RESUMEN
It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Grasos Omega-3/metabolismo , Resistencia a la Insulina/fisiología , Receptores Acoplados a Proteínas G/agonistas , Animales , Arginasa/biosíntesis , Linfocitos B Reguladores/inmunología , Secuencia de Bases , Diabetes Mellitus Tipo 2/genética , Ácidos Docosahexaenoicos/farmacología , Hígado Graso/tratamiento farmacológico , Hiperinsulinismo/tratamiento farmacológico , Inflamación , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Datos de Secuencia Molecular , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Obesidad/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Linfocitos T Reguladores/inmunologíaRESUMEN
Current knowledge of the effect of fish consumption on risk of venous thromboembolism (VTE) is scarce and diverging. Therefore, the purpose of the present study was to investigate the impact of fish consumption and fish oil supplements on the risk of VTE in a population-based cohort. Weekly intake of fish for dinner and intake of fish oil supplements during the previous year were registered in 23,621 persons aged 25-97 y who participated in the Tromsø Study from 1994 to 1995. Incident VTE events were registered throughout follow-up (31 December 2010). Cox-regression models were used to calculate HRs for VTE, adjusted for age, body mass index, sex, triglycerides, HDL cholesterol, physical activity, and education level. During a median of 15.8 y of follow-up there were 536 incident VTE events. High fish consumption was associated with a slightly reduced risk of VTE. Participants who ate fish ≥3 times/wk had 22% lower risk of VTE than those who consumed fish 1-1.9 times/wk (multivariable HR: 0.78; 95% CI: 0.60, 1.01; P = 0.06). The addition of fish oil supplements strengthened the inverse association with risk of VTE. Participants who consumed fish ≥3 times/wk who additionally used fish oil supplements had 48% lower risk than those who consumed fish 1-1.9 times/wk but did not use fish oil supplements (HR: 0.52; 95% CI: 0.34, 0.79; P = 0.002). In conclusion, a high weekly intake (≥3 times/wk) of fish was associated with a slightly reduced risk of VTE, and the addition of fish oil supplements strengthened the inverse effect.
Asunto(s)
Suplementos Dietéticos , Aceites de Pescado/administración & dosificación , Carne , Tromboembolia Venosa/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Animales , Índice de Masa Corporal , HDL-Colesterol/sangre , Ácidos Grasos Omega-3/administración & dosificación , Femenino , Peces , Estudios de Seguimiento , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Reproducibilidad de los Resultados , Factores de Riesgo , Encuestas y Cuestionarios , Suecia/epidemiología , Triglicéridos/sangre , Tromboembolia Venosa/epidemiologíaRESUMEN
Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies.
Asunto(s)
Ácidos Grasos Omega-3/metabolismo , Resistencia a la Insulina , Macrófagos/metabolismo , Co-Represor 1 de Receptor Nuclear/metabolismo , Receptores Nucleares Huérfanos/genética , Animales , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Co-Represor 1 de Receptor Nuclear/genéticaRESUMEN
Alterations in fat metabolism, in particular elevated plasma concentrations of free fatty acids and triglycerides (TG), have been implicated in the pathogenesis of Type 2 diabetes, obesity, and cardiovascular disease. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a member of the large family of membrane-bound O-acyltransferases, catalyzes the final step in triacylglycerol formation. In the intestine, DGAT1 is one of the acyltransferases responsible for the reesterficiation of dietary TG. Following a single dose of a selective pharmacological inhibitor of DGAT1, PF-04620110, a dose-dependent inhibition of TG and vitamin A absorption postprandially was demonstrated in rodents and human subjects. In C57/BL6J mice, acute DGAT1 inhibition alters the temporal and spatial pattern of dietary lipid absorption. To understand the impact of DGAT1 inhibition on enterocyte lipid metabolism, lipomic profiling was performed in rat intestine and plasma as well as human plasma. DGAT1 inhibition causes an enrichment of polyunsaturated fatty acids within the TG class of lipids. This pharmacological intervention gives us insight as to the role of DGAT1 in human dietary lipid absorption.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Absorción Intestinal/efectos de los fármacos , Oxazepinas/farmacología , Adolescente , Adulto , Animales , Estudios de Casos y Controles , Diacilglicerol O-Acetiltransferasa/genética , Diacilglicerol O-Acetiltransferasa/metabolismo , Grasas de la Dieta/sangre , Grasas de la Dieta/metabolismo , Relación Dosis-Respuesta a Droga , Enterocitos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Ácidos Grasos Insaturados/sangre , Ácidos Grasos Insaturados/metabolismo , Femenino , Humanos , Mucosa Intestinal/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Oxazepinas/farmacocinética , Periodo Posprandial , Ratas , Ratas Sprague-Dawley , Triglicéridos/sangre , Triglicéridos/metabolismo , Vitamina A/metabolismoRESUMEN
Sirt1 is a NAD(+)-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. To assess this idea, we generated Sirt1 neuron-specific knockout (SINKO) mice. On both standard chow and HFD, SINKO mice were more insulin sensitive than Sirt1(f/f) mice. Thus, SINKO mice had lower fasting insulin levels, improved glucose tolerance and insulin tolerance, and enhanced systemic insulin sensitivity during hyperinsulinemic euglycemic clamp studies. Hypothalamic insulin sensitivity of SINKO mice was also increased over controls, as assessed by hypothalamic activation of PI3K, phosphorylation of Akt and FoxO1 following systemic insulin injection. Intracerebroventricular injection of insulin led to a greater systemic effect to improve glucose tolerance and insulin sensitivity in SINKO mice compared with controls. In line with the in vivo results, insulin-induced AKT and FoxO1 phosphorylation were potentiated by inhibition of Sirt1 in a cultured hypothalamic cell line. Mechanistically, this effect was traced to a reduced effect of Sirt1 to directly deacetylate and repress IRS-1 function. The enhanced central insulin signaling in SINKO mice was accompanied by increased insulin receptor signal transduction in liver, muscle, and adipose tissue. In summary, we conclude that neuronal Sirt1 negatively regulates hypothalamic insulin signaling, leading to systemic insulin resistance. Interventions that reduce neuronal Sirt1 activity have the potential to improve systemic insulin action and limit weight gain on an obesigenic diet.
Asunto(s)
Metabolismo Energético/fisiología , Hipotálamo/metabolismo , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Sirtuina 1/metabolismo , Animales , Células Cultivadas , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Glucosa/genética , Glucosa/metabolismo , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Insulina/genética , Insulina/farmacología , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Especificidad de Órganos , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Sirtuina 1/genéticaRESUMEN
Omega-3 fatty acids (omega-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here, we show that the G protein-coupled receptor 120 (GPR120) functions as an omega-3 FA receptor/sensor. Stimulation of GPR120 with omega-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high-fat diet with or without omega-3 FA supplementation. The omega-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional omega-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation.
Asunto(s)
Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/metabolismo , Resistencia a la Insulina , Receptores Acoplados a Proteínas G/metabolismo , Células 3T3-L1 , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/metabolismo , Línea Celular , Grasas de la Dieta/metabolismo , Suplementos Dietéticos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/metabolismo , Macrófagos/inmunología , Ratones , Ratones Noqueados , Obesidad/complicaciones , Receptores Acoplados a Proteínas G/genéticaRESUMEN
Phosphatidylethanolamine-N-methyltransferase (PEMT) catalyzes the methylation of phosphatidylethanolamine to form phosphatidylcholine (PC) and represents one of the two major pathways for PC biosynthesis. Mice with a homozygous disruption of the PEMT gene are dependent on the 1,2-diacylglycerol cholinephosphotransferase (CDP-choline) pathway for the synthesis of PC and develop severe liver steatosis when fed a diet deficient in choline. The present study used quantitative lipid metabolite profiling to characterize lipid metabolism in PEMT-deficient mice fed diets containing varying concentrations of choline. Choline supplementation restored liver, but not plasma PC concentrations of PEMT-deficient mice to levels commensurate with control mice. Choline supplementation also restored plasma triglyceride concentrations to normal levels, but did not restore plasma cholesterol ester concentrations in the PEMT-deficient mice to those equal to control mice. PEMT-deficient mice also had substantially diminished concentrations of docosahexaenoic acid [22:6(n-3)] and arachidonic acid [20:4(n-6)] in plasma, independent of choline status. Thus, choline supplementation rescued some but not all of the phenotypes induced by the knockout. These findings indicate that PEMT activity functions beyond its recognized role as a compensatory pathway for PC biosynthesis and that, in contrast, PEMT activity is involved in many physiologic processes including the flux of lipid between liver and plasma and the delivery of essential fatty acids to blood and peripheral tissues via the liver-derived lipoproteins.
Asunto(s)
Colina/farmacología , Ácidos Grasos Esenciales/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Metiltransferasas/deficiencia , Metiltransferasas/metabolismo , Animales , Ésteres del Colesterol/metabolismo , Colina/administración & dosificación , Dieta , Lípidos/sangre , Hígado/efectos de los fármacos , Metiltransferasas/genética , Ratones , Ratones Noqueados , Fosfatidiletanolamina N-Metiltransferasa , Fosfolípidos/metabolismo , Triglicéridos/metabolismoRESUMEN
Foods are not purified compounds acting on single molecular targets, but complex mixtures of molecules that modulate many biochemical pathways simultaneously. Diet affects the probability of developing various diseases. Nevertheless, specific recommendations for individual diets are not simple. Recommending nutrient intakes above and beyond those needed to provide adequacy requires scientific knowledge and regulatory scrutiny to ensure the efficacy and safety even of essential nutrients. Designing a diet to improve metabolic health is a bold and ambitious goal. It is possible to design foods that will alter metabolism, but what change will make everyone who is otherwise healthy even healthier? Changing one aspect of metabolism to lower the risk of one disease does not improve overall health if it comes at the expense of disrupting another aspect of metabolism that increases the risk of another disease. This issue has: 1) frustrated nutritional recommendations that could provide benefits to the health of large subsets of the population, 2) caused the recall of drugs with many beneficial effects and 3) caused harm by implying that single nutrients/foods could be healthy for everyone. An individualized system for metabolic assessment would establish the efficacy and safety of nutrients such as amino acids or fatty acids when these are designed to be consumed at levels providing improved metabolic health. The need to document the lack of an adverse effect of a food or drug on physiology necessitates a global, i.e. metabolomic approach.