Reconstituting gut microbiota-colonocyte interactions reverses diet-induced cognitive deficits: The beneficial of eucommiae cortex polysaccharides.

Rationale: Consumption of a high-fat diet (HFD) has been implicated in cognitive deficits and gastrointestinal dysfunction in humans, with the gut microbiota emerging as a pivotal mediator of these diet-associated pathologies. The introduction of plant-based polysaccharides into the diet as a therapeutic strategy to alleviate such conditions is gaining attention. Nevertheless, the mechanistic paradigm by which polysaccharides modulate the gut microbiota remains largely undefined. This study investigated the mechanisms of action of Eucommiae cortex polysaccharides (EPs) in mitigating gut dysbiosis and examined their contribution to rectifying diet-related cognitive decline. Methods: Initially, we employed fecal microbiota transplantation (FMT) and gut microbiota depletion to verify the causative role of changes in the gut microbiota induced by HFD in synapse engulfment-dependent cognitive impairments. Subsequently, colonization of the gut of chow-fed mice with Escherichia coli (E. coli) from HFD mice confirmed that inhibition of Proteobacteria by EPs was a necessary prerequisite for alleviating HFD-induced cognitive impairments. Finally, supplementation of HFD mice with butyrate and treatment of EPs mice with GW9662 demonstrated that EPs inhibited the expansion of Proteobacteria in the colon of HFD mice by reshaping the interactions between the gut microbiota and colonocytes. Results: Findings from FMT and antibiotic treatments demonstrated that HFD-induced cognitive impairments pertaining to neuronal spine loss were contingent on gut microbial composition. Association analysis revealed strong associations between bacterial taxa belonging to the phylum Proteobacteria and cognitive performance in mice. Further, introducing E. coli from HFD-fed mice into standard diet-fed mice underscored the integral role of Proteobacteria proliferation in triggering excessive synaptic engulfment-related cognitive deficits in HFD mice. Crucially, EPs effectively counteracted the bloom of Proteobacteria and subsequent neuroinflammatory responses mediated by microglia, essential for cognitive improvement in HFD-fed mice. Mechanistic insights revealed that EPs promoted the production of bacteria-derived butyrate, thereby ameliorating HFD-induced colonic mitochondrial dysfunction and reshaping colonocyte metabolism. This adjustment curtailed the availability of growth substrates for facultative anaerobes, which in turn limited the uncontrolled expansion of Proteobacteria. Conclusions: Our study elucidates that colonocyte metabolic disturbances, which promote Proteobacteria overgrowth, are a likely cause of HFD-induced cognitive deficits. Furthermore, dietary supplementation with EPs can rectify behavioral dysfunctions associated with HFD by modifying gut microbiota-colonocyte interactions. These insights contribute to the broader understanding of the modulatory effects of plant prebiotics on the microbiota-gut-brain axis and suggest a potential therapeutic avenue for diet-associated cognitive dysfunction.

Dysregulation of mitochondrial dynamics and mitophagy are involved in High-fat diet-induced steroidogenesis inhibition.

Male obesity is a pandemic health issue and can disrupt testicular steroidogenesis. Here, we explored the mechanism by which High-fat diet (HFD)-induced steroidogenic inhibition. As expected, HFD induced lipid droplet accumulation and reduced the expression of StAR, P450scc, and 3ß-HSD, three steroidogenic enzymes, in mouse testes. Palmitic acid (PA), a saturated fatty acid is usually used to trigger lipotoxicity in vitro, induced greater accumulation of lipid droplets and the downregulation of steroidogenic enzymes in TM3 cells. Mechanistically, both HFD and PA disturbed mitochondrial fusion/fission dynamics, and then induced mitochondrial dysfunction and mitophagy inhibition in mouse Leydig cells. Additionally, mitochondrial fusion promoter M1 attenuated PA-induced imbalance of mitochondrial dynamics, mitophagy inhibition, mitochondrial reactive oxygen species (ROS) production and mitochondrial dysfunction in TM3 cells. Mitofusin 2 (MFN2) knock-down further aggravated PA-induced imbalance of mitochondrial dynamics, mitochondrial ROS production and mitochondrial dysfunction in TM3 cells. Importantly, M1 rescued PA-induced downregulation of steroidogenic enzymes, whereas MFN2 knock-down further aggravated PA-induced downregulation of steroidogenic enzymes in TM3 cells. Overall, our results provide laboratory evidence that mitochondrial dysfunction and mitophagy inhibition caused by dysregulation of mitochondrial fusion may be involved in HFD-induced steroidogenesis inhibition in mouse Leydig cells.

Time-restricted feeding does not prevent adverse effects of palatable cafeteria diet on adiposity, cognition and gut microbiota in rats.

Time-restricted feeding (TRF) is a popular dietary strategy whereby daily food intake is limited to a <12h window. As little is known about the effects of TRF on cognitive and behavioural measures, the present study examined the effects of time-restricted (8h/day; zeitgeber time [ZT]12-20) or continuous access to a high-fat, high-sugar cafeteria-style diet (Caf; Caf and Caf-TRF groups; n=12 adult male Sprague-Dawley rats) or standard chow (Chow and Chow-TRF groups) on short-term memory, anxiety-like behaviour, adiposity and gut microbiota composition over 13-weeks with daily food intake measures. TRF significantly reduced daily energy intake in Caf- but not chow-fed groups. In Caf-fed groups, TRF reduced the proportion of energy derived from sugar while increasing that derived from protein. Caf diet significantly increased weight gain, adiposity and fasting glucose within 4 weeks; TRF partially reduced these effects. Caf diet increased anxiety-like behaviour in the Elevated Plus Maze in week 3 but not week 12, and impaired hippocampal-dependent place recognition memory in week 11; neither measure was affected by TRF. Global microbiota composition differed markedly between chow and Caf groups, with a small effect of TRF in rats fed chow. In both chow and Caf diet groups, TRF reduced microbiota alpha diversity measures of Shannon diversity and evenness relative to continuous access. Results indicate only limited benefits of TRF access to an obesogenic diet under these conditions, suggesting that more severe time restriction may be required to offset adverse metabolic and cognitive effects when using highly palatable diets.

Hepatic changes following a high-fat diet: effects of Cornus mas and gold nanoparticles phytoreduced with Cornus mas on oxidative stress, inflammation, and histological damage.

Background and aims: High fat diet (HFD) can lead to liver injury, through oxidative stress and inflammation. The use of natural compounds with antioxidant and anti-inflammatory properties can have a protective potential. We aimed to investigate the effects of Cornus mas (CM) and gold nanoparticles phytoreduced with CM (GNPsCM) on hepatic alterations induced by HFD in rats. Methods: Female Sprague Dawley rats were randomly divided into four groups: control, HFD, HFD +CM and HFD + GNPsCM. The high fat diet was administered for 32 weeks and CM and GNPsCM were administered for 4 weeks after the HFD period. The high fat diet induced oxidative stress in liver, with lipid peroxidation and decreased antioxidant capacity, inflammation and minimal histological alterations. Results: The administration of CM and GNPsCM reduced lipid peroxidation produced by HFD and increased antioxidant potential in liver homogenates, while increasing inflammatory markers. Histological alterations were slightly improved by the intervention of compounds, and hyaluronic acid content of the liver without statistical significance as compared to HFD group. Conclusion: These findings support the potential of these treatments in addressing liver oxidative stress, mitigating liver damage induced by a high-fat diet. This investigation sheds light on the oxidative stress dynamics and histological alterations associated with high-fat diet-induced liver injury, contributing to our understanding of potential therapeutic interventions.

Matcha alleviates obesity by modulating gut microbiota and its metabolites.

Matcha shows promise for diabetes, obesity, and gut microbiota disorders. Studies suggest a significant link between gut microbiota, metabolites, and obesity. Thus, matcha may have a positive impact on obesity by modulating gut microbiota and metabolites. This study used 16S rDNA sequencing and untargeted metabolomics to examine the cecal contents in mice. By correlation analysis, we explored the potential mechanisms responsible for the positive effects of matcha on obesity. The results indicated that matcha had a mitigating effect on the detrimental impacts of a high-fat diet (HFD) on multiple physiological indicators in mice, including body weight, adipose tissue weight, serum total cholesterol (TC), and low-density lipoprotein (LDL) levels, as well as glucose tolerance. Moreover, it was observed that matcha had an impact on the structural composition of gut microbiota and gut metabolites. Specifically, matcha was able to reverse the alterations in the abundance of certain obesity-improving bacteria, such as Alloprevotella, Ileibacterium, and Rikenella, as well as the abundance of obesity-promoting bacteria Romboutsia, induced by a HFD. Furthermore, matcha can influence the levels of metabolites, including formononetin, glutamic acid, pyroglutamic acid, and taurochenodeoxycholate, within the gastrointestinal tract. Additionally, matcha enhances caffeine metabolism and the HIF-1 signaling pathway in the KEGG pathway. The results of the correlation analysis suggest that formononetin, theobromine, 1,3,7-trimethyluric acid, and Vitamin C displayed negative correlation with both the obesity phenotype and microbiota known to exacerbate obesity, while demonstrating positive correlations with microbiota that alleviated obesity. However, glutamic acid, pyroglutamic acid, and taurochenodeoxycholate had the opposite effect. In conclusion, the impact of matcha on gut metabolites may be attributed to its modulation of the abundance of Alloprevotella, Ileibacterium, Rikenella, and Romboutsia within the gastrointestinal tract, thereby potentially contributing to the amelioration of obesity.

Melinjo (Gnetum gnemon L.) seed extract for treatment of sleep/wake fragmentation in diet-induced obese mice.

Dietary supplementation with melinjo (Gnetum gnemon L.) seed extract (MSE) has been an integral part of an anti-obesity therapeutic regimen. To examine the relationship between anti-obesity and sleep, we explored the effect of MSE on sleep structure in high-fat diet (HFD)-induced obese mice. Although HFD did not alter the total amount of daily sleep, it significantly reduced the average duration of non-rapid eye movement (NREM) sleep and wakefulness episodes and significantly increased the number of these episodes. These findings indicate fragmented NREM sleep due to repeated brief awakenings in the HFD-fed mice. When 1% (w/v) MSE was given to HFD-fed mice, their weight or sleep structure were comparable to those of ND-fed mice, proving that dietary MSE completely hindered HFD-induced weight gain and sleep/wake fragmentation. Our data provide compelling evidence that MSE is a novel and promising dietary supplement that restores obesity-induced sleep architecture changes in mice.

Mice lacking ASIC2 and ßENaC are protected from high-fat-diet-induced metabolic syndrome.

Introduction: Degenerin proteins, such as ßENaC and ASIC2, have been implicated in cardiovascular function. However, their role in metabolic syndrome have not been studied. To begin to assess this interaction, we evaluated the impact of a high fat diet (HFD) on mice lacking normal levels of ASIC2 (ASIC2-/-) and ßENaC (ßENaCm/m). Methods: Twenty-week-old male and female mice were placed on a 60% HFD for 12 weeks. Body weight was measured weekly, and body composition by non-invasive ECHO MRI and fasting blood glucose were measured at 0, 4, 8 and 12 weeks. A glucose tolerance test was administered after 12 weeks. Differences between ASIC2-/-/ßENaCm/m and WT groups were compared using independent t-tests or ANOVA where appropriate within each sex. Data are presented as mean ± SEM and ASIC2-/-/ßENaCm/m vs. WT. Results: At 20 weeks of age, ASIC2-/-/ßENaCm/m mice (n=9F/10M) weighed less and gained less weight than WT (n=12F/16M). Total body fat and lean body masses were reduced in female and male ASIC2-/-/ßENaCm/m mice. Total body fat and lean body masses as % control were identical at the end of 12 weeks. Fasting blood glucoses were lower in female and male ASIC2-/-/ßENaCm/m vs. WT mice after 12 weeks HFD. The area under the curve for the glucose tolerance test was reduced in female and tended (p=.079) to decrease in male ASIC2-/-/ßENaCm/m. Plasma leptin and insulin were reduced in female and male ASIC2-/-/ßENaCm/m vs. WT mice. Plasma insulin in female ASIC2-/-/ßENaCm/m mice remained unchanged throughout the HFD period. Liver and liver fat masses, as well as percent liver fat, were reduced in both female and male ASIC2-/-/ßENaCm/m mice after HFD. Plasma triglycerides, cholesterol, LDL- and HDL-cholesterols were markedly improved in male and/or female ASIC2-/-/ßENaCm/m following the HFD. Discussion: These novel findings suggest that loss of ASIC2 and ßENaC offer a significant protection against HFD-induced metabolic syndrome.

Age and duration of obesity modulate the inflammatory response and expression of neuroprotective factors in mammalian female brain.

Obesity has become a global epidemic and is associated with comorbidities, including diabetes, cardiovascular, and neurodegenerative diseases, among others. While appreciable insight has been gained into the mechanisms of obesity-associated comorbidities, effects of age, and duration of obesity on the female brain remain obscure. To address this gap, adolescent and mature adult female mice were subjected to a high-fat diet (HFD) for 13 or 26 weeks, whereas age-matched controls were fed a standard diet. Subsequently, the expression of inflammatory cytokines, neurotrophic/neuroprotective factors, and markers of microgliosis and astrogliosis were analyzed in the hypothalamus, hippocampus, and cerebral cortex, along with inflammation in visceral adipose tissue. HFD led to a typical obese phenotype in all groups independent of age and duration of HFD. However, the intermediate duration of obesity induced a limited inflammatory response in adolescent females' hypothalamus while the hippocampus, cerebral cortex, and visceral adipose tissue remained unaffected. In contrast, the prolonged duration of obesity resulted in inflammation in all three brain regions and visceral adipose tissue along with upregulation of microgliosis/astrogliosis and suppression of neurotrophic/neuroprotective factors in all brain regions, denoting the duration of obesity as a critical risk factor for neurodegenerative diseases. Importantly, when female mice were older (i.e., mature adult), even the intermediate duration of obesity induced similar adverse effects in all brain regions. Taken together, our findings suggest that (1) both age and duration of obesity have a significant impact on obesity-associated comorbidities and (2) early interventions to end obesity are critical to preserving brain health.

Downregulation of CerS4 Instead of CerS2 in Liver Effectively Alleviates Hepatic Insulin Resistance in HFD Male Mice.

OBJECTIVE: Consumption of a high-fat diet (HFD) induces insulin resistance (IRes), significantly affecting the maintenance of normal glucose homeostasis. Nevertheless, despite decades of extensive research, the mechanisms and pathogenesis of IRes remain incomplete. Recent studies have primarily explored lipid intermediates such as diacylglycerol (DAG), given a limited knowledge about the role of ceramide (Cer) that is a potential mediator of the IRes in the liver. METHODS: In order to investigate the role of ceramide produced by CerS2 and CerS4 for the purpose of inducing the hepatic IRes, we utilised a unique in vivo model employing shRNA-mediated hydrodynamic gene delivery (HGD) in the liver of HFD-fed C57BL/6J mice. RESULTS: Downregulation of CerS4 instead of CerS2 reduced specific liver ceramides, notably C18:0-Cer and C24:0-Cer, as well as acylcarnitine levels. It concurrently promoted glycogen accumulation, leading to enhanced insulin sensitivity and glucose homeostasis. CONCLUSION: Those findings demonstrate that CerS4 downregulating lowers fasting blood glucose levels and mitigates the HFD-induced hepatic insulin resistance (IRes). It suggests that inhibiting the CerS4-mediated ceramide C18:0-Cer synthesis holds a promise to effectively address insulin resistance in obesity.

Tirzepatide administration improves cognitive impairment in HFD mice by regulating the SIRT3-NLRP3 axis.

PURPOSE: High-fat diet (HFD) currently is reported that in connection with cognitive impairment. Tirzepatide is a novel dual receptor agonist for glycemic control. But whether Tirzepatide exerts a protective effect in HFD-related cognitive impairment remains to be explore. METHODS: During the study, the cognitive dysfunction mice model induced by HFD were established. The expressions synapse-associated protein and other target proteins were detected. The oxidative stress parameters, levels of inflammatory cytokine were also detected. RESULTS: Our findings proved that Tirzepatide administration attenuates high fat diet-related cognitive impairment. Tirzepatide administration suppresses microglia activation, alleviates oxidative stress as well as suppressed the expression of NLRP3 in HFD mice by up-regulating SIRT3 expression. In conclusion, Tirzepatide attenuates HFD-induced cognitive impairment through reducing oxidative stress and neuroinflammation via SIRT3-NLRP3 signaling. CONCLUSION: This study suggest that Tirzepatide has neuroprotective effects in HFD-related cognitive dysfunction mice model, which provides a promising treatment of HFD-related cognitive impairment.

High fat diet consumption and social instability stress impair stress adaptation and maternal care in C57Bl/6 dams.

Poor maternal diet and psychosocial stress represent two environmental factors that can significantly impact maternal health during pregnancy. While various mouse models have been developed to study the relationship between maternal and offspring health and behaviour, few incorporate multiple sources of stress that mirror the complexity of human experiences. Maternal high-fat diet (HF) models in rodents are well-established, whereas use of psychosocial stress interventions in female mice are still emerging. The social instability stress (SIS) paradigm, serves as a chronic and unpredictable form of social stress. To evaluate the combined effects of a poor maternal diet and intermittent social stress on maternal health and behaviour, we developed a novel maternal stress model using adult female C57Bl/6 mice. We observed that all HF+ mice demonstrated rapid weight gain, elevated fasting blood glucose levels and impaired glucose tolerance independent of the presence (+) or absence (-) of SIS. Behavioural testing output revealed anxiety-like behaviours remained similar across all groups prior to pregnancy. However, integrated anxiety z-scores revealed a mixed anxious profile amongst HF+/SIS+ females prior to pregnancy. HF+/SIS+ females also did not show reduced plasma ACTH and corticosterone levels that were observed in our other HF+ and HF- stress groups after SIS exposure. Further, HF+/SIS+ females demonstrated significant postpartum maternal neglect, resulting in fewer numbers of live offspring. These findings suggest that prolonged maternal HF diet consumption, coupled with previous exposure to SIS, places a significant burden on the maternal stress response system, resulting in reduced parental investment and negative postpartum behaviour towards offspring.

Mapping lipid species remodeling in high fat diet-fed mice: Unveiling adipose tissue dysfunction with Raman microspectroscopy.

Dysregulated lipid metabolism in obesity leads to adipose tissue expansion, a major contributor to metabolic dysfunction and chronic disease. Lipid metabolism and fatty acid changes play vital roles in the progression of obesity. In this proof-of-concept study, Raman techniques combined with histochemical imaging methods were utilized to analyze the impact of a high-fat diet (HFD) on different types of adipose tissue in mice, using a small sample size (n = 3 per group). After six weeks of high-fat diet (HFD) feeding, our findings showed hypertrophy, elevated collagen levels, and increased macrophage presence in the adipose tissues of the HFD group compared to the low-fat diet (LFD) group. Statistical analysis of Raman spectra revealed significantly lower unsaturated lipid levels and higher lipid to protein content in different fat pads (brown adipose tissue (BAT), subcutaneous white adipose tissue (SWAT), and visceral white adipose tissue (VWAT)) with HFD. Raman images of adipose tissues were analyzed using Empty modeling and DCLS methods to spatially profile unsaturated and saturated lipid species in the tissues. It revealed elevated levels of ω-3, ω-6, cholesterol, and triacylglycerols in BAT adipose tissues of HFD compared to LFD tissues. These findings indicated that while cholesterol, ω-6/ω-3 ratio, and triacylglycerol levels have risen in the SWAT and VWAT adipose tissues of the HFD group, the levels of ω-3 and ω-6 have decreased following the HFD. The study showed that Raman spectroscopy provided invaluable information at the molecular level for investigating lipid species remodeling and spatial mapping of adipose tissues during HFD.

The effects of a diet with high fat content from lard on the health and adipose-markers' mRNA expression in mice.

Pork is one type of the most frequently consumed meat with about 30% globally. Thus, the questions regarding to the health effects of diet with high fat content from lard are raised. Here, we developed a model of mice fed with high fat (HF) from lard to investigate and have more insights on the effects of long-time feeding with HF on health. The results showed that 66 days on HF induced a significant gain in the body weight of mice, and this weight gain was associated to the deposits in the white fat, but not brown fat. The glucose tolerance, not insulin resistance, in mice was decreased by the HF diet, and this was accompanied with significantly higher blood levels of total cholesterol and triglycerides. Furthermore, the weight gains in mice fed with HF seemed to link to increased mRNA levels of adipose biomarkers in lipogenesis, including Acly and Acaca genes, in white fat tissues. Thus, our study shows that a diet with high fat from lard induced the increase in body weight, white fat depots' expansion, disruption of glucose tolerance, blood dyslipidemia, and seemed to start affecting the mRNA expression of some adipose biomarkers in a murine model.

Impact of Lipids on Insulin Resistance: Insights from Human and Animal Studies.

Insulin resistance (IR) is a complex pathological condition central to metabolic diseases such as type 2 diabetes mellitus (T2DM), cardiovascular disease, non-alcoholic fatty liver disease, and polycystic ovary syndrome (PCOS). This review evaluates the impact of lipids on insulin resistance (IR) by analyzing findings from human and animal studies. The articles were searched on the PubMed database using two keywords: (1) "Role of Lipids AND Insulin Resistance AND Humans" and (2) "Role of Lipids AND Insulin Resistance AND Animal Models". Studies in humans revealed that elevated levels of free fatty acids (FFAs) and triglycerides (TGs) are closely associated with reduced insulin sensitivity, and interventions like metformin and omega-3 fatty acids show potential benefits. In animal models, high-fat diets disrupt insulin signaling and increase inflammation, with lipid mediators such as diacylglycerol (DAG) and ceramides playing significant roles. DAG activates protein kinase C, which eventually impairs insulin signaling, while ceramides inhibit Akt/PKB, further contributing to IR. Understanding these mechanisms is crucial for developing effective prevention and treatment strategies for IR-related diseases.

Opuntia humifusa stems rich in quercetin and isorhamnetin alleviate insulin resistance in high-fat diet-fed rats.

BACKGROUND/OBJECTIVES: Obesity, characterized by abnormal fat accumulation and metabolic disturbances, presents a significant health challenge. Opuntia humifusa Raf., commonly known as Korean Cheonnyuncho, is rich in various beneficial compounds and has demonstrated antioxidant and anti-inflammatory effects. However, its potential impact on glucose and lipid metabolism, particularly in obese rats, remains unexplored. We aimed to investigate whether O. humifusa stems and fruits could beneficially alter glucose metabolism and lipid profiles in a rat model of high-fat diet (HFD)-induced obesity. MATERIALS/METHODS: Thirty-two rats were allocated into 4 groups: normal diet (NF), HFD control (HF), HFD treated with 2% O. humifusa stems (HF-OS), and HFD treated with 2% O. humifusa fruits (HF-OF). Experimental diets were administered for 6 weeks. At the end of the treatment, liver and fat tissues were isolated, and serum was collected for biochemical analysis. The major flavonoid from O. humifusa stems and fruits was identified and quantified. RESULTS: After 6 weeks of treatment, the serum fasting glucose concentration in the HF-OS group was significantly lower than that in the HF group. Serum fasting insulin concentrations in both HF-OS and HF-OF groups tended to be lower than those in the HF group, indicating a significant improvement in insulin sensitivity in the HF-OS group. Additionally, the HF-OS group exhibited a tendency towards the restoration of adiponectin levels to that of the NF group. CONCLUSION: The 2% O. humifusa stems contain abundant quercetin and isorhamnetin, which alter fasting blood glucose levels in rats fed a HFD, leading to a favorable improvement in insulin resistance.

Global deletion of G protein-coupled receptor 55 impairs glucose homeostasis during obesity by reducing insulin secretion and ß-cell turnover.

AIM: To investigate the effect of G protein-coupled receptor 55 (GPR55) deletion on glucose homeostasis and islet function following diet-induced obesity. METHODS: GPR55-/- and wild-type (WT) mice were fed ad libitum either standard chow (SC) or a high-fat diet (HFD) for 20 weeks. Glucose and insulin tolerance tests were performed at 9/10 and 19/20 weeks of dietary intervention. Insulin secretion in vivo and dynamic insulin secretion following perifusion of isolated islets were also determined, as were islet caspase-3/7 activities and ß-cell 5-bromo-20-deoxyuridine (BrdU) incorporation. RESULTS: GPR55-/- mice fed a HFD were more susceptible to diet-induced obesity and were more glucose intolerant and insulin resistant than WT mice maintained on a HFD. Islets isolated from HFD-fed GPR55-/- mice showed impaired glucose- and pcacahorbol 12-myristate 13-acetate-stimulated insulin secretion, and they also displayed increased cytokine-induced apoptosis. While there was a 5.6 ± 1.6-fold increase in ß-cell BrdU incorporation in the pancreases of WT mice fed a HFD, this compensatory increase in ß-cell proliferation in response to the HFD was attenuated in GPR55-/- mice. CONCLUSIONS: Under conditions of diet-induced obesity, GPR55-/- mice show impaired glucose handling, which is associated with reduced insulin secretory capacity, increased islet cell apoptosis and insufficient compensatory increases in ß-cell proliferation. These observations support that GPR55 plays an important role in positively regulating islet function.

Sex Differences Affect the NRF2 Signaling Pathway in the Early Phase of Liver Steatosis: A High-Fat-Diet-Fed Rat Model Supplemented with Liquid Fructose.

Sex differences may play a role in the etiopathogenesis and severity of metabolic dysfunction-associated steatotic liver disease (MASLD), a disorder characterized by excessive fat accumulation associated with increased inflammation and oxidative stress. We previously observed the development of steatosis specifically in female rats fed a high-fat diet enriched with liquid fructose (HFHFr) for 12 weeks. The aim of this study was to better characterize the observed sex differences by focusing on the antioxidant and cytoprotective pathways related to the KEAP1/NRF2 axis. The KEAP1/NRF2 signaling pathway, autophagy process (LC3B and LAMP2), and endoplasmic reticulum stress response (XBP1) were analyzed in liver homogenates in male and female rats that were fed a 12-week HFHFr diet. In females, the HFHFr diet resulted in the initial activation of the KEAP1/NRF2 pathway, which was not followed by the modulation of downstream molecular targets; this was possibly due to the increase in KEAP1 levels preventing the nuclear translocation of NRF2 despite its cytosolic increase. Interestingly, while in both sexes the HFHFr diet resulted in an increase in the levels of LC3BII/LC3BI, a marker of autophagosome formation, only males showed a significant upregulation of LAMP2 and XBP1s; this did not occur in females, suggesting impaired autophagic flux in this sex. Overall, our results suggest that males are characterized by a greater ability to cope with an HFHFr metabolic stimulus mainly through an autophagic-mediated proteostatic process while in females, this is impaired. This might depend at least in part upon the fine modulation of the cytoprotective and antioxidant KEAP1/NRF2 pathway resulting in sex differences in the occurrence and severity of MASLD. These results should be considered to design effective therapeutics for MASLD.

Nobiletin restores HFD-induced enteric nerve injury by regulating enteric glial activation and the GDNF/AKT/FOXO3a/P21 pathway.

BACKGROUND: To explore whether nobiletin has a protective effect on high-fat diet (HFD)-induced enteric nerve injury and its underlying mechanism. METHODS: An obesity model was induced by a HFD. Nobiletin (100 mg/kg and 200 mg/kg) and vehicle were administered by gastric gavage for 4 weeks. Lee's index, body weight, OGTT and intestinal propulsion assays were performed before sacrifice. After sampling, lipids were detected using Bodipy 493/503; lipid peroxidation was detected using MDA and SOD kits and the expression of PGP 9.5, Trem2, GFAP, ß-tubulin 3, Bax, Bcl2, Nestin, P75 NTR, SOX10 and EDU was detected using immunofluorescence. The GDNF, p-AKT, AKT, p-FOXO3a, FOXO3a and P21 proteins were detected using western blotting. The relative mRNA expression levels of NOS2 were detected via qPCR. Primary enteric neural stem cells (ENSCs) were cultured. After ENSCs were treated with palmitic acid (PA) and nobiletin, CCK-8 and caspase-3/7 activity assays were performed to evaluate proliferation and apoptosis. RESULTS: HFD consumption caused colon lipid accumulation and peroxidation, induced enteric nerve damage and caused intestinal motor dysfunction. However, nobiletin reduced lipid accumulation and peroxidation in the colon; promoted Trem2, ß-tubulin 3, Nestin, P75NTR, SOX10 and Bcl2 expression; inhibited Bax and GFAP expression; reduced NOS2 mRNA transcription; and regulated the GDNF/AKT/FOXO3a/P21 pathway. Nobiletin also promoted PA-induced impairment of ENSCs. CONCLUSIONS: Nobiletin restored HFD-induced enteric nerve injury, which may be associated with inhibiting enteric nerve apoptosis, promoting enteric nerve survival and regulating the GDNF/AKT/FOXO3a/P21 pathway.

Dietary Polycan, a ß-glucan originating from Aureobasidium pullulansSM-2001, attenuates high-fat-diet-induced intestinal barrier damage in obese mice by modulating gut microbiota dysbiosis.

Various metabolic diseases caused by a high-fat diet (HFD) are closely related to gut microbiota dysbiosis and epithelial barrier dysfunction. Polycan, a type of ß-glucan, is effective in treating anti-obesity and metabolic diseases caused by HFD. However, the effect of Polycan on dysbiosis and epithelial barrier damage is still unknown. In this study, the effects of Polycan on dysbiosis and intestinal barrier damage were investigated using HFD-induced obese model mice. C57BL/6 mice were fed a HFD for 12 weeks and treated with two different doses of Polycan (250 and 500 mg/kg) orally administered during weeks 9 to 12. Polycan supplementation increased the expression of tight junction genes (zonula occludens-1, occludin, and claudin-3) and short-chain fatty acid (SCFA) content while reducing toxic substances (phenol, p-cresol, and skatole). Most significantly, Polycan enriched SCFA-producing bacteria (i.e., Phocaeicola, Bacteroides, Faecalibaculum, Oscillibacter, Lachnospiraceae, and Muribaculaceae), and decreased the Firmicutes/Bacteroidetes ratio and toxic substances-producing bacteria (i.e., Olsenella, Clostridium XVIII, and Schaedlerella). Furthermore, microbial functional capacity prediction of the gut microbiota revealed that Polycan enriched many SCFA-related KEGG enzymes while toxic substance-related KEGG enzymes were depleted. These findings indicated that Polycan has the potential to alleviate HFD-induced intestinal barrier damage by modulating the function and composition of the gut microbiota.

Effects of a high-fat diet on cognition and brain distribution of intranasal insulin in E3 and E4 male and female mice.

There are genetic and environmental risk factors that contribute to the development of cognitive decline in Alzheimer's disease (AD). Some of these include the genetic predisposition of the apolipoprotein E4 genotype, consuming a high-fat diet (HFD), and the female sex. Brain insulin receptor resistance and deficiency have also been shown to be associated with AD and cognitive impairment. Intranasal (INL) insulin enhances cognition in AD, but the response varies due to genotype, diet, and sex. We investigated here the combination of these risk factors in a humanized mouse model, expressing E3 or E4, following a HFD in males and females on cognitive performance and the brain distribution of insulin following INL delivery. The HFD had a negative effect on survival in male mice only, requiring sex to be collapsed. We found many genotype, diet, and genotype x diet effects in anxiety-related tasks. We further found beneficial effects of INL insulin in our memory tests, with the most important findings showing a beneficial effect of INL insulin in mice on a HFD. We found insulin distribution throughout the brain after INL delivery was largely unaffected by diet and genotype, indicating these susceptible groups can still receive adequate levels of insulin following INL delivery. Our findings support the involvement of brain insulin signaling in cognition and highlight continuing efforts investigating mechanisms resulting from treatment with INL insulin.