RESUMEN
There is a strong correlation between obesity and cancer. Here, we investigated the influence of IL-6 and gut microbiota of obese mice in melanoma development. We first evaluated B16F10 melanoma growth in preclinical models for obesity: mice deficient for leptin (ob/ob) or adiponectin (AdpKO) and in wild-type mice (WT, C57BL/6J) fed a high-fat diet (HFD; 60% kcal from fat) for 12 weeks. The survival rates of ob/ob and HFD-fed mice were lower than those of their respective controls. AdpKO mice also died earlier than WT control mice. We then verified the involvement of IL-6 signaling in obese mice that were inoculated with melanoma cells. Both ob/ob and AdpKO mice had higher circulating IL-6 levels than wild-type mice. Melanoma tumor volumes in IL-6 KO mice fed an HFD were reduced compared to those of WT mice subjected to the same diet. Also evaluated the effect of microbiota in tumor development. Cohousing and fecal matter transfer experiments revealed that microbiota from ob/ob mice can stimulate tumor development in lean WT mice. Taken together, our data show that in some conditions IL-6 and the gut microbiota are key mediators that link obesity and melanoma.
Asunto(s)
Microbioma Gastrointestinal , Melanoma , Animales , Dieta Alta en Grasa/efectos adversos , Interleucina-6 , Leptina , Ratones , Ratones Endogámicos C57BL , Ratones ObesosRESUMEN
Fructose consumption by rodents modulates both hepatic and intestinal lipid metabolism and gluconeogenesis. We have previously demonstrated that in utero exposure to dexamethasone (DEX) interacts with fructose consumption during adult life to exacerbate hepatic steatosis in rats. The aim of this study was to clarify if adult rats born to DEX-treated mothers would display differences in intestinal gluconeogenesis after excessive fructose intake. To address this issue, female Wistar rats were treated with DEX during pregnancy and control (CTL) mothers were kept untreated. Adult offspring born to CTL and DEX-treated mothers were assigned to receive either tap water (Control-Standard Chow (CTL-SC) and Dexamethasone-Standard Chow (DEX-SC)) or 10% fructose in the drinking water (CTL-fructose and DEX-fructose). Fructose consumption lasted for 80 days. All rats were subjected to a 40 h fasting before sample collection. We found that DEX-fructose rats have increased glucose and reduced lactate in the portal blood. Jejunum samples of DEX-fructose rats have enhanced phosphoenolpyruvate carboxykinase (PEPCK) expression and activity, higher facilitated glucose transporter member 2 (GLUT2) and facilitated glucose transporter member 5 (GLUT5) content, and increased villous height, crypt depth, and proliferating cell nuclear antigen (PCNA) staining. The current data reveal that rats born to DEX-treated mothers that consume fructose during adult life have increased intestinal gluconeogenesis while recapitulating metabolic and morphological features of the neonatal jejunum phenotype.
Asunto(s)
Dexametasona/efectos adversos , Carbohidratos de la Dieta/efectos adversos , Células Epiteliales/patología , Fructosa/efectos adversos , Gluconeogénesis , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Yeyuno/metabolismo , Exposición Materna/efectos adversos , Intercambio Materno-Fetal/fisiología , Efectos Tardíos de la Exposición Prenatal , Fenómenos Fisiológicos Nutricionales de los Animales/fisiología , Animales , Femenino , Transportador de Glucosa de Tipo 2/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metabolismo de los Lípidos , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Fosfoenolpiruvato Carboxiquinasa (GTP)/metabolismo , Embarazo , Ratas WistarRESUMEN
Distinct environmental insults might interact with fructose consumption and contribute to the development of metabolic disorders. To address whether in utero glucocorticoid exposure and fructose intake modulate metabolic responses, adult female Wistar rats were exposed to dexamethasone (DEX) during pregnancy, and the offspring were administered fructose at a later time. Briefly, dams received DEX during the third period of pregnancy, while control dams remained untreated. Offspring born to control and DEX-treated mothers were defined as CTL-off and DEX-off, respectively, while untreated animals were designated CTL-off-CTL and DEX-off-CTL. CLT-off and DEX-off treated with 10% fructose in the drinking water for 8 weeks are referred to as CTL-off-FRU and DEX-off-FRU. We found that fructose promoted glucose intolerance and whole-body gluconeogenesis in both CTL-off-FRU and DEX-off-FRU animals. On the other hand, hepatic lipid accumulation was significantly stimulated in DEX-off-FRU rats when compared to the CTL-off-FRU group. The DEX-off-FRU group also displayed impaired very-low-density lipoprotein (VLDL) production and reduced hepatic expression of apoB, mttp, and sec22b. DEX-off-FRU has lower hepatic levels of autophagy markers. Taken together, our results support the unprecedented notion that in utero glucocorticoid exposure exacerbates hepatic steatosis caused by fructose consumption later in life.
Asunto(s)
Dexametasona/toxicidad , Azúcares de la Dieta/toxicidad , Hígado Graso/inducido químicamente , Fructosa/toxicidad , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Animales , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Hígado Graso/genética , Hígado Graso/metabolismo , Hígado Graso/patología , Femenino , Edad Gestacional , Gluconeogénesis/efectos de los fármacos , Metabolismo de los Lípidos/genética , Lipoproteínas VLDL/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Embarazo , Proteínas R-SNARE/genética , Proteínas R-SNARE/metabolismo , Ratas WistarRESUMEN
INTRODUCTION: Impaired wound healing has been widely reported in diabetes. Linoleic acid (LA) accelerates the skin wound healing process in non-diabetic rats. However, LA has not been tested in diabetic animals. OBJECTIVES: We investigated whether oral administration of pure LA improves wound healing in streptozotocin-induced diabetic rats. METHODS: Dorsal wounds were induced in streptozotocin-induced type-1 diabetic rats treated or not with LA (0.22 g/kg b.w.) for 10 days. Wound closure was daily assessed for two weeks. Wound tissues were collected at specific time-points and used to measure fatty acid composition, and contents of cytokines, growth factors and eicosanoids. Histological and qPCR analyses were employed to examine the dynamics of cell migration during the healing process. RESULTS: LA reduced the wound area 14 days after wound induction. LA also increased the concentrations of cytokine-induced neutrophil chemotaxis (CINC-2αß), tumor necrosis factor-α (TNF-α) and leukotriene B4 (LTB4), and reduced the expression of macrophage chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1). These results together with the histological analysis, which showed accumulation of leukocytes in the wound early in the healing process, indicate that LA brought forward the inflammatory phase and improved wound healing in diabetic rats. Angiogenesis was induced by LA through elevation in tissue content of key mediators of this process: vascular-endothelial growth factor (VEGF) and angiopoietin-2 (ANGPT-2). CONCLUSIONS: Oral administration of LA hastened wound closure in diabetic rats by improving the inflammatory phase and angiogenesis.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Ácido Linoleico/administración & dosificación , Neovascularización Fisiológica/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Administración Oral , Angiopoyetina 2/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Citocinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Ácido Linoleico/farmacología , Ratas , Estreptozocina , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The aim of this study was to investigate whether treatment with tributyrin (Tb; a butyrate prodrug) results in protection against diet-induced obesity and associated insulin resistance. C57BL/6 male mice fed a standard chow or high-fat diet were treated with Tb (2 g/kg body wt, 10 wk) and evaluated for glucose homeostasis, plasma lipid profile, and inflammatory status. Tb protected mice against obesity and obesity-associated insulin resistance and dyslipidemia without food consumption being affected. Tb attenuated the production of TNFα and IL-1ß by peritoneal macrophages and their expression in adipose tissue. Furthermore, in the adipose tissue, Tb reduced the expression of MCP-1 and infiltration by leukocytes and restored the production of adiponectin. These effects were associated with a partial reversion of hepatic steatosis, reduction in liver and skeletal muscle content of phosphorylated JNK, and an improvement in muscle insulin-stimulated glucose uptake and Akt signaling. Although part of the beneficial effects of Tb are likely to be secondary to the reduction in body weight, we also found direct protective actions of butyrate reducing TNFα production after LPS injection and in vitro by LPS- or palmitic acid-stimulated macrophages and attenuating lipolysis in vitro and in vivo. The results, reported herein, suggest that Tb may be useful for the treatment and prevention of obesity-related metabolic disorders.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Resistencia a la Insulina , Obesidad/prevención & control , Triglicéridos/uso terapéutico , Adiponectina/biosíntesis , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Glucemia/efectos de los fármacos , Quimiocina CCL2/biosíntesis , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Interleucina-1beta/biosíntesis , Lípidos/sangre , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Obesidad/etiología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Short chain fatty acids (SCFAs) are fermentation products of anaerobic bacteria. More than just being an important energy source for intestinal epithelial cells, these compounds are modulators of leukocyte function and potential targets for the development of new drugs. The aim of this study was to evaluate the effectsof SCFAs (acetate, propionate and butyrate) on production of nitric oxide (NO) and proinflammatory cytokines [tumor necrosis factor á (TNF-á) and cytokineinduced neutrophil chemoattractant-2 (CINC-2áâ)] by rat neutrophils. The involvement of nuclear factor êB (NF-êB) and histone deacetylase (HDAC) wasexamined. The effect of butyrate was also investigated in vivo after oral administration of tributyrin (a pro-drug of butyrate). Propionate and butyrate diminished TNF-á, CINC-2áâ and NO production by LPS-stimulated neutrophils. We also observed that these fatty acids inhibit HDAC activity and NF-êB activation, which might be involved in the attenuation of the LPS response. Products of cyclooxygenase and 5-lipoxygenase are not involved in the effects of SCFAs as indicated by the results obtained with the inhibitors of these enzymes. The recruitment of neutrophils to the peritonium after intraperitoneal administration of a glycogen solution (1%) and the ex vivo production of cytokines and NO by neutrophils were attenuated in rats that previously received tributyrin. These results argue that this triglyceride may be effective in the treatment of inflammatory conditions.