Mulberroside A repairs high fructose diet-induced damage of intestinal epithelial and blood-brain barriers in mice: A potential for preventing hippocampal neuroinflammatory injury.

Our previous studies showed that high fructose diet (HFrD)-driven gut dysbiosis caused fecal short-chain fatty acids (SCFAs) reduction and intestinal epithelial barrier (IEB) damage in mice, which might play an important role in hippocampal neuroinflammatory injury. Mulberroside A is reported to have neuroprotective effects in animal experiments, while the underlying mechanisms are not yet fully elucidated. Here, we investigated whether and how mulberroside A prevented HFrD-induced neuroinflammatory injury. HFrD-fed mice were treated orally with mulberroside A (20 and 40 mg/kg) for 8 weeks. Mulberroside A was found to inhibit hippocampal neuroinflammation and neurogenesis reduction in HFrD-fed mice. It reshaped gut dysbiosis, increased fecal and serum SCFAs contents, reactivated signaling of the colonic NLR family, pyrin domain containing 6 (NLRP6) inflammasome, and up-regulated Muc2 expression to prevent IEB damage, as well as subsequently, reduced serum endotoxin levels in this animal model. Additionally, mulberroside A inhibited oxidative stress in colon of HFrD-fed mice and hydrogen peroxide (H2 O2 )-stimulated Caco-2 cells. Blood-brain barrier (BBB) structure defects were also observed in HFrD-driven hippocampal neuroinflammatory injury of mice. Interestingly, mulberroside A maintained astrocyte morphology and up-regulated tight junction proteins to repair BBB structure defects in hippocampus dentate gyrus (DG). Our results demonstrated that mulberroside A was capable of preventing HFrD-induced damage of IEB and BBB in mice, which might contribute to the suppression of hippocampal neuroinflammatory injury.

Dietary copper-fructose interactions alter gut microbial activity in male rats.

Dietary copper-fructose interactions contribute to the development of nonalcoholic fatty liver disease (NAFLD). Gut microbiota play critical roles in the pathogenesis of NAFLD. The aim of this study was to determine the effect of different dietary doses of copper and their interactions with high fructose on gut microbiome. Male weanling Sprague-Dawley rats were fed diets with adequate copper (6 ppm CuA), marginal copper (1.5 ppm CuM) (low copper), or supplemented copper (20 ppm CuS) (high copper) for 4 wk. Deionized water or deionized water containing 30% fructose (wt/vol) was given ad libitum. Copper status, liver enzymes, gut barrier function, and gut microbiome were evaluated. Both low- and high-copper diets led to liver injury in high-fructose-fed rats, and this was associated with gut barrier dysfunction, as shown by the markedly decreased tight junction proteins and increased gut permeability. 16S rDNA sequencing analysis revealed distinct alterations of the gut microbiome associated with dietary low- and high-copper/high-fructose feeding. The common features of the alterations of the gut microbiome were the increased abundance of Firmicutes and the depletion of Akkermansia. However, they differed mainly within the phylum Firmicutes. Our data demonstrated that a complex interplay among host, microbes, and dietary copper-fructose interaction regulates gut microbial metabolic activity, which may contribute to the development of liver injury and hepatic steatosis. The distinct alterations of gut microbial activity, which were associated with the different dietary doses of copper and fructose, imply that separate mechanism(s) may be involved. NEW & NOTEWORTHY First, dietary low- and high-copper/high-fructose-induced liver injury are associated with distinct alterations of gut microbiome. Second, dietary copper level plays a critical role in maintaining the gut barrier integrity, likely by acting on the intestinal tight junction proteins and the protective commensal bacteria Akkermansia. Third, the alterations of gut microbiome induced by dietary low and high copper with or without fructose differ mainly within the phylum Firmicutes.

Evaluation of high-fat high-fructose diet treatment in factor VIII (coagulation factor)-deficient mouse model.

Non-alcoholic fatty liver disease (NAFLD)-like conditions enhance the production and action of clotting factors in humans. However, studies examining the effect of NAFLD due to high-fat high-fructose (HFHF) diet in factor VIII-deficient (haemophilia A) animals or patients have not been reported previously. In this study, we investigated the individual role of factor VIII in the progression of diet-induced NAFLD in the factor 8-/- (F8-/- ) mouse model system and its consequences on the haemophilic status of the mice. The F8-/- mice were fed with HFHF diet for 14 weeks. Physiological, biochemical, haematological, molecular, pathological, and immune histochemical analyses were performed to evaluate the effect of this diet. The F8-/- mice developed hepatic steatosis after 14 weeks HFHF diet and displayed lower energy metabolism, higher myeloid cell infiltration in the liver, decreased platelet count, upregulated de novo fatty acid synthesis, lipid accumulation, and collagen deposition. This study helps to understand the role of factor VIII in NAFLD pathogenesis and to analyse the severity and consequences of steatosis in haemophilic patients as compared to normal population. This study suggests that haemophilic animals (F8-/- mice) are highly prone to hepatic steatosis and thrombocytopenia.

Maternal high fructose diet exacerbates white adipose tissue thermogenic process in offspring upon exposure to cold temperature.

AIM: An adverse endogenous environment during early life predisposes to metabolic disorder development. We previously reported adverse metabolic and adipose tissue effects in adult male rats born to dams fed with a fructose-rich diet (FRD). The aim of this work was to determine the effect of a FRD consumed by the pregnant mother on the white adipose tissue (WAT) browning capacity of male offspring at adulthood. MAIN METHODS: Adult SD male offspring from control (C) and FRD-fed mothers were exposed during one week to a cold stimulus. WAT browning capacity was studied through in vivo and in vitro approaches. KEY FINDINGS: After cold exposure, WAT browning was higher in fructose-programmed animals as evidenced by an increase in ucp-1 gene expression, protein levels, and higher UCP-1 positive foci. Moreover, pgc1-α gene expression was increased. In vitro studies showed a lower adipogenic capacity in cells of prenatally fructose-exposed animals differentiated with a white differentiation cocktail, while a higher ucp-1 expression was noted when their cells were treated with a pro-beige differentiation cocktail. SIGNIFICANCE: For the first time we demonstrate that pre-natal fructose exposure predisposes programmed male rats to a higher WAT browning-induced response, under stimulated conditions, despite an apparent lower basal thermogenic capacity. These results should be considered in future studies to generate new therapeutic approaches to deal with adverse programming malnutrition effects.

In Utero Dexamethasone Exposure Exacerbates Hepatic Steatosis in Rats That Consume Fructose During Adulthood.

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.

Acute toxic effects of telmisartan in spontaneously hypertensive rats fed a high fructose diet.

Telmisartan is an angiotensin receptor blocker (ARB) and a selective peroxisome proliferator activated receptor gamma (PPARG) modulator. Recently, we tested metabolic effects of telmisartan (5 mg/kg body weight) in spontaneously hypertensive rats (SHR) fed a diet containing 60 % fructose, a widely used model of the metabolic syndrome. Surprisingly, we observed acute toxic effects of telmisartan. Rats lost body weight rapidly and died within 2 to 3 weeks due to bleeding into the upper gastrointestinal tract. SHR fed a high fructose diet and treated with telmisartan exhibited rapid decrease in blood pressure when compared to the SHR fed a high fructose diet and treated with valsartan. Concentrations of both unconjugated telmisartan and telmisartan glucuronide in the liver of SHR rats fed a high fructose diet were approximately 4 fold higher when compared to Brown Norway (BN) rats fed the same diet. Plasma concentrations of unconjugated telmisartan in the SHR were about 5 fold higher when compared to BN rats while plasma levels of telmisartan glucuronide were similar between the strains. Testing of other rat strains, diets, and the ARB valsartan showed that toxic effects of telmisartan in combination with high fructose diet are specific for the SHR. These results are consistent with the possibility that in some circumstances, SHR are predisposed to telmisartan toxicity possibly because of a genetically determined disturbance in telmisartan metabolism.

Maternal High Fructose Intake Increases the Vulnerability to Post-Weaning High-Fat Diet-Induced Programmed Hypertension in Male Offspring.

Widespread consumption of high-fructose and high-fat diets relates to the global epidemic of hypertension. Hypertension may originate from early life by a combination of prenatal and postnatal nutritional insults. We examined whether maternal high-fructose diet increases vulnerability to post-weaning high-fructose or high-fat diets induced hypertension in adult offspring and determined the underlying mechanisms. Pregnant Sprague-Dawley rats received regular chow (ND) or chow supplemented with 60% fructose (HFR) during the entire pregnancy and lactation periods. Male offspring were onto either the regular chow, 60% fructose, or high-fat diet (HFA) from weaning to 12 weeks of age and assigned to four groups: ND/ND, HFR/ND, HFR/HFR, and HFR/HFA. Maternal high-fructose diet exacerbates post-weaning high-fat diet-induced programmed hypertension. Post-weaning high-fructose and high-fat diets similarly reduced Sirt4, Prkaa2, Prkag2, Ppara, Pparb, and Ppargc1a mRNA expression in offspring kidneys exposed to maternal high-fructose intake. Additionally, post-weaning high-fat diet significantly reduced renal mRNA levels of Ulk1, Atg5, and Nrf2 and induced greater oxidative stress than did high-fructose diet. Although maternal high-fructose intake increases soluble epoxide hydrolase (SEH) expression in the kidney, which was restored by post-weaning high-fructose and high-fat diets. Maternal high-fructose diet programs differential vulnerability to developing hypertension in male offspring in response to post-weaning high-fructose and high-fat diets. Our data implicated that specific therapy targeting on nutrient sensing signals, oxidative stress, and SEH may be a promising approach to prevent hypertension in children and mothers exposed to high-fructose and high-fat consumption.

Protective Effects of Ellagitannin-Rich Strawberry Extracts on Biochemical and Metabolic Disturbances in Rats Fed a Diet High in Fructose.

The present study compares the effects of two dietary strawberry extracts rich in monomeric (ME) or dimeric (DE) ellagitannins (ETs) on gastrointestinal, blood and tissue biomarkers in Wistar rats fed high-fructose diets. Both strawberry extracts beneficially affect the antioxidant status and lipid profile of the liver and serum. The ME extract shows a greater ability to inhibit lipid peroxidation in kidneys, more effectively decreases serum and liver triglycerides, and exerts greater anti-inflammatory effects in blood serum than the DE extract. The DE extract significantly reduces the activity of microbial enzymes in the cecum. These effects might be associated with higher cecum and urine levels of ET metabolites in rats fed with ME than in rats fed with DE. In conclusion, the diet-induced fructose-related disturbances observed in biochemical parameters are regulated by both extracts; nevertheless, the beneficial effects of the ME extract are mostly associated with systemic parameters, while those of the DE extracts are associated with local microbial activity.

Elevation of ß-galactoside α2,6-sialyltransferase 1 in a fructoseresponsive manner promotes pancreatic cancer metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of pancreatic cancer with clinical characteristics of local invasion and early metastasis. Recent cohort studies indicate high fructose intake is associated with an increase in pancreatic cancer risk. However, the mechanisms by which fructose promotes pancreatic tumorigenesis remain unclear. Herein, Kras+/LSLG12D mice were crossed with Elas-CreER transgenic mice to determine whether fructose intake directly contributes to tumor formation. Orthotopic tumor-xenograft experiments were performed to determine whether fructose substitution enhances the metastatic potential of PDAC cells. The mechanisms underlying the effects of fructose were explored by RNAseq analysis in combination with high-performance anion exchange chromatography. Dietary fructose was initially found to promote the development of aggressive pancreatic cancer in mice conditionally expressing KrasG12D in the adult pancreas. We further revealed that fructose substitution enhanced the metastatic potential of human PDAC cell via selective outgrowth of aggressive ABCG2-positive subpopulations and elevating N-acetylmannosamine levels that upregulated ß-galactoside α2,6-sialyltransferase 1 (ST6Gal1), thereby promoting distant metastasis. Finally, we observed that PDAC patients expressing higher levels of ST6Gal1 and GLUT5 presented poorer prognosis compared to other groups. In conclusion, our findings have elucidated a crucial role of ST6Gal1 in regulating the invasiveness of PDACs in a fructose-responsive manner.

Assessment of fructose overload in the metabolic profile and oxidative/nitrosative stress in the kidney of senescent female rats.

The aging process is a complex phenomenon that leads the body to several changes, affecting its integrity and resulting in chronic pathologies, which compromises health and quality of life of elderly people. Animals supplemented with fructose have been used as an experimental model for induction of insulin resistance. The objective of this study was to evaluate the metabolic effects and the levels of oxidative/nitrosative stress in the kidney of senescent rats with a high fructose intake. The animals were allocated into 4 groups: young control (Y), aged control (A), young fructose (YF) and aged fructose (AF). Groups Y and A received water and groups YF and AF received fructose (100g/L) in the water, both ad libitum. After 12weeks of high fructose intake, the animals were sacrificed to collect their kidneys, blood and the thoracic aorta. The results are presented as mean±SE, analyzed by the One-Way ANOVA test with Newman-Keuls post-test; significant at p<0.05. The fructose overload caused metabolic dysfunctions and insulin resistance, confirming the efficacy of the chosen model. In this study, we observed a body weight gain in the studied groups (except in the elderly fructose group), and an increase in general caloric intake, diuresis and adipose tissue; insulin resistance, increased fasting glucose, triglycerides and cholesterol in the fructose groups. We also found a loss of renal function, increased oxidative/nitrosative stress and inflammation, and a reduction of antioxidants and a lower vasodepressor response in the studied groups, especially those who consumed fructose. In summary, our data showed that aging or high fructose intake contributed to the increase of oxidative/nitrosative stress in animals, demonstrating that at the dose and the period of fructose treatment utilized in this study, fructose was not able to aggravate several aspects which were already altered by aging. We believe that the high fructose intake simulates most of the effects of aging, and this understanding would be useful to prevent or minimize many of the alterations caused by this condition.