored HDL binding protein 1-deficient mice. The data show that apoAV and TG levels are positively correlated in mice (r = +0.798, P < 0.001). In addition, we show that LPL gene transfer caused a simultaneous decrease in TG and apoAV in LPL-deficient mice. The combined data suggest that apoAV levels follow TG levels due to an intimate link between the apoAV molecule and TG-rich lipoproteins, comprising both secretion and removal of these lipoproteins. Taken together, the data suggest that higher plasma apoAV levels reflect an increased demand for plasma TG hydrolysis under normal physiological conditions.
Assuntos
Apolipoproteínas A/sangue , Triglicerídeos/sangue , Animais , Apolipoproteína A-V , Humanos , Lipase Lipoproteica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutAssuntos
Apolipoproteína C-I/sangue , Aterosclerose/sangue , Inflamação/sangue , Síndrome Metabólica/sangue , Idoso , Aterosclerose/complicações , Proteína C-Reativa/biossíntese , Dislipidemias/sangue , Dislipidemias/complicações , Endotélio Vascular/patologia , Humanos , Inflamação/complicações , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Triglicerídeos/metabolismoRESUMO
Inhibition of cholesteryl ester transfer protein (CETP) is generally regarded as a promising strategy to reduce atherosclerosis by increasing HDL cholesterol. Therefore, the potent CETP inhibitor torcetrapib was given in addition to atorvastatin in half of the 15,067 patients with a high cardiovascular risk in the randomized, double-blind 'Investigation of lipid level management to understand its impact in atherosclerotic events' (ILLUMINATE) study. Torcetrapib caused a large increase of 72.1% in HDL cholesterol and a concomitant reduction of 24.9% in LDL-cholesterol. However, the trial was terminated prematurely because of an increased risk of cardiovascular events and death. Besides increasing blood pressure, torcetrapib decreased potassium and increased sodium, bicarbonate and aldosterone in serum. Post hoc analyses showed an increased risk of death in patients whose change in electrolytes was greater than the median change. These adverse effects of torcetrapib are presumably compound-specific, but should be taken into account in future studies with novel CETP inhibitors. Furthermore, it is suggested that the efficacy of CETP inhibition with regard to cardiovascular event reduction may depend on the lipid profile of the patient.
Assuntos
Anticolesterolemiantes/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Quinolinas/efeitos adversos , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Humanos , Hipercolesterolemia/tratamento farmacológico , Seleção de Pacientes , Quinolinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Equilíbrio Hidroeletrolítico/fisiologiaRESUMO
Previous studies with hypertriglyceridemic APOC3 transgenic mice have suggested that apolipoprotein C-III (apoC-III) may inhibit either the apoE-mediated hepatic uptake of TG-rich lipoproteins and/or the lipoprotein lipase (LPL)-mediated hydrolysis of TG. Accordingly, apoC3 knockout (apoC3(-/-)) mice are hypotriglyceridemic. In the present study, we attempted to elucidate the mechanism(s) underlying these phenomena by intercrossing apoC3(-/-) mice with apoE(-/-) mice to study the effects of apoC-III deficiency against a hyperlipidemic background. Similar to apoE(+/+) apoC3(-/-) mice, apoE(-/-)apoC3(-/-) mice exhibited a marked reduction in VLDL cholesterol and TG, indicating that the mechanism(s) by which apoC-III deficiency exerts its lipid-lowering effect act independent of apoE. On both backgrounds, apoC3(-/-) mice showed normal intestinal lipid absorption and hepatic VLDL TG secretion. However, turnover studies showed that TG-labeled emulsion particles were cleared much more rapidly in apoC3(-/-) mice, whereas the clearance of VLDL apoB, as a marker for whole particle uptake by the liver, was not affected. Furthermore, it was shown that cholesteryl oleate-labeled particles were also cleared faster in apoC3(-/-) mice. Thus the mechanisms underlying the hypolipidemia in apoC3(-/-) mice involve both a more efficient hydrolysis of VLDL TG as well as an enhanced selective clearance of VLDL cholesteryl esters from plasma. In summary, our studies of apoC3(-/-) mice support the concept that apoC-III is an effective inhibitor of VLDL TG hydrolysis and reveal a potential regulating role for apoC-III with respect to the selective uptake of cholesteryl esters.
Assuntos
Apolipoproteínas C/deficiência , Apolipoproteínas E/metabolismo , Deleção de Genes , Lipase Lipoproteica/metabolismo , Triglicerídeos/metabolismo , Animais , Apolipoproteína C-III , Apolipoproteínas C/genética , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Quilomícrons/metabolismo , Cruzamentos Genéticos , Feminino , Hidrólise , Lipoproteínas VLDL/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Tempo , Triglicerídeos/sangueRESUMO
The asialoglycoprotein receptor (ASGPr) on hepatocytes plays a role in the clearance of desialylated proteins from the serum. Although its sugar preference (N-acetylgalactosamine (GalNAc) >> galactose) and the effects of ligand valency (tetraantennary > triantennary >> diantennary >> monoantennary) and sugar spacing (20 A 10 A 4 A) are well documented, the effect of particle size on recognition and uptake of ligands by the receptor is poorly defined. In the present study, we assessed the maximum ligand size that still allows effective processing by the ASGPr of mouse hepatocytes in vivo and in vitro. Here too, we synthesized a novel glycolipid, which possesses a highly hydrophobic steroid moiety for stable incorporation into liposomes, and a triantennary GalNAc(3)-terminated cluster glycoside with a high nanomolar affinity (2 nm) for the ASGPr. Incorporation of the glycolipid into small (30 nm) [(3)H]cholesteryl oleate-labeled long circulating liposomes (1-50%, w/w) caused a concentration-dependent increase in particle clearance that was liver-specific (reaching 85 +/- 7% of the injected dose at 30 min after injection) and mediated by the ASGPr on hepatocytes, as shown by competition studies with asialoorosomucoid in vivo. By using glycolipid-laden liposomes of various sizes between 30 and 90 nm, it was demonstrated that particles with a diameter of >70 nm could no longer be recognized and processed by the ASGPr in vivo. This threshold size for effective uptake was not related to the physical barrier raised by the fenestrated sinusoidal endothelium, which shields hepatocytes from the circulation, because similar results were obtained by studying the uptake of liposomes on isolated mouse hepatocytes in vitro. From these data we conclude that in addition to the species, valency, and orientation of sugar residues, size is also an important determinant for effective recognition and processing of substrates by the ASGPr. Therefore, these data have important implications for the design of ASGPr-specific carriers that are aimed at hepatocyte-directed delivery of drugs and genes.
Assuntos
Hepatócitos/metabolismo , Lipossomos/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Receptor de Asialoglicoproteína , Transporte Biológico , Glicolipídeos/metabolismo , Técnicas In Vitro , Ligantes , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Lipoproteins are endogenous particles that transport lipids through the blood to various cell types, where they are recognised and taken up via specific receptors. These particles are, therefore, excellent candidates for the targeted delivery of drugs to various tissues. For example, the remnant receptor and the asialoglycoprotein receptor (ASGPr), which are uniquely localised on hepatocytes, recognise chylomicrons and lactosylated high density lipopoteins (HDL), respectively. In addition, tumour cells of various origins overexpress the low density lipoprotein (LDL) receptor that recognises apolipoprotein E (apoE) on small triglyceride-rich particles and apoB-100 on LDL. Being endogenous, lipoproteins are biodegradable, do not trigger immune reactions, and are not recognised by the reticuloendothelial system (RES). However, their endogenous nature also hampers large-scale pharmaceutical application. In the past two decades, various research groups have successfully synthesised recombinant lipoproteins from commercially available natural and synthetic lipids and serum-derived or recombinant apolipoproteins, which closely mimic the metabolic behaviour of their native counterparts in animal models as well as humans. In this paper, we will summarise the studies that led to the development of these recombinant lipoproteins, and we will address the possibility of using these lipidic particles to selectively deliver a wide range of lipophilic, amphiphilic, and polyanionic compounds to hepatocytes and tumour cells. In addition, the intrinsic therapeutic activities of recombinant chylomicrons and HDL in sepsis and atherosclerosis will be discussed.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Hepatócitos/metabolismo , Lipoproteínas/administração & dosagem , Pró-Fármacos/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Animais , Arteriosclerose/tratamento farmacológico , Quilomícrons/administração & dosagem , Quilomícrons/química , Humanos , Lipoproteínas/química , Lipoproteínas HDL/administração & dosagem , Lipoproteínas HDL/química , Lipoproteínas LDL/administração & dosagem , Lipoproteínas LDL/química , Pró-Fármacos/química , Proteínas Recombinantes/química , Choque Séptico/tratamento farmacológico , Tensoativos/administração & dosagem , Tensoativos/química , Células Tumorais Cultivadas/metabolismoRESUMO
Septic shock is the most common cause of death in intensive care units and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gram-negative sepsis by inducing the production of macrophage-derived cytokines. Previously, we showed that apolipoprotein E (apoE), an established modulator of lipid metabolism, can bind LPS, thereby redirecting LPS from macrophages to hepatocytes in vivo. We now report that intravenously administered LPS strongly increases the serum levels of apoE. In addition, apoE can prevent the LPS-induced production of cytokines and subsequent death in rodents. Finally, apoE-deficient mice show a significantly higher sensitivity toward LPS than control wild-type mice. These findings indicate that apoE may have a physiological role in the protection against sepsis, and recombinant apoE may be used therapeutically to protect against LPS-induced endotoxemia.