High-fat High-fructose Diet Research Articles

Intestine epithelial-specific hypoxia-inducible factor-1α overexpression ameliorates western diet-induced MASLD.

Intestine epithelial hypoxia-inducible factor-1α (HIF-1α) plays a critical role in maintaining gut barrier function. The aim of this study was to determine whether pharmacological or genetic activation of intestinal HIF-1α ameliorates western diet-induced metabolic dysfunction-associated steatotic liver disease. Metabolic effects of pharmacological activation of HIF-1α by dimethyloxalylglycine were evaluated in HIF-α luciferase reporter (ODD-luc) mice. Male and/or female intestinal epithelial-specific Hif1α overexpression mice (Hif1αLSL/LSL;VilERcre) and wild-type littermates (Hif1αLSL/LSL) were fed with regular chow diet, high fructose (HFr) or high-fat (60% Kcal) high-fructose diet (HFHFr) for 8 weeks. Metabolic phenotypes were profiled. Dimethyloxalylglycine treatment led to increased intestine HIF-α luciferase activity and decreased blood glucose levels in HFr diet-fed male ODD-luc mice. Male Hif1αLSL/LSL;VilERcre mice exhibited markedly improved glucose tolerance compared to Hif1αLSL/LSL mice in response to HFr diet. Eight weeks HFHFr feeding led to obesity in both Hif1αLSL/LSL;VilERcre and Hif1αLSL/LSL mice. However, male Hif1αLSL/LSL;VilERcre mice exhibited markedly attenuated hepatic steatosis along with reduced liver size and liver weight compared to male Hif1αLSL/LSL mice. Moreover, HFHFr-induced systemic inflammatory responses were mitigated in male Hif1αLSL/LSL;VilERcre mice compared to male Hif1αLSL/LSL mice, and those responses were not evident in female mice. Ileum RNA-seq analysis revealed that glycolysis/gluconeogenesis was up in male Hif1αLSL/LSL;VilERcre mice, accompanied by increased epithelial cell proliferation. Moreover, an in vitro study showed that HIF stabilization enhances glycolysis in intestine organoids. Our data provide evidence that pharmacological or genetic activation of intestinal HIF-1α markedly ameliorates western diet-induced metabolic dysfunction-associated steatotic liver disease in a sex-dependent manner. The underlying mechanism is likely attributed to HIF-1α activation-induced upregulation of glycolysis, which, in turn, leads to enhanced epithelial cell proliferation and augmented gut barrier function.

Effect of Resveratrol on the Development of Non-Alcoholic Fatty Liver Disease in Rats Fed on High-Fat High-Fructose Diet

Effect of Resveratrol on the Development of Non-Alcoholic Fatty Liver Disease in Rats Fed on High-Fat High-Fructose Diet

Changes associated with dietary beetroot extract on diet-induced damage in the common carotid artery of the albino rat (<i>Rattus norvegicus</i>)

The high-fat high-fructose diet (HFHFr) has become widespread globally corresponding to a rise in obesity and cardiovascular diseases. Traditionally, these diseases were managed by multiple-drug regimens whose adherence was limited by side effects, hence leading to consideration of natural compounds. Recent studies have exploited the phytochemical properties of numerous plant extracts in ameliorating the histological changes seen in common carotid artery (CCA) damage, however, hardly any studies have investigated the effect of beetroot extract. The CCA were obtained from a biobank of a study that induced HFHFr in 45 male rats. Rats in the control group had received standard rat chow and water, and the positive control group received HFHFr. Those in the experimental group received HFHFr and 200mg/kg beetroot extract. These rats were randomly selected, euthanized and perfused on weeks 4,8,10 and 16. Their CCA were harvested, processed and stereological techniques applied to determine the densities of different histological components of the CCA.The HFHFr fed experimental animals revealed medial vascular thickening with a resultant increase in carotid intima-media thickness, increased vascular smooth muscle density, reduced elastic fiber density, and increased collagen fiber density compared to controls. Beetroot coadministration was protective against most of these structural changes. Dietary administration of beetroot extract has been found to be ameliorative to structural changes on the CCA following administration of HFHFr. Therefore, dietary beetroot extract may be indicated to mitigate harmful changes following long term exposure to a high fat high fructose diet.

Green Tea Yoghurt with Encapsulated Lacticaseibacillus paracasei E1 Improves Hepatocyte Damage in High-Fat High-Fructose Diet Mice by Reducing MDA and Increasing SOD

Green Tea Yoghurt with Encapsulated Lacticaseibacillus paracasei E1 Improves Hepatocyte Damage in High-Fat High-Fructose Diet Mice by Reducing MDA and Increasing SOD

Neuroprotective Roles of Lauric Acid and Resveratrol: Shared Benefits in Neuroinflammation and Anxiety, Distinct Effects on Memory Enhancement.

Neuroinflammation can be triggered by a high-fat/high-fructose diet (HFFD), and CD36 may be an underlying mechanism. Lauric acid (LA), the major fatty acid in coconut oil, and resveratrol, the plant-based polyphenolic compound, may exert anti-inflammatory effects. Therefore, this study investigated the possible effects of LA and resveratrol on diet-induced neuroinflammation and CD36. Healthy male C57BL/6 mice (8 weeks of age, n = 31) were fed a control diet (10%kcal fat) or diets containing high fat (60%kcal fat) and fructose (5% w/v fructose drinking water) for 6 weeks, ad libitum. Supplemented to the HFFD, mice daily received resveratrol (7.5 mg/kg) (HFFD-RSV) or LA (750 mg/kg) (HFFD-LA). At the end of the study, HFFD resulted in anxiety-like behavior, reduced locomotor activity, neuroinflammation (increased brain GFAP, IL-6, MCP-1, IFN-γ, TNF-α), and systemic inflammation (increased plasma GFAP, IFN-γ, TNF-α, IL-12p70, reduced plasma IL-10). HFFD-RSV and HFFD-LA alleviated HFFD-induced anxiety-like behavior, neuroinflammation, and systemic inflammation. HFFD-LA improved memory. Brain and plasma CD36 levels were increased by HFFD and reduced by HFFD-RSV or HFFD-LA. Dietary resveratrol and LA intake may alleviate HFFD-induced neuroinflammation, systemic inflammation, and anxiety-like behavior and improve memory, as CD36 may be an underlying mechanism.

Unveiling Lipidomic Alterations in Metabolic Syndrome: A Study of Plasma, Liver, and Adipose Tissues in a Dietary-Induced Rat Model

Metabolic syndrome (MetS) is a complex condition characterized by fat accumulation, dyslipidemia, impaired glucose control and hypertension. In this study, rats were fed a high-fat high-fructose (HFF) diet in order to develop MetS. After ten weeks, the dietary-induced MetS was confirmed by higher body fat percentage, lower HDL-cholesterol and increased blood pressure in the HFF-fed rats compared to the normal-fed control animals. However, the effect of MetS development on the lipidomic signature of the dietary-challenged rats remains to be investigated. To reveal the contribution of specific lipids to the development of MetS, the lipid profiling of rat tissues particularly susceptible to MetS was performed using untargeted UHPLC-QTOF-MS/MS lipidomic analysis. A total of 37 lipid species (mainly phospholipids, triglycerides, sphingolipids, cholesterol esters, and diglycerides) in plasma, 43 lipid species in liver, and 11 lipid species in adipose tissue were identified as dysregulated between the control and MetS groups. Changes in the lipid signature of selected tissues additionally revealed systemic changes in the dietary-induced rat model of MetS.

7005 Characterization of Clinical Candidate Miricorilant in Preclinical Models for NASH

Abstract Disclosure: T.J. Moll: None. E.M. Viho: None. M. Gentenaar: None. H. Hunt: Employee; Self; Corcept Therapeutics. O.C. Meijer: Grant Recipient; Self; Corcept Therapeutics. J. Kroon: Research Investigator; Self; Corcept Therapeutics. Background and aim: Miricorilant (CORT118335) is a selective glucocorticoid receptor (GR) modulator that is under clinical development for the treatment of non-alcohol steatohepatitis (NASH). It was previously shown that miricorilant treatment effectively lowers hepatic lipid content in mouse models of NASH. The aim of this study is to further characterize the effects of miricorilant in the mouse liver and in human liver tissue. Methods: In mouse liver tissue, we investigated the agonistic and antagonistic properties of miricorilant on GR activity. Eight-week-old male C57BL/6J mice were fed with a control diet or miricorilant-supplemented diet (resulting in an estimated dose of 60 mg/kg/day) for 6 days and 1.5 mg/kg corticosterone was injected to monitor the effects of miricorilant on GR-responsive gene expression. We next accessed the time-dependency of the lipid-lowering effects of miricorilant in the mouse liver. Mice were fed with a high-fat, high-fructose diet (HFHFD) for 3 weeks before treatment with 60 mg/kg/day miricorilant for one, three or six days by oral gavage, and triglyceride content in the liver was measured at endpoint. In human liver tissue, we investigated the effects of miricorilant on precision-cut liver slices (PCLS) obtained from two independent donors with pre-existing steatosis. PCLS were cultured for a total of 168 hours in the presence of 100 nM hydrocortisone, and with or without an exogenous lipid challenge. PCLS were treated with 200-600 nM miricorilant for 96 hours before triglyceride content was measured. RNA-sequencing was performed on PCLS after 24 hours of 200-400 nM miricorilant exposure. Results: In the mouse liver, miricorilant exhibited a unique combination of agonistic and antagonistic properties on GR-responsive gene expression. Miricorilant effectively lowered HFHFD-induced lipid accumulation in the mouse liver as soon as three days after treatment. In human PCLS, miricorilant treatment lowered triglyceride content in both donors. RNA-sequencing revealed respectively 40 and 128 differentially expressed genes after 200 and 400 nM miricorilant treatment. Pathway analysis revealed very-low-density lipoprotein (VLDL) particle remodeling as a significant enriched pathway, providing a possible explanation for the lowered triglyceride content upon miricorilant treatment. Conclusion: Miricorilant rapidly and effectively lowers hepatic lipid content in the mouse liver and in human PCLS, possibly via modulation of VLDL remodeling. Presentation: 6/2/2024

CHIP ameliorates nonalcoholic fatty liver disease via promoting K63- and K27-linked STX17 ubiquitination to facilitate autophagosome-lysosome fusion

The fusion of autophagosomes and lysosomes is essential for the prevention of nonalcoholic fatty liver disease (NAFLD). Here, we generate a hepatocyte-specific CHIP knockout (H-KO) mouse model that develops NAFLD more rapidly in response to a high-fat diet (HFD) or high-fat, high-fructose diet (HFHFD). The accumulation of P62 and LC3 in the livers of H-KO mice and CHIP-depleted cells indicates the inhibition of autophagosome-lysosome fusion. AAV8-mediated overexpression of CHIP in the murine liver slows the progression of NAFLD induced by HFD or HFHFD feeding. Mechanistically, CHIP induced K63- and K27-linked polyubiquitination at the lysine 198 residue of STX17, resulting in increased STX17-SNAP29-VAMP8 complex formation. The STX17 K198R mutant was not ubiquitinated by CHIP; it interfered with its interaction with VAMP8, rendering STX17 incapable of inhibiting steatosis development in mice. These results indicate that a signaling regulatory mechanism involving CHIP-mediated non-degradative ubiquitination of STX17 is necessary for autophagosome-lysosome fusion.

Lygodium microphyllum Inhibits de Novo Lipogenesis Activity in the Hepatocytes of High-Fat High-Fructose-Induced Rats by Increasing the Levels of SIRT1 and AMPK.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is currently of great concern due to its risk of developing T2DM and cardiovascular disease. The development of NAFLD may be initiated by de novo lipogenesis in the hepatocytes. Sirtuin1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK), are responsible for the lipogenesis mechanism. Interestingly, plant sterols, such as beta-sitosterol and stigmasterol, have the potential to lower the LDL-cholesterol in dyslipidemic patients. Beta-sitosterol was present in the ethanol extract of Lygodium microphyllum herbs at a concentration of 283.55µg/g extract. This sterol interacted with the active allosteric-binding site of SIRT1 and AMPK similarly to the proteins' activators. To investigate the anti-lipogenesis activity of the ethanol extract of L. microphyllum (ELM) in the liver tissue of rats through the SIRT1 and AMPK levels. Forty male Wistar rats were used in this study: (1) normal control group; (2) high-fat high-fructose diet (HFHFD) rats; (3) HFHFD rats treated with metformin; (4) HFHFD rats treated with resveratrol; (5) HFHFD rats treated with beta-sitosterol; (6-8) HFHFD rats treated with ELM doses of 200, 400, and 600 mg/kg BW. Rats in the normal control group were fed regular chow, while other groups of rats were given HFHFD for 35 days. All drugs were given orally on D15 till D35. On D35, the rats were sacrificed, and the liver organs were examined for the liver index, morphology, NAFLD activity score (NAS), and levels of SIRT1 and AMPK. ELM improves the morphology, the liver index, the steatosis condition, and the NAS of HFHFD-induced NAFLD rats. ELM increases the levels of SIRT1 and AMPK in the liver tissue of HFHFD-induced NAFLD rats. ELM may have the potential to inhibit de novo lipogenesis by increasing the levels of SIRT1 and AMPK.

Metformin and intermittent fasting mitigate high fat-fructose diet-induced liver and skeletal muscle injury through upregulation of mitophagy genes in rats

BackgroundHigh fat-fructose diet is a proinflammatory diet that increases risk of hepatocytes and myocytes steatosis and fibrosis. Finding anti-inflammatory strategies to fight these harmful effects is paid attention to nowadays. This study compared the effects of two widely anti-inflammatory interventions—metformin and intermittent fasting on myocytes and hepatocyte injury induced by proinflammatory diet and tracking possible underlying mechanisms. In this work, rats fed high fat-fructose diet were subdivided into untreated group, treated by metformin, and/or intermittent fasting.ResultsMetformin (300 mg/kg/day) and intermittent fasting (3 days/week) specially their combination for 4 weeks showed significant improvement in insulin resistance, lipid profile, antioxidants (p < 0.05), as well as enhanced hepatocytes and myocytes repair and reduced collagen deposition through upregulation of mitophagy-related genes: PINK1, PARKIN, LAMP2, and PPAR-α (p < 0.05).ConclusionsIntermittent fasting has beneficial metabolic and molecular therapeutic effects against proinflammatory diet-induced injury. Their results are like those of metformin sparing its adverse effects. Their combination showed additional effects against diet-induced myocytes and hepatocyte injury by upregulation of mitophagy-related genes without the need of increasing the dose of metformin.Graphic abstract

Physiological responses and microbiota shifts after spermidine administration as a postbiotic on rodents fed a high-fat high-fructose diet.

The consumption of a high-fat high-fructose diet partly resemble the western dietary patterns, which is closely associated with excessive body adiposity and metabolic disorders, such as obesity and type 2 diabetes. Moreover, this unhealthy regime produces unfavourable changes on the faecal microbiota, potentially interfering with microorganisms postbiotic function, such as spermidine, a natural polyamine that has been involved in the control of weight gain. The study aimed to analyse the repercussions of spermidine supplementation on somatic measurements, metabolic markers, and the faecal microbiota profile of rats fed a diet rich in fat and fructose. Indeed, Wistar males with oral administration of spermidine (20mg/kg/day) for 6 weeks were evaluated for food and energy intake, biochemical markers, and faecal microbiota signatures. The daily use of spermidine decreased weight gain ( P < 0.01), reduced feed efficiency ( P < 0.01), and attenuated visceral fat deposition ( P < 0.01), although no effect on energy intake, hepatic weight, triglyceride and glucose index and atherogenic indexes. Similarly, the consumption of spermidine partially restored the presence of microbial species, notably Akkermansia muciniphila. Elevated concentrations of this species were linked to a decrease in triglycerides ( P = 0.04), indicating that the supplementation of spermidine might contribute to managing energy fuel homeostasis in association with an obesogenic diet.

Comparative effects of viable Lactobacillus rhamnosus GG and its heat-inactivated paraprobiotic in the prevention of high-fat high-fructose diet-induced non-alcoholic fatty liver disease in rats.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver alterations worldwide, being gut microbiota dysbiosis one of the contributing factors to its development. The aim of this research is to compare the potential effects of a viable probiotic (Lactobacillus rhamnosus GG) with those exerted by its heat-inactivated paraprobiotic counterpart in a dietary rodent model of NAFLD. The probiotic administration effectively prevented the hepatic lipid accumulation induced by a high-fat high-fructose diet feeding, as demonstrated by chemical (lower TG content) and histological (lower steatosis grade and lobular inflammation) analyses. This effect was mainly mediated by the downregulation of lipid uptake (FATP2 protein expression) and upregulating liver TG release to bloodstream (MTTP activity) in rats receiving the probiotic. By contrast, the effect of the paraprobiotic preventing diet-induced liver lipid accumulation was milder, and mainly derived from the downregulation of hepatic de novo lipogenesis (SREBP-1c protein expression and FAS activity) and TG assembly (DGAT2 and AQP9 protein expression). The obtained results demonstrate that under these experimental conditions, the effects induced by the administration of viable L. rhamnosus GG preventing liver lipid accumulation in rats fed a diet rich in saturated fat and fructose differ from those induced by its heat-inactivated paraprobiotic counterpart.

The Effect of Sacha Inchi Tempe on Blood Glucose, HOMA-IR, and TNF-ɑ in Rats with Metabolic Syndrome

This research aimed to evaluate the impact of sacha inchi tempe (Plukenetia volubilis L.) on Fasting Blood Glucose (FBG), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and Tumor Necrosis Factor Alpha (TNF-ɑ) levels. In addition, metabolic syndrome was induced in 36 male Wistar rats aged 2 months at 150–200 g weight by giving a High-Fat High-Fructose diet (HFFD) for 2 weeks. The extract was administered through oral gavage in dose-dependent manner and rats were allocated into 6 groups, namely: 1). Normal control or K0; 2). Negative control or K-; 3). Positive control or K+ with 0.18 mg/200 g BB of simvastatin; 4). Intervention with 0.9 g sacha inchi tempe or P1; 5). Intervention with 1.8 g sacha inchi tempe or P2, and; 6). Intervention with 3.6 g sacha inchi tempe or P3. Meanwhile, normal chow rats were used and served as the control group. After 2 and 5 weeks of induction and intervention, blood was drawn to determine FBG. Blood insulin was examined after 5 week of intervention. Rats were euthanized at the end of the intervention for hepatic TNF-α analysis before calculating HOMA-IR. The result showed that there was a significant difference (p&lt;0.05) in FBG, HOMA-IR and hepatic TNF-α levels after sacha inchi tempe treatment. Rats receiving the highest dose of sacha inchi tempe had the most significant reduction (p&lt;0.05) in FBG, HOMA-IR and hepatic TNF-α, when compared to simvastatin group. Therefore, sacha inchi tempe could attenuate glycemic and inflammation profiles in metabolic syndrome.

Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease

There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD.

Aronia melanocarpa fruit juice prevents hepatic impairment in rats subjected to metabolic syndrome

AbstractThis study evaluated the effects of Aronia melanocarpa fruit juice (AMFJ) on the liver in a model of high-fat, high-fructose (HFHF) diet-induced metabolic syndrome (MS). Fifty rats were allocated to five groups – Control, MS, MS+AMFJ2.5, MS+AMFJ5, and MS+AMFJ10. The control group was fed a standard diet, while the other groups were provided a HFHF diet. During MS induction, daily oral treatment was performed. Control and MS groups received 10.0 mL kg−1 distilled water, while the other three groups received AMFJ at doses of 2.5, 5.0, and 10.0 mL kg−1, respectively. After 10 weeks, liver samples were collected and inspected histologically as well as immunohistochemically to determine the expression of Bax, Bcl-2, and MAC387. Bax/Bcl-2 ratio was calculated. In MS rats, steatotic, inflammatory and degenerative alterations of the liver were detected, Bax and MAC387 were markedly elevated, while Bcl-2 was non-significantly reduced. The Bax/Bcl-2 ratio significantly increased. The histopathological alterations were prevented by the AMFJ treatment. Compared to MS group, Bax and MAC387 values were significantly lower and Bcl-2 value was higher resulting in significantly lower (P &lt; 0.001) Bax/Bcl-2 ratio in all AMFJ-treated groups. AMFJ, administered during MS induction in rats, prevented the occurrence of inflammatory, steatotic, degenerative, and pro-apoptotic changes in the liver.

Single high-dose intravenous injection of Wharton’s jelly-derived mesenchymal stem cell exerts protective effects in a rat model of metabolic syndrome

BackgroundMetabolic syndrome (MetS) is a significant epidemiological problem worldwide. It is a pre-morbid, chronic and low-grade inflammatory disorder that precedes many chronic diseases. Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) could be used to treat MetS because they express high regenerative capacity, strong immunomodulatory properties and allogeneic biocompatibility. This study aims to investigate WJ-MSCs as a therapy against MetS in a rat model.MethodsTwenty-four animals were fed with high-fat high-fructose (HFHF) diet ad libitum. After 16 weeks, the animals were randomised into treatment groups (n = 8/group) and received a single intravenous administration of vehicle, that is, 3 × 106 cells/kg or 10 × 106 cells/kg of WJ-MSCs. A healthy animal group (n = 6) fed with a normal diet received the same vehicle as the control (CTRL). All animals were periodically assessed (every 4 weeks) for physical measurements, serum biochemistry, glucose tolerance test, cardiovascular function test and whole-body composition. Post-euthanasia, organs were weighed and processed for histopathology. Serum was collected for C-reactive protein and inflammatory cytokine assay.ResultsThe results between HFHF-treated groups and healthy or HFHF-CTRL did not achieve statistical significance (α = 0.05). The effects of WJ-MSCs were masked by the manifestation of different disease subclusters and continuous supplementation of HFHF diet. Based on secondary analysis, WJ-MSCs had major implications in improving cardiopulmonary morbidities. The lungs, liver and heart show significantly better histopathology in the WJ-MSC-treated groups than in the untreated CTRL group. The cells produced a dose-dependent effect (high dose lasted until week 8) in preventing further metabolic decay in MetS animals.ConclusionsThe establishment of safety and therapeutic proof-of-concept encourages further studies by improving the current therapeutic model.

Behavioral Effects of Chronic Japanese Quince Fruit Juice Administration to Rats with Diet-Induced Metabolic Syndrome

Abstract Introduction Metabolic syndrome (MS) is often associated with anxiety and depression. Chaenomeles japonica (Thunb.) Lindl, also known as Chaenomeles maulei or Japanese quince, is a medicinal plant with a long history of use forits health-promoting properties. Aim The aim of this study was to investigate the effects of Japanese quince fruit juice (JQFJ) administration on locomotor activity, anxiety and depressive behavior in rats with diet-induced MS. Materials and methods Forty adult male Wistar rats were divided into 4 groups: MS, MS+JQFJ2.5, MS+JQFJ5 and MS+JQFJ10. All groups received a high-fat high-fructose diet for the induction of MS. MS animals were daily orally treated with distilled water and the other groups with JQFJ at doses of 2.5 ml/kg, 5 ml/kg and 10 ml/kg, respectively. During the 10th week of the experiment, behavioral tests were carried out. Results In the open Held test, no effect of JQFJ treatment on locomotor activity was observed. In the elevated plus maze test, a dose-dependent increase in the time spent in the open arms (OA) of the apparatus and in the ratio time spent in OA vs. total time spent in any of the arms was interpreted as an anxiolytic effect. The immobility time in the forced swim test did not differ significantly among the groups, which demonstrated a lack of anti-depressant action. Conclusions Chronic Japanese quince fruit juice administration produced a dose-dependent anxiolytic-like effect in rats with diet-induced MS, probably due to its high content of polyphenols.

Preventive and Therapeutic Efficacy of Roselle Beverage Residue in Late-Stage Type 2 Diabetic Rats

The residue from roselle beverage production is rich in polyphenols and dietary fiber. We investigated its potential as a preventive and therapeutic agent for type 2 diabetes mellitus (T2DM). Male Wistar rats were fed a high-fat high-fructose diet (HFFD) for 17 weeks, reaching insulin resistance by week 9, and induced to T2DM with streptozotocin (STZ) at week 13. Roselle beverage residue (RBR) was administered ad libitum mixed at 6% with the HFFD. Rats received HFFD+RBR as a preventive strategy starting at week 1 (healthy) and week 9 (insulin resistant), whereas the treatment strategy in T2DM rats started at week 14 alone or in combination with metformin (200 mg/kg/day), with a control metformin-treated group. All RBR-supplemented groups showed reduced serum glucose levels (1.4-fold to 1.8-fold) compared with the HFFD+STZ control group. Preventive RBR administration enhanced pancreatic function, leading to improved insulin sensitivity (6.5-fold to 7.9-fold). Gene expression analysis identified slight alterations in hepatic and skeletal muscle glucose metabolism. Additionally, RBR supplementation demonstrated a preventive role in mitigating hyperuricemia (2.1-fold to 2.2-fold), with no effect on glomerular hyperfiltration. While the exact mechanisms underlying RBR effects remain to be fully elucidated, our findings highlight its promising potential as a dietary supplement for preventing and treating T2DM.

High-Fat-High-Fructose Diet Elicits Brown Adipocyte Dysfunction through miRNA-103 Induced miRNA Biogenesis Pathway

Background: Obesity is a critical public health concern with its prevalence growing at an alarming rate worldwide. The Western diet that typically includes high-fat or high-fructose components is one of the leading contributing factors of obesity. Recent findings demonstrate the essential role of BAT in regulating whole-body metabolism. However, the explicit mechanism through which BAT maintains homeostasis is still unknown. Methods: Six-week-old C57BL/6 male mice were fed either a low-fat diet (LFD) or a high-fat high-fructose diet (HFHFD) for 4, 12, and 20 weeks. Results: We observed a significant increase in BAT weight under HFHFD along with BAT whitening in a time-dependent manner. This was also accompanied by a significant decrease in UCP1 and PGC1α protein, as well as a significant increase in the Bax/Bcl-2 ratio as early as 12 weeks, indicating increased apoptosis under HFHFD. Interestingly, miRNA-103 expression that holds a seed sequence within the miRNA biogenesis machinery, Dicer, was significantly upregulated after 12 and 20 weeks of HFHFD. Dicer and another biogenesis regulator, TRBP2, exhibited significant upregulation at 4 weeks of HFHFD. Conversely, those gene expressions were significantly downregulated at 12 and 20 weeks of HFHFD, followed by a significant decrease in the protein level at 12 weeks. To confirm the mechanistic connection, miRNA-103 knockdown in vitro significantly upregulated Dicer and the TRBP2 gene. However, only Dicer exhibited a significant increase at the translational level. Conclusion: Overall, we conclude that HFHFD may elicit BAT dysfunction by inhibiting Dicer via miRNA-103.

Modulatory effects of rutin and vitamin A on hyperglycemia induced glycation, oxidative stress and inflammation in high-fat-fructose diet animal model.

In the current study we investigated the impact of combination of rutin and vitamin A on glycated products, the glyoxalase system, oxidative markers, and inflammation in animals fed a high-fat high-fructose (HFFD) diet. Thirty rats were randomly divided into six groups (n = 5). The treatments, metformin (120 mg/kg), rutin (100 mg/kg), vitamin A (43 IU/kg), and a combination of rutin (100 mg/kg) and vitamin A (43 IU/kg) were given to relevant groups of rats along with high-fructose high-fat diet for 42 days. HbA1c, D-lactate, Glyoxylase-1, Hexokinase 2, malondialdehyde (MDA), glutathione peroxidase (GPx), catalase (CAT), nuclear transcription factor-B (NF-κB), interleukin-6 (IL-6), interleukin-8 (IL-8) and histological examinations were performed after 42 days. The docking simulations were conducted using Auto Dock package. The combined effects of rutin and vitamin A in treated rats significantly (p < 0.001) reduced HbA1c, hexokinase 2, and D-lactate levels while preventing cellular damage. The combination dramatically (p < 0.001) decreased MDA, CAT, and GPx in treated rats and decreased the expression of inflammatory cytokines such as IL-6 andIL-8, as well as the transcription factor NF-κB. The molecular docking investigations revealed that rutin had a strong affinity for several important biomolecules, including as NF-κB, Catalase, MDA, IL-6, hexokinase 2, and GPx. The results propose beneficial impact of rutin and vitamin A as a convincing treatment strategy to treat AGE-related disorders, such as diabetes, autism, alzheimer's, atherosclerosis.