Nonalcoholic fatty liver disease (NAFLD), often associated with obesity, is becoming one of the most common liver diseases worldwide. It is estimated to affect one billion individuals and may be ...present in approximately 25% of the population globally. NAFLD is viewed as a hepatic manifestation of metabolic syndrome, with humans and animal models presenting dyslipidemia, hypertension, and diabetes. The gut-liver axis has been considered the main pathogenesis branch for NAFLD development. Considering that foods or beverages could modulate the gastrointestinal tract, immune system, energy homeostasis regulation, and even the gut-liver axis, we conducted an exploratory study to analyze the effects of kombucha probiotic on hepatic steatosis, glucose tolerance, and hepatic enzymes involved in carbohydrate and fat metabolism using a pre-clinical model. The diet-induced obese mice presented glucose intolerance, hyperinsulinemia, hepatic steatosis, increased collagen fiber deposition in liver vascular spaces, and upregulated TNF-alpha and SREBP-1 gene expression. Mice receiving the kombucha supplement displayed improved glucose tolerance, reduced hyperinsulinemia, decreased citrate synthase and phosphofructokinase-1 enzyme activities, downregulated G-protein-coupled bile acid receptor, also known as TGR5, and farnesol X receptor gene expression, and attenuated steatosis and hepatic collagen fiber deposition. The improvement in glucose tolerance was accompanied by the recovery of acute insulin-induced liver AKT serine phosphorylation. Thus, it is possible to conclude that this probiotic drink has a beneficial effect in reducing the metabolic alterations associated with diet-induced obesity. This probiotic beverage deserves an extension of studies to confirm or refute its potentially beneficial effects.
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•Gut-liver axis is involved in the pathogenesis for NAFLD development.•Prebiotics and probiotics modulate the intestinal microbiota.•Kombucha tea can attenuate NAFLD and improve glycemic parameters in obese mice.•Inflammatory targets were reduced with kombucha tea supplementation.•Potential link between fermented tea and gut microbiota dysbiosis.
Smoking has been associated with renal disease progression in ADPKD but the underlying deleterious mechanisms and whether it specifically worsens the cardiac phenotype remain unknown. To investigate ...these matters, Pkd1-deficient cystic mice and noncystic littermates were exposed to smoking from conception to 18 weeks of age and, along with nonexposed controls, were analyzed at 13-18 weeks. Renal cystic index and cyst-lining cell proliferation were higher in cystic mice exposed to smoking than nonexposed cystic animals. Smoking increased serum urea nitrogen in cystic and noncystic mice and independently enhanced tubular cell proliferation and apoptosis. Smoking also increased renal fibrosis, however this effect was much higher in cystic than in noncystic animals. Pkd1 deficiency and smoking showed independent and additive effects on reducing renal levels of glutathione. Systolic function and several cardiac structural parameters were also negatively affected by smoking and the Pkd1-deficient status, following independent and additive patterns. Smoking did not increase, however, cardiac apoptosis or fibrosis in cystic and noncystic mice. Notably, smoking promoted a much higher reduction in body weight in Pkd1-deficient than in noncystic animals. Our findings show that smoking aggravated the renal and cardiac phenotypes of Pkd1-deficient cystic mice, suggesting that similar effects may occur in human ADPKD.
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•The Novel Nutraceutical supplement recovers gut epithelium morpho-histology.•The supplementation increases gut microbiota diversity in high-fat-diet ...dysbiosis.•Firmicutes/Bacteroidetes ratio increased by the Novel Nutraceutical supplement.•The supplementation restores gut epithelium without Akkermansia genus interaction.
Gut dysbiosis contributes to chronic inflammation and oxidative stress associated with metabolic syndrome, and non-pharmacological, health-promoting supplements like nutraceuticals have been studied and used as a way to prevent or treat several illnesses. Thus, male C57BL/6 mice were divided into the following groups: control (CTL)_Vehicle and CTL_Nutraceutical; high-fat diet (HFD)_Vehicle, HFD_Nutraceutical, HFD_Nutraceutical_S, and isolated compounds. The vehicle and experimental formulations were administered by gavage once a day for four weeks with a high-fat diet simultaneously. In addition, we evaluated the composition of the fecal microbiota by partial 16S rRNA sequences directly amplified using a bacterial/archaeal primer set 515F/806R, and large intestine histomorphology was examined by H&E (Hematoxylin and Eosin), Masson's trichrome (MT), and PAS-AB (Periodic Acid Schiff-Alcian Blue) stains in these groups of mice. After four weeks of supplementation, only the Novel Nutraceutical supplement was able to increase α and β-diversities, modulate the relative abundance in gut microbiota, decrease Firmicutes, and increase Bacteroidetes bacteria, meanwhile recovering the large intestine’s (colon) histomorphology in CTL and HFD groups.
Pathological cardiac hypertrophy leads to derangements in lipid metabolism that may contribute to the development of cardiac dysfunction. Since previous studies, using high saturated fat diets, have ...yielded inconclusive results, we investigated whether provision of a high-unsaturated fatty acid (HUFA) diet was sufficient to restore impaired lipid metabolism and normalize diastolic dysfunction in the pathologically hypertrophied heart. Male, Wistar rats were subjected to supra-valvar aortic stenosis (SVAS) or sham surgery. After 6 weeks, diastolic dysfunction and pathological hypertrophy was confirmed and both sham and SVAS rats were treated with either normolipidic or HUFA diet. At 18 weeks post-surgery, the HUFA diet failed to normalize decreased E/A ratios or attenuate measures of cardiac hypertrophy in SVAS animals. Enzymatic activity assays and gene expression analysis showed that both normolipidic and HUFA-fed hypertrophied hearts had similar increases in glycolytic enzyme activity and down-regulation of fatty acid oxidation genes. Mass spectrometry analysis revealed depletion of unsaturated fatty acids, primarily linoleate and oleate, within the endogenous lipid pools of normolipidic SVAS hearts. The HUFA diet did not restore linoleate or oleate in the cardiac lipid pools, but did maintain body weight and adipose mass in SVAS animals. Overall, these results suggest that, in addition to decreased fatty acid oxidation, aberrant unsaturated fatty acid metabolism may be a maladaptive signature of the pathologically hypertrophied heart. The HUFA diet is insufficient to reverse metabolic remodeling, diastolic dysfunction, or pathologically hypertrophy, possibly do to preferentially partitioning of unsaturated fatty acids to adipose tissue.
Trypanosoma cruzi, the parasite causing Chagas disease, is a digenetic flagellated protist that infects mammals (including humans) and reduviid insect vectors. Therefore, T. cruzi must colonize ...different niches in order to complete its life cycle in both hosts. This fact determines the need of adaptations to face challenging environmental cues. The primary environmental challenge, particularly in the insect stages, is poor nutrient availability. In this regard, it is well known that T. cruzi has a flexible metabolism able to rapidly switch from carbohydrates (mainly glucose) to amino acids (mostly proline) consumption. Also established has been the capability of T. cruzi to use glucose and amino acids to support the differentiation process occurring in the insect, from replicative non-infective epimastigotes to non-replicative infective metacyclic trypomastigotes. However, little is known about the possibilities of using externally available and internally stored fatty acids as resources to survive in nutrient-poor environments, and to sustain metacyclogenesis. In this study, we revisit the metabolic fate of fatty acid breakdown in T. cruzi. Herein, we show that during parasite proliferation, the glucose concentration in the medium can regulate the fatty acid metabolism. At the stationary phase, the parasites fully oxidize fatty acids. U-14C-palmitate can be taken up from the medium, leading to CO2 production. Additionally, we show that electrons are fed directly to oxidative phosphorylation, and acetyl-CoA is supplied to the tricarboxylic acid (TCA) cycle, which can be used to feed anabolic pathways such as the de novo biosynthesis of fatty acids. Finally, we show as well that the inhibition of fatty acids mobilization into the mitochondrion diminishes the survival to severe starvation, and impairs metacyclogenesis.
We investigated the effect of the crude herbal extract from Uncaria tomentosa (UT) on non-alcoholic fatty liver disease (NAFLD) in two models of obesity: high fat diet (HFD) and genetically obese ...(ob/ob) mice. Both obese mouse models were insulin resistant and exhibited an abundance of lipid droplets in the hepatocytes and inflammatory cell infiltration in the liver, while only the HFD group had collagen deposition in the perivascular space of the liver. UT treatment significantly reduced liver steatosis and inflammation in both obese mouse models. Furthermore, serine phosphorylation of IRS-1 was reduced by 25% in the HFD mice treated with UT. Overall, UT treated animals exhibited higher insulin sensitivity as compared to vehicle administration. In conclusion, Uncaria tomentosa extract improved glucose homeostasis and reverted NAFLD to a benign hepatic steatosis condition and these effects were associated with the attenuation of liver inflammation in obese mice.
Lifestyle and increased consumption of high fat diets contribute greatly to the development of obesity, insulin resistance, type 2 diabetes (DM2), and cardiovascular diseases, which are less ...prevalent in young women than in men of the same age or postmenopausal women. One of the consequences of the Western lifestyle and high fat diet is Nonalcoholic Fatty Liver Disease (NAFLD) and its aggressive form, Nonalcoholic Steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular cancer (HCC) and is rapidly becoming the leading cause for end-stage liver disease or liver transplantation. Therefore, we evaluated if female mice were protected against Western Diet (WD)-induced NASH in apolipoprotein E (ApoE) KO animals. Female ApoE KO mice ovariectomized (OVX) or sham operated (SHAM) were fed a WD for 7 weeks. Whole-body fat was increased by ∼65% (P<0.001) in OVX mice associated with an increase of glucose intolerance of by ∼75% (P<0.01) and increased hepatic triglycerides (TAG) by 130% (P<0.01) compared with SHAM mice. OVX mice also displayed increased plasma ALT (∼130, P<0.001) and AST (∼65%, P<0.05) compared with SHAM mice. These data were associated with increased hepatic inflammation in OVX mice, demonstrated by an increased of F4/80 of by ∼70% (P<0.01). Hepatic fibrosis was also increased in OVX mice by ∼80% (P<0.001) compared with SHAM mice. Estradiol treatment of OVX mice reversed some of these effects, reducing whole-body fat (P<0.01), glucose intolerance (P<0.01), and hepatic TAG content (P<0.001). Taken together, these data support the hypothesis that estradiol protects OVX mice from WD-induced NASH and glucose intolerance, by protecting female mice against hepatic steatosis, inflammation and fibrosis.
Disclosure
G.V. Moreira: None. S.L. Matos: None. F.N. Camargo: None. L. Araujo: None. G.M. Murata: None. C.R.O. Carvalho: None. J. Camporez: None.
Funding
Fundação de Amparo a Pesquisa do Estado de São Paulo (2018/04956-5)
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.
The effect of fenofibrate on the metabolism of skeletal muscle and visceral white adipose tissue of diet‐induced obese (DIO) mice was investigated. C57BL/6J male mice were fed either a control or ...high‐fat diet for 8 weeks. Fenofibrate (50 mg/Kg BW, daily) was administered by oral gavage during the last two weeks of the experimental period. Insulin‐stimulated glucose metabolism in soleus muscles, glucose tolerance test, insulin tolerance test, indirect calorimetry, lipolysis of visceral white adipose tissue, expression of miR‐103‐3p in adipose tissue, and miR‐1a, miR‐133a/b, miR‐206, let7b‐5p, miR‐23b‐3p, miR‐29‐3p, miR‐143‐3p in soleus muscle, genes related to glucose and fatty acid metabolism in adipose tissue and soleus muscle, and proteins (phospho‐AMPKα2, Pgc1α, Cpt1b), intramuscular lipid staining, and activities of fatty acid oxidation enzymes in skeletal muscle were investigated. In DIO mice, fenofibrate prevented weight gain induced by HFD feeding by increasing energy expenditure; improved whole body glucose homeostasis, and in skeletal muscle, increased insulin dependent glucose uptake, miR‐1a levels, reduced intramuscular lipid accumulation, and phospho‐AMPKα2 levels. In visceral adipose tissue of obese mice, fenofibrate decreased basal lipolysis rate and visceral adipocytes hypertrophy, and induced the expression of Glut‐4, Irs1, and Cav‐1 mRNA and miR‐103‐3p suggesting a higher insulin sensitivity of the adipocytes. The evidence is presented herein that beneficial effects of fenofibrate on body weight, glucose homeostasis, and muscle metabolism might be related to its action in adipose tissue. Moreover, fenofibrate regulates miR‐1a‐3p in soleus and miR‐103‐3p in adipose tissue, suggesting these microRNAs might contribute to fenofibrate beneficial effects on metabolism.
We demonstrated that miR‐1a regulates glucose uptake. Fenofibrate actions in metabolism may be related to its effects on specific miRNA in isolated tissues. Moreover, no other work has evaluated in depth the effect of fenofibrate on muscle and adipose tissue, and more importantly, has shown the crosstalk between these tissues under fenofibrate treatment.
This study investigated the effects of palmitoleic acid on different phases of the healing process. Macroscopic analyses were performed on wounds in rats with or without palmitoleic acid treatment, ...and the results showed that palmitoleic acid directly hastened wound closure. The topical treatment of wounds with palmitoleic acid resulted in smaller wounds than those observed in the control group. The anti-inflammatory activity of palmitoleic acid may be responsible for healing, especially in the stages of granulation tissue formation and remodelling. Palmitoleic acid modified TNF-α, IL-1β, IL-6, CINC-2α/β, MIP-3α and VEGF-α profiles at the wound site 24, 48, 120, 216 and 288 hours post-wounding. Assays assessing neutrophil migration and exudate formation in sterile inflammatory air pouches revealed that palmitoleic acid had potent anti-inflammatory activity, inhibiting the LPS-induced release of TNF-α (73.14%, p≤0.05), IL-1β (66.19%, p≤0.001), IL-6 (75.19%, p≤0.001), MIP-3α (70.38%, p≤0.05), and l-selectin (16%, p≤0.05). Palmitoleic acid also inhibited LPS-stimulated neutrophil migration. We concluded that palmitoleic acid accelerates wound healing via an anti-inflammatory effect.
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