RESUMEN
High fat diets (HFDs) have been linked to several diseases including obesity, diabetes, fatty liver, inflammatory bowel disease (IBD) and colon cancer. In this study, we examined the impact on intestinal gene expression of three isocaloric HFDs that differed only in their fatty acid composition-coconut oil (saturated fats), conventional soybean oil (polyunsaturated fats) and a genetically modified soybean oil (monounsaturated fats). Four functionally distinct segments of the mouse intestinal tract were analyzed using RNA-seq-duodenum, jejunum, terminal ileum and proximal colon. We found considerable dysregulation of genes in multiple tissues with the different diets, including those encoding nuclear receptors and genes involved in xenobiotic and drug metabolism, epithelial barrier function, IBD and colon cancer as well as genes associated with the microbiome and COVID-19. Network analysis shows that genes involved in metabolism tend to be upregulated by the HFDs while genes related to the immune system are downregulated; neurotransmitter signaling was also dysregulated by the HFDs. Genomic sequencing also revealed a microbiome altered by the HFDs. This study highlights the potential impact of different HFDs on gut health with implications for the organism as a whole and will serve as a reference for gene expression along the length of the intestines.
Asunto(s)
Neoplasias del Colon , Enfermedades Inflamatorias del Intestino , Microbiota , Animales , Ratones , Dieta Alta en Grasa/efectos adversos , Aceite de Soja , Grasas de la Dieta/farmacología , Grasas de la Dieta/metabolismo , Ácidos Grasos , Íleon/metabolismo , Expresión GénicaRESUMEN
Inflammatory bowel disease (IBD) is a multifactorial disease with increasing incidence in the U.S. suggesting that environmental factors, including diet, are involved. It has been suggested that excessive consumption of linoleic acid (LA, C18:2 omega-6), which must be obtained from the diet, may promote the development of IBD in humans. To demonstrate a causal link between LA and IBD, we show that a high fat diet (HFD) based on soybean oil (SO), which is comprised of ~55% LA, increases susceptibility to colitis in several models, including IBD-susceptible IL10 knockout mice. This effect was not observed with low-LA HFDs derived from genetically modified soybean oil or olive oil. The conventional SO HFD causes classical IBD symptoms including immune dysfunction, increased intestinal epithelial barrier permeability, and disruption of the balance of isoforms from the IBD susceptibility gene Hepatocyte Nuclear Factor 4α (HNF4α). The SO HFD causes gut dysbiosis, including increased abundance of an endogenous adherent invasive Escherichia coli (AIEC), which can use LA as a carbon source. Metabolomic analysis shows that in the mouse gut, even in the absence of bacteria, the presence of soybean oil increases levels of LA, oxylipins and prostaglandins. Many compounds in the endocannabinoid system, which are protective against IBD, are decreased by SO both in vivo and in vitro. These results indicate that a high LA diet increases susceptibility to colitis via microbial and host-initiated pathways involving alterations in the balance of bioactive metabolites of omega-6 and omega-3 polyunsaturated fatty acids, as well as HNF4α isoforms.
Asunto(s)
Colitis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Humanos , Ratones , Animales , Endocannabinoides , Aceite de Soja , Ácido Linoleico , Colitis/inducido químicamente , Colitis/genética , Colitis/microbiología , Dieta Alta en Grasa/efectos adversosRESUMEN
Polybrominated diphenyl ethers (PBDEs) are a class of flame-retardant organohalogen pollutants that act as endocrine/neuroendocrine disrupting chemicals (EDCs). In humans, exposure to brominated flame retardants (BFR) or other environmentally persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and novel organophosphate flame retardants has been associated with increasing trends of diabetes and metabolic disease. However, the effects of PBDEs on metabolic processes and their associated sex-dependent features are poorly understood. The metabolic-disrupting effects of perinatal exposure to industrial penta-PBDE mixture, DE-71, on male and female progeny of C57BL/6N mouse dams were examined in adulthood. Dams were exposed to environmentally relevant doses of PBDEs daily for 10 weeks (p.o.): 0.1 (L-DE-71) and 0.4 mg/kg/d (H-DE-71) and offspring parameters were compared to corn oil vehicle controls (VEH/CON). The following lipid metabolism indices were measured: plasma cholesterol, triglycerides, adiponectin, leptin, and liver lipids. L-DE-71 female offspring were particularly affected, showing hypercholesterolemia, elevated liver lipids and fasting plasma leptin as compared to same-sex VEH/CON, while L- and H-DE-71 male F1 only showed reduced plasma adiponectin. Using the quantitative Folch method, we found that mean liver lipid content was significantly elevated in L-DE-71 female offspring compared to controls. Oil Red O staining revealed fatty liver in female offspring and dams. General measures of adiposity, body weight, white and brown adipose tissue (BAT), and lean and fat mass were weighed or measured using EchoMRI. DE-71 did not produce abnormal adiposity, but decreased BAT depots in L-DE-71 females and males relative to same-sex VEH/CON. To begin to address potential central mechanisms of deregulated lipid metabolism, we used RT-qPCR to quantitate expression of hypothalamic genes in energy-regulating circuits that control lipid homeostasis. Both doses of DE-71 sex-dependently downregulated hypothalamic expression of Lepr, Stat3, Mc4r, Agrp, Gshr in female offspring while H-DE-71 downregulated Npy in exposed females relative to VEH/CON. In contrast, exposed male offspring displayed upregulated Stat3 and Mc4r. Intestinal barrier integrity was measured using FITC-dextran since it can lead to systemic inflammation that leads to liver damage and metabolic disease, but was not affected by DE-71 exposure. These findings indicate that maternal transfer of PBDEs disproportionately endangers female offspring to lipid metabolic reprogramming that may exaggerate risk for adult metabolic disease.
Asunto(s)
Disruptores Endocrinos , Contaminantes Ambientales , Retardadores de Llama , Bifenilos Policlorados , Animales , Femenino , Masculino , Ratones , Embarazo , Adiponectina , Proteína Relacionada con Agouti , Colesterol , Aceite de Maíz , Disruptores Endocrinos/toxicidad , Contaminantes Ambientales/toxicidad , Retardadores de Llama/toxicidad , Éteres Difenilos Halogenados/toxicidad , Homeostasis , Leptina , Ratones Endogámicos C57BL , Organofosfatos , Contaminantes Orgánicos Persistentes , Triglicéridos , Factores SexualesRESUMEN
Soybean oil consumption has increased greatly in the past half-century and is linked to obesity and diabetes. To test the hypothesis that soybean oil diet alters hypothalamic gene expression in conjunction with metabolic phenotype, we performed RNA sequencing analysis using male mice fed isocaloric, high-fat diets based on conventional soybean oil (high in linoleic acid, LA), a genetically modified, low-LA soybean oil (Plenish), and coconut oil (high in saturated fat, containing no LA). The 2 soybean oil diets had similar but nonidentical effects on the hypothalamic transcriptome, whereas the coconut oil diet had a negligible effect compared to a low-fat control diet. Dysregulated genes were associated with inflammation, neuroendocrine, neurochemical, and insulin signaling. Oxt was the only gene with metabolic, inflammation, and neurological relevance upregulated by both soybean oil diets compared to both control diets. Oxytocin immunoreactivity in the supraoptic and paraventricular nuclei of the hypothalamus was reduced, whereas plasma oxytocin and hypothalamic Oxt were increased. These central and peripheral effects of soybean oil diets were correlated with glucose intolerance but not body weight. Alterations in hypothalamic Oxt and plasma oxytocin were not observed in the coconut oil diet enriched in stigmasterol, a phytosterol found in soybean oil. We postulate that neither stigmasterol nor LA is responsible for effects of soybean oil diets on oxytocin and that Oxt messenger RNA levels could be associated with the diabetic state. Given the ubiquitous presence of soybean oil in the American diet, its observed effects on hypothalamic gene expression could have important public health ramifications.
Asunto(s)
Diabetes Mellitus/etiología , Expresión Génica/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Oxitocina/sangre , Aceite de Soja/efectos adversos , Animales , Inflamación/etiología , Ácido Linoleico/efectos adversos , Masculino , Ratones , Enfermedades del Sistema Nervioso/etiología , Obesidad/etiología , Estigmasterol/efectos adversosRESUMEN
Dimethylsulfoxide (DMSO) is widely used as a solvent and cryopreservative in laboratories and considered to have many beneficial health effects in humans. Oxylipins are a class of biologically active metabolites of polyunsaturated fatty acids (PUFAs) that have been linked to a number of diseases. In this study, we investigated the effect of DMSO on oxylipin levels in mouse liver. Liver tissue from male mice (C57Bl6/N) that were either untreated or injected with 1% DMSO at 18 weeks of age was analyzed for oxylipin levels using ultrahigh performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). A decrease in oxylipin diols from linoleic acid (LA, C18:2n6), alpha-linolenic acid (ALA, C18:3n3) and docosahexeanoic acid (DHA, C22:6n3) was observed 2 h after injection with DMSO. In contrast, DMSO had no effect on the epoxide precursors or other oxylipins including those derived from arachidonic acid (C20:4n6) or eicosapentaenoic acid (EPA, C20:5n3). It also did not significantly affect the diol:epoxide ratio, suggesting a pathway distinct from, and potentially complementary to, soluble epoxide hydrolase inhibitors (sEHI). Since oxylipins have been associated with a wide array of pathological conditions, from arthritis pain to obesity, our results suggest one potential mechanism underlying the apparent beneficial health effects of DMSO. They also indicate that caution should be used in the interpretation of results using DMSO as a vehicle in animal experiments.
RESUMEN
Soybean oil consumption is increasing worldwide and parallels a rise in obesity. Rich in unsaturated fats, especially linoleic acid, soybean oil is assumed to be healthy, and yet it induces obesity, diabetes, insulin resistance, and fatty liver in mice. Here, we show that the genetically modified soybean oil Plenish, which came on the U.S. market in 2014 and is low in linoleic acid, induces less obesity than conventional soybean oil in C57BL/6 male mice. Proteomic analysis of the liver reveals global differences in hepatic proteins when comparing diets rich in the two soybean oils, coconut oil, and a low-fat diet. Metabolomic analysis of the liver and plasma shows a positive correlation between obesity and hepatic C18 oxylipin metabolites of omega-6 (ω6) and omega-3 (ω3) fatty acids (linoleic and α-linolenic acid, respectively) in the cytochrome P450/soluble epoxide hydrolase pathway. While Plenish induced less insulin resistance than conventional soybean oil, it resulted in hepatomegaly and liver dysfunction as did olive oil, which has a similar fatty acid composition. These results implicate a new class of compounds in diet-induced obesity-C18 epoxide and diol oxylipins.
Asunto(s)
Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-6/metabolismo , Hepatomegalia/etiología , Obesidad/etiología , Oxilipinas/metabolismo , Aceite de Soja/efectos adversos , Animales , Aceite de Coco/administración & dosificación , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Dieta con Restricción de Grasas/métodos , Grasas de la Dieta/efectos adversos , Ácidos Grasos Omega-3/clasificación , Ácidos Grasos Omega-6/clasificación , Perfilación de la Expresión Génica , Hepatomegalia/genética , Hepatomegalia/metabolismo , Hepatomegalia/patología , Resistencia a la Insulina , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Metaboloma/genética , Ratones , Ratones Endogámicos C57BL , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Oxilipinas/clasificación , Proteoma/genética , Proteoma/metabolismoRESUMEN
The obesity epidemic in the U.S. has led to extensive research into potential contributing dietary factors, especially fat and fructose. Recently, increased consumption of soybean oil, which is rich in polyunsaturated fatty acids (PUFAs), has been proposed to play a causal role in the epidemic. Here, we designed a series of four isocaloric diets (HFD, SO-HFD, F-HFD, F-SO-HFD) to investigate the effects of saturated versus unsaturated fat, as well as fructose, on obesity and diabetes. C57/BL6 male mice fed a diet moderately high in fat from coconut oil and soybean oil (SO-HFD, 40% kcal total fat) showed statistically significant increases in weight gain, adiposity, diabetes, glucose intolerance and insulin resistance compared to mice on a diet consisting primarily of coconut oil (HFD). They also had fatty livers with hepatocyte ballooning and very large lipid droplets as well as shorter colonic crypt length. While the high fructose diet (F-HFD) did not cause as much obesity or diabetes as SO-HFD, it did cause rectal prolapse and a very fatty liver, but no balloon injury. The coconut oil diet (with or without fructose) increased spleen weight while fructose in the presence of soybean oil increased kidney weight. Metabolomics analysis of the liver showed an increased accumulation of PUFAs and their metabolites as well as γ-tocopherol, but a decrease in cholesterol in SO-HFD. Liver transcriptomics analysis revealed a global dysregulation of cytochrome P450 (Cyp) genes in SO-HFD versus HFD livers, most notably in the Cyp3a and Cyp2c families. Other genes involved in obesity (e.g., Cidec, Cd36), diabetes (Igfbp1), inflammation (Cd63), mitochondrial function (Pdk4) and cancer (H19) were also upregulated by the soybean oil diet. Taken together, our results indicate that in mice a diet high in soybean oil is more detrimental to metabolic health than a diet high in fructose or coconut oil.