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1.
Sci Rep ; 14(1): 3077, 2024 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-38321177

RESUMEN

Overconsumption of added sugars has been pointed out as a major culprit in the increasing rates of obesity worldwide, contributing to the rising popularity of non-caloric sweeteners. In order to satisfy the growing demand, industrial efforts have been made to purify the sweet-tasting molecules found in the natural sweetener stevia, which are characterized by a sweet taste free of unpleasant aftertaste. Although the use of artificial sweeteners has raised many concerns regarding metabolic health, the impact of purified stevia components on the latter remains poorly studied. The objective of this project was to evaluate the impact of two purified sweet-tasting components of stevia, rebaudioside A and D (RebA and RebD), on the development of obesity, insulin resistance, hepatic health, bile acid profile, and gut microbiota in a mouse model of diet-induced obesity. Male C57BL/6 J mice were fed an obesogenic high-fat/high-sucrose (HFHS) diet and orally treated with 50 mg/kg of RebA, RebD or vehicle (water) for 12 weeks. An additional group of chow-fed mice treated with the vehicle was included as a healthy reference. At weeks 10 and 12, insulin and oral glucose tolerance tests were performed. Liver lipids content was analyzed. Whole-genome shotgun sequencing was performed to profile the gut microbiota. Bile acids were measured in the feces, plasma, and liver. Liver lipid content and gene expression were analyzed. As compared to the HFHS-vehicle treatment group, mice administered RebD showed a reduced weight gain, as evidenced by decreased visceral adipose tissue weight. Liver triglycerides and cholesterol from RebD-treated mice were lower and lipid peroxidation was decreased. Interestingly, administration of RebD was associated with a significant enrichment of Faecalibaculum rodentium in the gut microbiota and an increased secondary bile acid metabolism. Moreover, RebD decreased the level of lipopolysaccharide-binding protein (LBP). Neither RebA nor RebD treatments were found to impact glucose homeostasis. The daily consumption of two stevia components has no detrimental effects on metabolic health. In contrast, RebD treatment was found to reduce adiposity, alleviate hepatic steatosis and lipid peroxidation, and decrease LBP, a marker of metabolic endotoxemia in a mouse model of diet-induced obesity.


Asunto(s)
Adiposidad , Diterpenos de Tipo Kaurano , Glicósidos , Resistencia a la Insulina , Masculino , Ratones , Animales , Ratones Endogámicos C57BL , Hígado/metabolismo , Obesidad/metabolismo , Triglicéridos , Dieta Alta en Grasa , Sacarosa/metabolismo , Ácidos y Sales Biliares/metabolismo , Metabolismo de los Lípidos
2.
Nat Commun ; 13(1): 1343, 2022 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-35292630

RESUMEN

Meta-analyses suggest that yogurt consumption reduces type 2 diabetes incidence in humans, but the molecular basis of these observations remains unknown. Here we show that dietary yogurt intake preserves whole-body glucose homeostasis and prevents hepatic insulin resistance and liver steatosis in a dietary mouse model of obesity-linked type 2 diabetes. Fecal microbiota transplantation studies reveal that these effects are partly linked to the gut microbiota. We further show that yogurt intake impacts the hepatic metabolome, notably maintaining the levels of branched chain hydroxy acids (BCHA) which correlate with improved metabolic parameters. These metabolites are generated upon milk fermentation and concentrated in yogurt. Remarkably, diet-induced obesity reduces plasma and tissue BCHA levels, and this is partly prevented by dietary yogurt intake. We further show that BCHA improve insulin action on glucose metabolism in liver and muscle cells, identifying BCHA as cell-autonomous metabolic regulators and potential mediators of yogurt's health effects.


Asunto(s)
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/prevención & control , Fermentación , Hidroxiácidos/farmacología , Ratones , Ratones Obesos , Yogur
3.
Nat Commun ; 12(1): 3377, 2021 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-34099716

RESUMEN

Animal models of human diseases are classically fed purified diets that contain casein as the unique protein source. We show that provision of a mixed protein source mirroring that found in the western diet exacerbates diet-induced obesity and insulin resistance by potentiating hepatic mTORC1/S6K1 signaling as compared to casein alone. These effects involve alterations in gut microbiota as shown by fecal microbiota transplantation studies. The detrimental impact of the mixed protein source is also linked with early changes in microbial production of branched-chain fatty acids (BCFA) and elevated plasma and hepatic acylcarnitines, indicative of aberrant mitochondrial fatty acid oxidation. We further show that the BCFA, isobutyric and isovaleric acid, increase glucose production and activate mTORC1/S6K1 in hepatocytes. Our findings demonstrate that alteration of dietary protein source exerts a rapid and robust impact on gut microbiota and BCFA with significant consequences for the development of obesity and insulin resistance.


Asunto(s)
Proteínas en la Dieta/efectos adversos , Ácidos Grasos/metabolismo , Microbioma Gastrointestinal/fisiología , Resistencia a la Insulina , Obesidad/etiología , Alimentación Animal/efectos adversos , Animales , Línea Celular Tumoral , Dieta Alta en Grasa/efectos adversos , Dieta Occidental/efectos adversos , Sacarosa en la Dieta/efectos adversos , Modelos Animales de Enfermedad , Trasplante de Microbiota Fecal , Vida Libre de Gérmenes , Gluconeogénesis , Hepatocitos , Humanos , Hígado/metabolismo , Hígado/patología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Obesidad/metabolismo , Obesidad/patología , Ratas , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Transducción de Señal
4.
Am J Physiol Gastrointest Liver Physiol ; 320(6): G1014-G1033, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33881354

RESUMEN

Selecting the most relevant control diet is of critical importance for metabolic and intestinal studies in animal models. Chow and LF-purified diet differentially impact metabolic and gut microbiome outcomes resulting in major changes in intestinal integrity in LF-fed animals which contributes to altering metabolic homeostasis. Dietary fat and low fiber both contribute to the deleterious metabolic effect of purified HF diets through both selective and overlapping mechanisms.


Asunto(s)
Dieta , Grasas de la Dieta , Fibras de la Dieta , Tracto Gastrointestinal/metabolismo , Hígado/metabolismo , Obesidad/metabolismo , Alimentación Animal , Animales , Ácidos y Sales Biliares/metabolismo , Microbioma Gastrointestinal/fisiología , Resistencia a la Insulina/fisiología , Masculino , Ratones
5.
Nutrients ; 12(11)2020 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-33105775

RESUMEN

The search for bioactive compounds from enzymatic hydrolysates has increased in the last few decades. Fish by-products have been shown to be rich in these valuable molecules; for instance, herring milt is a complex matrix composed of lipids, nucleotides, minerals, and proteins. However, limited information is available on the potential health benefits of this by-product. In this context, three industrial products containing herring milt hydrolysate (HMH) were tested in both animal and cellular models to measure their effects on obesity-related metabolic disorders. Male C57Bl/6J mice were fed either a control chow diet or a high-fat high-sucrose (HFHS) diet for 8 weeks and received either the vehicle (water) or one of the three HMH products (HMH1, HMH2, and HMH3) at a dose of 208.8 mg/kg (representing 1 g/day for a human) by daily oral gavage. The impact of HMH treatments on insulin and glucose tolerance, lipid homeostasis, liver gene expression, and the gut microbiota profile was studied. In parallel, the effects of HMH on glucose uptake and inflammation were studied in L6 myocytes and J774 macrophages, respectively. In vivo, daily treatment with HMH2 and HMH3 improved early time point glycemia during the oral glucose tolerance test (OGTT) induced by the HFHS diet, without changes in weight gain and insulin secretion. Interestingly, we also observed that HMH2 consumption partially prevented a lower abundance of Lactobacillus species in the gut microbiota of HFHS diet-fed animals. In addition to this, modulations of gene expression in the liver, such as the upregulation of sucrose nonfermenting AMPK-related kinase (SNARK), were reported for the first time in mice treated with HMH products. While HMH2 and HMH3 inhibited inducible nitric oxide synthase (iNOS) induction in J774 macrophages, glucose uptake was not modified in L6 muscle cells. These results indicate that milt herring hydrolysates reduce some metabolic and inflammatory alterations in cellular and animal models, suggesting a possible novel marine ingredient to help fight against obesity-related immunometabolic disorders.


Asunto(s)
Productos Pesqueros , Intolerancia a la Glucosa/dietoterapia , Inflamación , Macrófagos/inmunología , Obesidad/complicaciones , Animales , Glucemia/metabolismo , Línea Celular , Dieta de Carga de Carbohidratos , Dieta Alta en Grasa , Sacarosa en la Dieta/administración & dosificación , Microbioma Gastrointestinal , Glucosa/metabolismo , Intolerancia a la Glucosa/etiología , Prueba de Tolerancia a la Glucosa , Insulina/metabolismo , Hígado/metabolismo , Activación de Macrófagos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células Musculares/metabolismo , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , RNA-Seq
6.
J Dev Orig Health Dis ; 11(4): 427-437, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-31525320

RESUMEN

Prenatal exposure to persistent organic pollutants (POPs) has been associated with the development of metabolic syndrome-related diseases in offspring. According to epidemiological studies, father's transmission of environmental effects in addition to mother's can influence offspring health. Moreover, maternal prenatal dietary folic acid (FA) may beneficially impact offspring health. The objective is to investigate whether prenatal FA supplementation can overcome the deleterious effects of prenatal exposure to POPs on lipid homeostasis and inflammation in three generations of male rat descendants through the paternal lineage. Female Sprague-Dawley rats (F0) were exposed to a POPs mixture (or corn oil) +/- FA supplementation for 9 weeks before and during gestation. F1 and F2 males were mated with untreated females. Plasma and hepatic lipids were measured in F1, F2, and F3 males after 12-h fast. Gene expression of inflammatory cytokines was determined by qPCR in epididymal adipose tissue. In F1 males, prenatal POPs exposure increased plasma lipids at 14 weeks old and hepatic lipids at 28 weeks old and prenatal FA supplementation decreased plasma total cholesterol at 14 weeks old. Prenatal POPs exposure decreased plasma triglycerides at 14 weeks old in F2 males. No change was observed in inflammatory markers. Our results show an impact of the paternal lineage on lipid homeostasis in rats up to the F2 male generation. FA supplementation of the F0 diet, regardless of POPs exposure, lowered plasma cholesterol in F1 males but failed to attenuate the deleterious effects of prenatal POPs exposure on plasma and hepatic lipids in F1 males.


Asunto(s)
Suplementos Dietéticos , Contaminantes Ambientales/toxicidad , Ácido Fólico/administración & dosificación , Inflamación/patología , Lípidos/análisis , Exposición Materna/efectos adversos , Efectos Tardíos de la Exposición Prenatal/patología , Animales , Animales Recién Nacidos , Femenino , Homeostasis , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley
7.
Nat Med ; 20(6): 664-9, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24813250

RESUMEN

We previously demonstrated that low biosynthesis of ω-3 fatty acid-derived proresolution mediators, termed protectins, is associated with an impaired global resolution capacity, inflammation and insulin resistance in obese high-fat diet-fed mice. These findings prompted a more direct study of the therapeutic potential of protectins for the treatment of metabolic disorders. Herein we show that protectin DX (PDX) exerts an unanticipated glucoregulatory activity that is distinct from its anti-inflammatory actions. We found that PDX selectively stimulated the release of the prototypic myokine interleukin-6 (IL-6) from skeletal muscle and thereby initiated a myokine-liver signaling axis, which blunted hepatic glucose production via signal transducer and activator of transcription 3 (STAT3)-mediated transcriptional suppression of the gluconeogenic program. These effects of PDX were abrogated in Il6-null mice. PDX also activated AMP-activated protein kinase (AMPK); however, it did so in an IL-6-independent manner. Notably, we demonstrated that administration of PDX to obese diabetic db/db mice raises skeletal muscle IL-6 levels and substantially improves their insulin sensitivity without any impact on adipose tissue inflammation. Our findings thus support the development of PDX-based selective muscle IL-6 secretagogues as a new class of therapy for the treatment of insulin resistance and type 2 diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Docosahexaenoicos/farmacología , Resistencia a la Insulina/fisiología , Interleucina-6/metabolismo , Hígado/metabolismo , Músculo Esquelético/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Etanol/administración & dosificación , Técnica de Clampeo de la Glucosa , Lípidos/administración & dosificación , Ratones , Ratones Endogámicos C57BL
8.
PLoS One ; 8(12): e81870, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24339975

RESUMEN

Modulation of mitochondrial function through inhibiting respiratory complex I activates a key sensor of cellular energy status, the 5'-AMP-activated protein kinase (AMPK). Activation of AMPK results in the mobilization of nutrient uptake and catabolism for mitochondrial ATP generation to restore energy homeostasis. How these nutrient pathways are affected in the presence of a potent modulator of mitochondrial function and the role of AMPK activation in these effects remain unclear. We have identified a molecule, named R419, that activates AMPK in vitro via complex I inhibition at much lower concentrations than metformin (IC50 100 nM vs 27 mM, respectively). R419 potently increased myocyte glucose uptake that was dependent on AMPK activation, while its ability to suppress hepatic glucose production in vitro was not. In addition, R419 treatment of mouse primary hepatocytes increased fatty acid oxidation and inhibited lipogenesis in an AMPK-dependent fashion. We have performed an extensive metabolic characterization of its effects in the db/db mouse diabetes model. In vivo metabolite profiling of R419-treated db/db mice showed a clear upregulation of fatty acid oxidation and catabolism of branched chain amino acids. Additionally, analyses performed using both (13)C-palmitate and (13)C-glucose tracers revealed that R419 induces complete oxidation of both glucose and palmitate to CO2 in skeletal muscle, liver, and adipose tissue, confirming that the compound increases mitochondrial function in vivo. Taken together, our results show that R419 is a potent inhibitor of complex I and modulates mitochondrial function in vitro and in diabetic animals in vivo. R419 may serve as a valuable molecular tool for investigating the impact of modulating mitochondrial function on nutrient metabolism in multiple tissues and on glucose and lipid homeostasis in diabetic animal models.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Experimental/metabolismo , Mitocondrias Hepáticas/metabolismo , Células Musculares/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , Animales , Diabetes Mellitus Experimental/patología , Activación Enzimática/efectos de los fármacos , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Células Hep G2 , Humanos , Hipoglucemiantes/farmacología , Metformina/farmacología , Ratones , Mitocondrias Hepáticas/patología , Células Musculares/patología , Oxidación-Reducción/efectos de los fármacos , Palmitatos/farmacología , Inhibidores de Proteínas Quinasas/farmacología
9.
Physiol Genomics ; 40(3): 189-94, 2010 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-19952281

RESUMEN

Numerous studies have demonstrated the beneficial effects of fish consumption on inflammatory markers. Until now, these beneficial effects of fish consumption have been mostly linked to the omega-3 fatty acids (FA). The objective of the present study was to examine, in vitro, whether expression levels of genes involved in the inflammatory response differ in human macrophages incubated with casein hydrolysates (CH) or fish protein hydrolysates (FPH) in the presence or absence of omega-3 FA compared with omega-3 FA alone. Peripheral blood monocytes differentiated into macrophages from 10 men were incubated in the presence of omega-3 FA (10 microM eicosapentaenoic acid and 5 microM docosahexaenoic acid) or CH or FPH (10, 100, 1,000 microg) with or without omega-3 FA for 48 h. Results demonstrate that expression levels of tumor necrosis factoralpha (TNFalpha) had a tendency to be lower after the addition of FPH alone or CH with omega-3 FA compared with omega-3 FA treatment. Furthermore, the combination of FPH and omega-3 FA synergistically decreased expression levels of TNFalpha compared to treatment with omega-3 FA or FPH alone. No difference on gene expression levels of interleukin-6 was observed between treatments. In conclusion, these preliminary results suggest that the anti-inflammatory effects of fish consumption can be explained by a synergistic effect of the omega-3 FA with the protein components of fish on TNFalpha expression and therefore contribute to the beneficial effects of fish consumption. Hence, follow-up studies should be performed to confirm the effects of a diet rich in FPH and omega-3 FA on serum proinflammatory cytokine concentrations.


Asunto(s)
Aceites de Pescado/farmacología , Macrófagos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adulto , Humanos , Macrófagos/efectos de los fármacos , Masculino
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