Impact of maternal high-fat diet on offspring gut microbiota during short-term high-fat diet exposure in mice.

Alterations in the gut microbiome have been linked to obesity, with maternal high-fat diet (HF) playing a role in shaping offspring microbiome composition. However, the sex-specific responses to maternal HF diet and the impact of subsequent dietary challenges remain unclear. This study investigated the effects of maternal HF diet on offspring gut microbiota structure and predicted functional profile in response to short-term postnatal HF diet exposure with a focus on sex-specific responses. Female and male offspring of maternal control (C) diet or maternal HF diet were weaned onto C diet or HF diet. Offspring were euthanized at 13 weeks of age and cecal contents were collected for bacterial taxonomic profiling. Maternal HF diet reduced α-diversity, notably in male offspring weaned onto HF diet. Sex-specific differences were observed in the gut microbial composition and predicted functional potential. Furthermore, the influence of maternal diet on bacterial community structure and functional potential varied depending on postnatal diet. Maternal HF diet led to increased relative abundance of Corynebacterium in female offspring and decreased abundance of Akkermansia and Roseburia in male offspring. These findings underscore the sexually dimorphic nature of maternal HF diet effects on gut microbiota composition and function, with implications for developmental programming and metabolic health.

Long-Term High-Fat Diet Aggravates Absence Seizures and Neurobehavioral Disorders Without Inducing Metabolic Disorders in WAG/Rij Rats: Involvement of Systemic and Central Inflammation.

The consumption of a high-fat diet (HFD) represents a risk factor for diseases such as obesity, diabetes, insulin resistance (IR), and different brain disorders. HFD-induced obesity is linked with systemic and neuroinflammation implicated in the pathogenesis of metabolic impairment and epilepsy. In this study, we studied the negative effects of HFD consumption (16 weeks) on absence epilepsy and behavior comorbidities in WAG/Rij rats, a well-validated idiopathic model of absence epilepsy and comorbidities. Moreover, we investigated how, by restoring a normocaloric diet (NCD; 12 weeks), epileptic seizures and neuropsychiatric comorbidities could improve. We found that the HFD group showed a worsening of absence seizures, aggravation of depressive-like behavior, and performance in learning and memory than the NCD group even in the absence of hyperglycemia and/or obesity. In addition, intestinal villus rupture, inflammatory infiltrate, and intestinal permeability alteration increased after prolonged HFD intake, which could prevent weight gain. Inflammatory protein levels were found higher in the colon of the HFD group than in the NCD group, and also in the cortex and hippocampus, regions involved in absence seizures and behavioral alterations. After replacing HFD with NCD, a reduction in absence seizures and behavioral alterations was observed, and this decrease was well correlated with an improvement in inflammatory pathways. In conclusion, HFD consumption is sufficient to disrupt gut integrity resulting in systemic and brain inflammation contributing to the worsening of absence epilepsy and its comorbidities also without obesity development. These alterations can be improved by switching back the diet to NCD.

Dietary Intervention with Omega-3 Fatty Acids Mitigates Maternal High-Fat Diet-Induced Behavioral and Myelin-Related Alterations in Adult Offspring.

BACKGROUND: Maternal high-fat diet (HFD) during pregnancy and lactation induces depression- like phenotype and provokes myelin-related changes in rat offspring in the prefrontal cortex (PFCTX), which persist even to adulthood. OBJECTIVE: Due to the plasticity of the developing brain, it was decided to analyze whether depressionlike phenotype and myelin-related changes in the early lifetime induced by maternal HFD (60% energy from fat) could be reversed by the omega-3 fatty acid-enriched diet (Ω3D) given from the postweaning period until adulthood (63rd day of life) in offspring. METHODS: We analyzed the effect of post-weaning Ω3D on the depressive-like phenotype (assessed by the forced swimming test) and myelin-related changes (measured using RT-qPCR, ELISA, and immunofluorescence staining) in the PFCTX of adult offspring. RESULTS: Ω3D reversed increased immobility time in adult offspring induced by maternal HFD, without affecting the animals' locomotor activity. Molecularly, Ω3D normalized the reduced expression levels of myelin-oligodendrocyte glycoprotein (MOG), as well as myelin and lymphocyte protein (MAL) in males and MOG in females in the PFCTX, changes initially induced by maternal HFD. Additionally, Ω3D normalized the quantity of oligodendrocyte precursor cells and mature oligodendrocytes in the prelimbic, infralimbic, and cingulate cortex in males, which were reduced following maternal HFD exposure. In females, the Ω3D effect was less pronounced, with normalization of oligodendrocyte precursors occurring only in the infralimbic cortex. CONCLUSION: These findings suggest that Ω3D may play a significant role in correcting behavioral and neurobiological changes caused by adverse prenatal conditions.

High-fat diet-induced obesity exacerbated collagenase-induced tendon injury with upregulation of interleukin-1beta and matrix metalloproteinase-1.

AIMS: Obesity increases tendinopathy's risk, but its mechanisms remain unclear. This study examined the effect of high-fat diet (HFD)-induced obesity on the outcomes and inflammation of collagenase-induced (CI) tendon injury. METHODS: Mice were fed with standard chow (SC) or HFD for 12 weeks. Bacterial collagenase I or saline was injected over the patellar tendons of each mouse. At weeks 2 and 8 post-injection, the patellar tendons were harvested for histology, immunohistochemical staining, and gait analysis. The difference (Δ) of limb-idleness index (LII) at the time of post-injury and pre-injury states was calculated. Biomechanical test of tendons was also performed at week 8 post-injection. RESULTS: HFD aggravated CI tendon injury with an increase in vascularity and cellularity compared to SC treatment. The histopathological score (week 2: p = 0.025; week 8: p = 0.013) and ΔLII (week 2: p = 0.012; week 8: p = 0.005) were significantly higher in the HFD group compared to those in the SC group after CI tendon injury. Stiffness (saline: p = 0.003; CI: p = 0.010), ultimate stress (saline: p < 0.001; CI: p = 0.006), and Young's modulus (saline: p = 0.017; CI: p = 0.007) were significantly lower in the HFD group compared to the SC group at week 8 after saline or collagenase injection. HFD induced higher expression of IL-1ß (week 2: p = 0.010; week 8: p = 0.025) and MMP-1 (week 2: p = 0.010; week 8: p = 0.004) compared to SC treatment after CI tendon injury at both time points. CONCLUSIONS: HFD-induced obesity exacerbated histopathological, functional, and biomechanical changes in the CI tendon injury model, which was associated with an upregulation of IL-1ß and MMP-1.

High-fat diet-induced L-saccharopine accumulation inhibits estradiol synthesis and damages oocyte quality by disturbing mitochondrial homeostasis.

High-fat diet (HFD) has been linked to female infertility. However, the specific age at which HFD impacts ovarian function and the underlying mechanisms remain poorly understood. Here, we administered a HFD to female mice at various developmental stages: pre-puberty (4 weeks old), post-puberty (6 weeks old), young adult (9 weeks old), and middle age (32 weeks old). Our observations indicated that ovarian function was most significantly compromised when HFD was initiated at post-puberty. Consequently, post-puberty mice were chosen for further investigation. Through transplantation of fecal bacteria from the HFD mice to the mice on a normal diet, we confirmed that gut microbiota dysbiosis contributed to HFD-induced deteriorated fertility and disrupted estradiol synthesis. Utilizing untargeted and targeted metabolomics analyses, we identified L-saccharopine as a key metabolite, which was enriched in the feces, serum, and ovaries of HFD and HFD-FMT mice. Subsequent in vitro and in vivo experiments demonstrated that L-saccharopine disrupted mitochondrial homeostasis by impeding AMPKα/MFF-mediated mitochondrial fission. This disruption ultimately hindered estradiol synthesis and compromised oocyte quality. AICAR, an activator of AMPKα, ameliorated L-saccharopine induced mitochondrial damage in granulosa cells and oocytes, thereby enhancing E2 synthesis and improving oocyte quality. Collectively, our findings indicate that the accumulation of L-saccharopine may play a pivotal role in mediating HFD-induced ovarian dysfunction. This highlights the potential therapeutic benefits of targeting the gut microbiota-metabolite-ovary axis to address HFD-induced ovarian dysfunction.

Fagopyrum dibotrys extract improves nonalcoholic fatty liver disease via inhibition of lipogenesis and endoplasmic reticulum stress in high-fat diet-fed mice.

OBJECTIVE: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing, presenting a treatment challenge due to limited options. Endoplasmic reticulum (ER) stress and associated lipid metabolism disorders are main causes of NAFLD, making it important to inhibit ER stress for effective treatment. Fagopyrum dibotrys has hypolipidemic, anti-inflammatory and hepatoprotective properties, showing promise in treating NAFLD. However, its effects on ER stress in NAFLD remain unclear. This study used a high-fat diet (HFD) to establish NAFLD mouse models and supplemented with Fagopyrum dibotrys extract (FDE) to evaluate its therapeutic effect and underlying mechanisms. RESULTS: We showed that FDE supplementation reduced the severity of hepatic steatosis and lowered triglycerides (TG) and total cholesterol (TC) levels in NAFLD mice. At the molecular level, FDE supplementation reduced hepatic lipid deposition by downregulating lipogenic markers (SREBP-1c, SCD1) and upregulating fatty acid oxidase CPT1α expression. Additionally, FDE treatment inhibited the overexpression of ER stress markers (GRP78, CHOP, and P-EIF2α) in NAFLD mice livers, and blocked the activation of the PERK-EIF2α-CHOP pathway, demonstrating its role in maintaining ER homeostasis. Considering that activation of the PERK pathway could exacerbate lipid deposition, our findings suggest that FDE has a protective effect against hepatic steatosis in NAFLD mice by attenuating ER stress, and the potential mechanism is through inhibiting the PERK pathway.

Obesity alters circadian and behavioral responses to constant light in male mice.

Exposure to artificial light during the night is known to promote disruption to the biological clock, which can lead to impaired mood and metabolism. Metabolic hormone secretion is modulated by the circadian pacemaker and recent research has shown that hormones such as insulin and leptin can also directly affect behavioral outcomes and the circadian clock. In turn, obesity itself is known to modulate the circadian rhythm and alter emotionality. This study investigated the behavioral and metabolic effects of constant light exposure in two models of obesity - a leptin null mutant (OB) and diet-induced obesity via high-fat diet. For both experiments, mice were placed into either a standard Light:Dark cycle (LD) or constant light (LL) and their circadian locomotor rhythms were continuously monitored. After 10 weeks of exposure to their respective lighting conditions, all mice were subjected to an open field assay to assess their explorative behaviors. Their metabolic hormone levels and inflammation levels were also measured. Behaviorally, exposure to constant light led to increased period lengthening and open field activity in the lean mice compared to both obesity models. Metabolically, LL led to increased cytokine levels and poorer metabolic outcomes in both lean and obese mice, sometimes exacerbating the metabolic issues in the obese mice, independent of weight gain. This study illustrates that LL can produce altered behavioral and physiological outcomes, even in lean mice. These results also indicate that obesity induced by different reasons can lead to shortened circadian rhythmicity and exploratory activity when exposed to chronic light.

EZH2-Mediated H3K27 Trimethylation in the Liver of Mice Is an Early Epigenetic Event Induced by High-Fat Diet Exposure.

BACKGROUND/OBJECTIVES: Methyltransferase EZH2-mediated H3K27me3 is involved in liver inflammation and fibrosis, but its role in hepatic metabolic derangements is not yet clearly defined. We investigated if a high-fat diet (HFD) induced early changes in EZH2 expression and H3K27 me3 in the liver of mice. METHODS: Five-week-old mice were fed an HFD or a low-fat diet (Control) for 2 weeks (2 W) or 8 weeks (8 W). Body weight was recorded weekly. Glycemia and oral glucose tolerance were assessed at baseline and after 2 W-8 W. Finally, livers were collected for further analysis. RESULTS: As expected, mice that received 8 W HFD showed an increase in body weight, glycemia, and liver steatosis and an impairment in glucose tolerance; no alterations were observed in 2 W HFD mice. Eight weeks of HFD caused hepatic EZH2 nuclear localization and increased H3 K27me3; surprisingly, the same alterations occurred in 2 W HFD mice livers, even before overweight onset. We demonstrated that selective EZH2 inhibition reduced H3K27me3 and counteracted lipid accumulation in HUH-7 cells upon palmitic acid treatment. CONCLUSIONS: In conclusion, we point to EZH2/H3K27me3 as an early epigenetic event occurring in fatty-acid-challenged livers both in vivo and in vitro, thus establishing EZH2 as a potential pharmacological target for metabolic derangements.

Evaluation of the Effects of Diet-Induced Obesity in Zebrafish (Danio rerio): A Comparative Study.

OBJECTIVES: This study aimed to compare diet-induced obesity (DIO) models in zebrafish and investigate the complications and differences between sexes in biochemical and inflammatory parameters. METHODS: Adult animals of both sexes were divided into four groups (n = 50) and fed for eight weeks: control group 1: Artemia sp. (15-30 mg/day/fish); control group 2: commercial fish food (3.5% of average weight); obesity group 1: pasteurized egg yolk powder + soybean oil (5% of average weight); obesity group 2: Artemia sp. (60-120 mg/day/fish). Dietary intake, caloric intake and efficiency, body mass index, biochemical, inflammatory, behavioral, histopathological, and stereological parameters, and inflammation-related gene expression were investigated. RESULTS: Obesity group 1 was the most indicated to investigate changes in the anxious behavioral profile (p < 0.05), triglyceride elevation [52.67 (1.2) mg/dL], adipocyte hypertrophy [67.8 (18.1) µm2; p = 0.0004], and intestinal inflammation. Obesity group 2 was interesting to investigate in terms of weight gain [167 mg; p < 0.0001), changes in fasting glucose [48.33 (4.14) mg/dL; p = 0.003), and inflammatory parameters [IL-6: 4.24 (0.18) pg/mL; p = 0.0015]. CONCLUSIONS: Furthermore, both DIO models evaluated in the present study were effective in investigating hepatic steatosis. The data also highlighted that sex influences inflammatory changes and fasting blood glucose levels, which were higher in males (p > 0.05). The results show new metabolic routes to be explored in relation to DIO in zebrafish.

Impact of reduced hepatic ceramide levels in high-fat diet mice on glucose metabolism.

Dysregulation of insulin action in hepatocytes, common in obesity, significantly contributes to insulin resistance, type 2 diabetes, and metabolic syndrome. Previous research highlights ceramides' role in these conditions. This study explores the impact of ceramides by silencing the serine palmitoyltransferase (Sptlc2) gene, crucial for the initial ceramide biosynthesis, using hydrodynamic gene delivery. Male C57BL/6 mice were randomly divided into three groups: one on a low-fat diet (LFD) receiving scrambled shRNA plasmids, another on a high-fat diet (HFD) with scrambled shRNA plasmids, and a third on HFD with a plasmid targeting Sptlc2. Analyses included RT-PCR for gene expression, western blot for protein levels, and UHPLC/MS/MS for lipid profiling. Glucose metabolism was evaluated via oral glucose tolerance tests, homeostatic model assessment of insulin resistance, and glucose-6-phosphate analysis. Results showed that HFD induces insulin resistance by inhibiting insulin signaling and increasing active lipid levels in hepatocytes. Sptlc2 silencing reduced ceramide accumulation, improving insulin signaling and glucose metabolism. Notably, ceramide synthesis inhibition did not significantly affect other lipid levels, highlighting ceramide's critical role in hepatic insulin resistance.

Delphinidin or α-amyrin attenuated liver steatosis and metabolic disarrangement in rats fed a high-fat diet.

Non-alcoholic fatty liver disease (NAFLD) is a liver pathology concomitant with metabolic disarrangement. This study assessed the therapeutic impacts of delphinidin, an anthocyanin, or α-amyrin, a pentacyclic triterpenoid, on NAFLD in rats and the underlying mechanisms involved. NAFLD was established by feeding a high-fat diet (HFD) for 10 weeks, either alone or in combination with delphinidin (40 mg/kg, oral) or α-amyrin (20 mg/kg, oral). Delphinidin or α-amyrin ameliorated the metabolic and histopathological perturbations induced by HFD. These compounds markedly attenuated NAFLD-induced hepatic steatosis, as evidenced by a substantial decrease in body weight, insulin resistance, and liver and adipose tissue indices. Alongside normalization of the atherogenic index, both improved HFD-mediated abnormalities in serum lipids, liver enzymes, leptin, and ghrelin levels. Moreover, their intervention activated the NFE2 like bZIP transcription factor 2 and heme oxygenase 1 pathways and abrogated HFD-triggered activation of mitogen-activated protein kinase 1 signaling. These remedies inhibited hepatic apoptosis and modulated the gene expression of lipogenic enzymes. Furthermore, histological analysis corroborated the suppression of lipid accumulation and amelioration of hepatic architecture in the treated rats. Our findings highlight the hepatoprotective value of delphinidin or α-amyrin against NAFLD and related metabolic diseases through their insulin-sensitizing, anti-inflammatory, antioxidant, and antiapoptotic effects.

The high-fat diet and low-dose streptozotocin type-2 diabetes model induces hyperinsulinemia and insulin resistance in male but not female C57BL/6J mice.

Translation of preclinical findings on the efficacy of dietary interventions for metabolic disease to human clinical studies is challenging due to the predominant use of male rodents in animal research. Our objective was to evaluate a combined high-fat (HF) diet and low-dose streptozotocin (STZ) model for induction of type-2 diabetes (T2D) in male and female C57BL/6J mice. We hypothesized that T2D biomarkers would differ significantly between sexes. Mice were administered either a low-fat (LF) diet (10% kcal from fat), or HF diet (60% kcal from fat) + STZ injections (30 mg/kg/d for 3 days). Both sexes gained weight and developed impaired postprandial oral glucose tolerance on the HF+STZ treatment compared to LF. Only male mice on HF + STZ developed fasting hyperglycemia, fasting hyperinsulinemia and insulin resistance, suggesting that the underlying causes of postprandial hyperglycemia differed between sexes. Principal component analysis of measures such as body weights, glucose and insulin concentrations indicated metabolic derangement for males only on HF+STZ treatment, while LF group males and both groups of females significantly overlapped. Based on our data, we accept our hypothesis that the combined high-fat diet and low-dose STZ model for T2D phenotypes differs significantly in its effect on mice based on sex. The HF diet + low-dose STZ model is not useful for studying insulin resistance in females. Other models are needed to model T2D, and study the effects of dietary interventions in this disease, in females. Sexual dimorphism remains a significant challenge for both preclinical and clinical research.

Arctigenin ameliorates high-fat diet-induced metabolic disorders by reshaping gut microbiota and modulating GPR/HDAC3 and TLR4/NF-κB pathways.

BACKGROUND: Arctigenin (AG), a phenylpropanoid lignan from the medicinal and food homologous plant Arctium lappa l., is known for its anti-cancer, anti-inflammatory and antioxidant properties. However, the pharmacological effects of AG on metabolic disorders remain limited, and specific mechanisms based on gut microbiota have not been reported. PURPOSE: This study aimed to evaluate the regulation of glycolipid metabolism by AG in obese mice and investigate the potential mechanisms associated with gut microbes. METHODS: The anti-obesity efficacy of AG was evaluated in high-fat diet (HFD)-fed mice. 16S rRNA gene sequencing and GC-MS were used to detect changes in gut microbes and metabolite levels. Immunohistochemistry, immunofluorescence, and polymerase chain reaction were used to validate the molecular mechanisms of gut microbe-derived metabolites involved in the improvement of intestinal homeostasis and hepatic metabolism by AG. RESULTS: We found that AG significantly ameliorated HFD-induced glucolipid metabolism disorders, liver degeneration and the imbalance of macrophage M1/M2 polarization. In addition, AG attenuated intestinal barrier damage, inflammation and imbalance of Th17/Treg immune in HFD mice. Importantly, AG promoted short-chain fatty acid (SCFA)-producing bacteria and SCFA levels, which regulated the G protein-coupled receptor (GPR)41/43 and HDAC3 pathways to induce FOXP3 protein expression and consequently maintained intestinal Th17/Treg immunity. AG also inhibited lipopolysaccharide (LPS) production leading to attenuation of TLR4/NF-κB-mediated intestinal inflammation. Furthermore, AG upregulated intestinal MCT1 protein levels to promote absorption of SCFA and activated the hepatic GPR41/43/109a-AMPK pathway to regulate lipid metabolism, and thus reduced lipid accumulation. CONCLUSION: This study first demonstrated that AG could modulate the gut microbiota and derived metabolites to repair intestinal damage and regulate hepatic metabolic pathways, thereby ameliorating metabolic disorders induced by HFD. These findings support the great potential of AG as a novel prebiotic to fight obesity and chronic metabolic diseases by targeting the gut microbiota.

Curcumin Modulates the Differential Effects of Fructose and High-Fat Diet on Renal Damage, Inflammation, Fibrosis, and Lipid Metabolism.

BACKGROUND: Dyslipidemia and obesity hypercaloric diet-induced lead to kidney damage. We investigated the effect of curcumin on the expression of proteins related to inflammation, fibrosis, fatty acids metabolism, kidney damage, and morphological changes in the kidneys of mice hypercaloric diets-fed. METHODS: Groups of 5-week-old C57BL/6 mice (n=6) were formed: Control (C), High-fructose diet (F), Highfructose diet and curcumin (F+Cur), High-fat diet (HFD), High-fat diet and curcumin (HFD+Cur), High-fat diet and fructose (HFD+F), High-fat diet, fructose and curcumin (HFD+F+Cur), treated for 16 weeks with 30% (w/v) fructose, 60% (w/w) fat and 0.75% (w/w) curcumin. Kidneys were obtained for histomorphological and Western Blot analysis. RESULTS: Curcumin prevented TNF-α overexpression in the F and HFD+F groups. VLCAD expression was higher in the F, HFD, and HFD+F groups. PPARγ expression was lower in the F+Cur, HFD+Cur, and HFD+F+Cur groups. Curcumin prevented overexpression of CPT1 and KIM1 in the HFD+F and HFD groups. Curcumin prevented morphological lesions, fibrosis, and lipid deposition that were hypercaloric diet-induced. CONCLUSION: Chronic consumption of hypercaloric diets causes inflammation, fibrosis, and lipid deposition in the kidney. It is suggested that curcumin prevents renal structural damage, limits tissue lipid deposition, and differentially modulates renal injury depending on diet composition in mice fed high-fat and/or high-fructose diets.

No Difference in Liver Damage Induced by Isocaloric Fructose or Glucose in Mice with a High-Fat Diet.

Background/Objectives: The diverse effects of fructose and glucose on the progression of metabolic dysfunction-associated steatotic liver disease remain uncertain. This study investigated the effects, in animal models, of high-fat diets (HFDs) supplemented with either glucose or fructose. Methods: Six-week-old, male C57BL/6J mice were randomly allocated to four groups: normal diet (ND), HFD, HFD supplemented with fructose (30% w/v, HFD + Fru), and HFD supplemented with glucose (initially 30%, HFD + Glu). After 24 weeks, liver and plasma samples were gathered for analysis. In addition, 39 patients with obesity undergoing bariatric surgery with wedge liver biopsy were enrolled in the clinical study. Results: The HFD + Glu group consumed more water than did the HFD and HFD + Fru groups. Thus, we reduced the glucose concentration from 30% at baseline to 15% at week 2 and 10% starting from week 6. The HFD + Fru and HFD + Glu groups had a similar average caloric intake (p = 0.463). The HFD increased hepatic steatosis, plasma lipid levels, lipogenic enzymes, steatosis-related oxidative stress, hepatic inflammation, and early-stage liver fibrosis. Supplementation with fructose or glucose exacerbated liver damage, but no significant differences were identified between the two. The expression patterns of hepatic ceramides in HFD-fed mice (with or without supplemental fructose or glucose) were similar to those observed in patients with obesity and severe hepatic steatosis or metabolic dysfunction-associated steatohepatitis. Conclusions: Fructose and glucose similarly exacerbated liver damage when added to an HFD. Ceramides may be involved in the progression of hepatic lipotoxicity.

Investigating the Hepatic Response to Orlistat and White Tea in Rats on a High-Fat Diet.

High-fat diets have detrimental health impacts that increase the likelihood of developing obesity and metabolic syndrome. This study aimed to examine the potential antioxidant and anti-inflammatory effects of orlistat and white tea in rats fed a high-fat diet. Thirty-two rats were randomized into four groups: control (standard diet), HFD (high-fat diet), HFD+Orlistat (high-fat diet+orlistat), and HFD+WT (high-fat diet+white tea extract). A significant increase in malondialdehyde (MDA) levels and a decrease in total thiol (TT) levels were detected in the HFD group (p < 0.001). On the other hand, a decrease in the MDA level (p < 0.001) and an increase in the TT level were observed in the orlistat and white tea groups compared with those in the HFD group (p < 0.001). Histopathological examinations revealed that, compared with the HFD alone, orlistat and white tea reduced fat accumulation, prevented degenerative changes in hepatocytes, and decreased the histopathological damage score (p = 0.001). Immunohistochemical examinations of nuclear factor-kappa B (NF-kB/p65) revealed that compared with the HFD, orlistat and white tea reduced immunopositivity (p = 0.001). White tea decreases lipid peroxidation and oxidative stress. Both white tea and orlistat decreased fat formation and inflammation in the liver and regulated inflammation by reducing Nf-kB positivity. Nevertheless, further research is needed to assess their impact on human subjects.

High-Fat Diet-Induced Blood-Brain Barrier Dysfunction: Impact on Allodynia and Motor Coordination in Rats.

The associations among increased pain sensitivity, obesity, and systemic inflammation have not been described as related to BBB dysfunctions. To analyze the metabolic, behavioral, and inflammatory effects of a high-fat diet (HFD) and ultrastructural modifications in brain regions, we used an in vivo experimental model. Adult male Wistar rats were randomly assigned to one of two conditions, an ad libitum control group or an HFD (60%)-fed group, for eight weeks. At the end of the protocol, glucose and insulin tolerance tests were performed. Additionally, we analyzed the response to a normally innocuous mechanical stimulus and changes in motor coordination. At the end of the protocol, HFD-fed rats presented increased HOMA-IR and metabolic syndrome (MetS) prevalence. HFD-fed rats also developed an increased nociceptive response to mechanical stimuli and neurological injury, resulting in impaired motor function. Hypothalamus and cerebellum neurons from HFD-fed rats presented with nuclear swelling, an absence of nucleoli, and karyolysis. These results reveal that HFD consumption affects vital brain structures such as the cerebellum, hippocampus, and hypothalamus. This, in turn, could be producing neuronal damage, impairing cellular communication, and consequently altering motricity and pain sensitivity. Although direct evidence of a causal link between BBB dysfunction and sensory-motor changes was not observed, understanding the association uncovered in this study could lead to targeted therapeutic strategies.

Thrombolysis exacerbates cerebrovascular injury after ischemic stroke via a VEGF-B dependent effect on adipose lipolysis.

Cerebrovascular injuries leading to edema and hemorrhage after ischemic stroke are common. The mechanisms underlying these events and how they are connected to known risk factors for poor outcome, like obesity and diabetes, is relatively unknown. Herein we demonstrate that increased adipose tissue lipolysis is a dominating risk factor for the development of a compromised cerebrovasculature in ischemic stroke. Reducing adipose lipolysis by VEGF-B antagonism improved vascular integrity by reducing ectopic cerebrovascular lipid deposition. Thrombolytic therapy in ischemic stroke using tissue plasminogen activator (tPA) leads to increased risk of hemorrhagic complications, substantially limiting the use of thrombolytic therapy. We provide evidence that thrombolysis with tPA promotes adipose tissue lipolysis, leading to a rise in plasma fatty acids and lipid accumulation in the ischemic cerebrovasculature after stroke. VEGF-B blockade improved the efficacy and safety of thrombolysis suggesting the potential use of anti-VEGF-B therapy to extend the therapeutic window for stroke management.

Targeted deletion of Fibroblast Growth Factor-23 rescues metabolic dysregulation of diet-induced obesity in female mice.

Fibroblast Growth Factor-23 (FGF23) is a bone secreted protein widely recognized as a critical regulator of skeletal and mineral metabolism. However, little is known about non-skeletal production of FGF23 and its role in tissues other than bone. Growing evidence indicates that circulating FGF23 levels rise with high fat diet (HFD) and they are positively correlated with body mass index (BMI) in humans. In the present study, we show for the first time that increased circulating FGF23 levels in obese humans correlate with increased expression of adipose Fgf23 and both positively correlate with BMI. To understand the role of adipose-derived Fgf23, we generated adipocyte-specific Fgf23 knockout mice (AdipoqFgf23Δfl/Δfl) using the Adiponectin (Adipoq)-Cre driver, which targets mature white, beige, and brown adipocytes. Our data show that targeted ablation of Fgf23 in adipocytes prevents HFD-fed female mice from gaining body weight and fat mass while preserving lean mass, but has no effect on male mice, indicating the presence of sexual dimorphism. These effects are observed in the absence of changes in food and energy intake. Adipose Fgf23 inactivation also prevents dyslipidemia, hyperglycemia, and hepatic steatosis in female mice. Moreover, these changes are associated with decreased respiratory exchange ratio (RER) and increased brown fat Ucp1 expression in KO mice compared to HFD-fed control mice (Fgf23fl/fl). In conclusion, this is the first study highlighting that targeted inactivation of Fgf23 is a promising therapeutic strategy for weight loss and lean mass preservation in humans.

Protective effects of lemon nanovesicles: evidence of the Nrf2/HO-1 pathway contribution from in vitro hepatocytes and in vivo high-fat diet-fed rats.

The cross-talk between plant-derived nanovesicles (PDNVs) and mammalian cells has been explored by several investigations, underlining the capability of these natural nanovesicles to regulate several molecular pathways. Additionally, PDNVs possess biological proprieties that make them applicable against pathological conditions, such as hepatic diseases. In this study we explored the antioxidant properties of lemon-derived nanovesicles, isolated at laboratory (LNVs) and industrial scale (iLNVs) in human healthy hepatocytes (THLE-2) and in metabolic syndrome induced by a high-fat diet (HFD) in the rat. Our findings demonstrate that in THLE-2 cells, LNVs and iLNVs decrease ROS production and upregulate the expression of antioxidant mediators, Nrf2 and HO-1. Furthermore, the in vivo assessment reveals that the oral administration of iLNVs improves glucose tolerance and lipid dysmetabolism, ameliorates biometric parameters and systemic redox homeostasis, and upregulates Nrf2/HO-1 signaling in HFD rat liver. Consequently, we believe LNVs/iLNVs might be a promising approach for managing hepatic and dysmetabolic disorders.