Search Results (42)

Diabetes, a major global healthcare challenge, is characterized by chronic hyperglycemia and significantly exacerbates the severity of systemic complications. Iron, an essential element ubiquitously present in biological systems, is involved in many biological processes facilitating cell proliferation and growth. However, excessive iron accumulation promotes oxidative damage through the Fenton reaction, thereby increasing the incidence of diabetes and worsening diabetic complications. Notably, ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key mechanism underlying diabetes and diabetic complications. In this review, we provide an update on the current understanding of iron metabolism dysregulation in diabetes risk, and disclose the mechanistic links between iron overload and diabetes evidenced in hereditary hemochromatosis and thalassemia. We particularly highlight iron-mediated oxidative stress as a central nexus impairing glucose metabolism and insulin sensitivity. Furthermore, we discuss the significance of dysmetabolic iron and ferroptosis activation in the progression of diabetes and diabetic complications, as well as the possible application of natural products for iron metabolism regulation and ferroptosis-inhibition-targeted therapeutic strategies to treat diabetes and diabetic complications. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) begins with hepatic lipid accumulation and triggers insulin resistance. Hibiscus leaf extract exhibits antioxidant and anti-atherosclerotic activities, and is rich in (−)-epicatechin gallate (ECG). Despite ECG’s well-known pharmacological activities and its total antioxidant capacity being stronger than that of other catechins, its regulatory effects on MASLD have not been fully described previously. Therefore, this study attempted to evaluate the anti-MASLD potential of ECG isolated from Hibiscus leaves on abnormal lipid and glucose metabolism in hepatocytes. First, oleic acid (OA) was used as an experimental model to induce lipid dysmetabolism in human primary hepatocytes. Treatment with ECG can significantly (p < 0.05) reduce the OA-induced cellular lipid accumulation. Nile red staining revealed, compared to the OA group, the inhibition percentages of 29, 61, and 82% at the tested doses of ECG, respectively. The beneficial effects of ECG were associated with the downregulation of SREBPs/HMGCR and upregulation of PPARα/CPT1 through targeting AMPK. Also, ECG at 0.4 µM produced a significant (p < 0.01) decrease in oxidative stress by 83%, and a marked (p < 0.05) increase in glycogen synthesis by 145% on the OA-exposed hepatocytes with insulin signaling blockade. Mechanistic assays indicated lipid and glucose metabolic homeostasis of ECG might be mediated via regulation of lipogenesis, fatty acid β-oxidation, and insulin resistance, as confirmed by an AMPK inhibitor. These results suggest ECG is a dual modulator of lipid and carbohydrate dysmetabolism in hepatocytes. Full article

Postprandial dysmetabolism, which refers to the impaired regulation of glucose and lipid levels after meals, is recognized as an independent risk factor for cardiovascular diseases (CVDs). Diets rich in polyphenols have demonstrated potential in improving postprandial hyperglycemia and hyperlipidemia. This study investigates the effects of olive leaf polyphenols on postprandial metabolic outcomes following a high-fat and high-carbohydrate meal. A total of 36 healthy adults participated in a three-arm randomized crossover trial. They ingested either a biscuit made from olive leaf powder (OLB), olive leaf tea (OLT), or a placebo meal (CTRL) to assess the impact of olive leaf polyphenols on postprandial glycemia, lipid levels, platelet aggregation factor (PAF), and plasma antioxidant status (TAC). Although no statistically significant differences were observed in the primary biomarkers, including glucose and lipid profiles, a delayed insulin response was noted in the interventions involving olive leaf. These findings suggest that while acute olive leaf supplementation did not significantly alter postprandial glycemia or lipidemia, it may subtly influence insulin kinetics. Further research is needed to explore the long-term effects of olive leaf polyphenols on metabolic health, especially in populations at risk for CVDs. Full article

Metabolic syndrome (MetS) poses considerable toxicological risks due to its association with an increased likelihood of metabolic dysfunction-associated steatotic liver disease (MASLD), and is characterized by hypertension, hyperglycemia, dyslipidemia, and obesity. This study aimed to investigate the therapeutic potential of flavonoid-rich lotus seedpod extract (LSE) in alleviating MetS and MASLD-related hepatic disturbances. In vivo, mice subjected to a high-fat diet (HFD) and streptozotocin (STZ) injection were supplemented with LSE or simvastatin for 6 weeks. Obesity indicators included body weight and epididymal fat, while insulin resistance was measured by fasting serum glucose, serum insulin, homeostasis model assessment–insulin resistance index (HOMA-IR), and oral glucose tolerance (OGTT). Also, the levels of serum lipid profiles and blood pressure were evaluated. Adipokines, proinflammatory cytokines, liver fat droplets, and peri-portal fibrosis were analyzed to clarify the mechanism of MetS. LSE significantly reduced the HFD/STZ-induced MetS markers better than simvastatin, as demonstrated by hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory effects. In vitro, LSE improved oleic acid (OA)-triggered phenotypes of MASLD in hepatocyte HepG2 cells by reducing lipid accumulation and enhancing cell viability. This effect might be mediated through proteins involved in lipogenesis that are downregulated by adenosine monophosphate-activated protein kinase (AMPK). In addition, LSE reduced reactive oxygen species (ROS) generation and glycogen levels, as demonstrated by enhancing insulin signaling involving reducing insulin receptor substrate-1 (IRS-1) Ser307 phosphorylation and increasing glycogen synthase kinase 3 beta (GSK3β) and protein kinase B (PKB) expression. These benefits were dependent on AMPK activation, as confirmed by the AMPK inhibitor compound C. These results indicate that LSE exhibits protective effects against MetS-caused toxicological disturbances in hepatic carbohydrate and lipid metabolism, potentially contributing to its efficacy in preventing MASLD or MetS. Full article

Chronic liver diseases (CLDs) in dogs are progressive conditions that often lead to liver failure. Metabolic dysfunctions such as cholestasis, obesity, hyperlipidemia, and endocrine disorders play a key role in human liver diseases like MASLD (Metabolic Dysfunction Associated Steatotic Liver Disease) and MASH (Metabolic Dysfunction Associated Steatohepatitis), but their significance in canine CLDs is poorly understood. This study aims to evaluate the association between hepatic lipid accumulation and inflammation or fibrosis in canine CLDs and its potential association with metabolic dysfunctions. Sixteen client-owned dogs with CLDs were assessed for clinical data, histological features, and liver immunohistochemistry (IHC). Histological and IHC markers of inflammation (Iba-1, iNOS, NF-κB), fibrosis (CD206, α-SMA, Sirius Red), and lipid accumulation (adipophilin) were assessed to identify correlations with clinical conditions. The applied markers showed effectiveness in their use on canine liver tissue. Adipophilin-marked lipid accumulation correlated positively with inflammatory markers, indicating a link between steatosis and inflammation. Metabolic dysfunctions were linked to hepatic lipid accumulation and inflammation. These findings show a potential alignment of canine CLDs with human MASLD/MASH, where lipid-induced inflammation drives disease progression. IHC markers could effectively assess these processes, suggesting potential for guiding diagnostics and therapies, though further research is needed to clarify clinical associations. Full article

Golden tomato (GT), harvested at the veraison stage, has gained attention due to its rich content of bioactive compounds and potential health benefits. Previous studies have highlighted GT’s antioxidant properties and its positive effects on metabolic syndrome (MetS), a condition characterized by obesity, dyslipidemia, and oxidative stress. This study investigates for the first time a derivative from GT, i.e., the juice (GTJ), which could be a potential candidate for development as a functional food. We first characterized GT juice, identifying 9-oxo-10(E),12(E)-octadecadienoic (9-oxo-10(E),12(E)-ODA) fatty acid, a known peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, using High-Performance Liquid Chromatography (HPLC)–mass spectrometry. Then, using a high-fat-diet (HFD) rat model, we assessed the impact of daily GT juice supplementation in addressing MetS. We outlined that GTJ improved body weight and leptin-mediated food intake. Moreover, it ameliorated glucose tolerance, lipid profile, systemic redox homeostasis, hepatic oxidative stress, and steatosis in HFD rats. Furthermore, GT juice enhances the hepatic transcription of PPAR-α, thus putatively promoting fatty acid oxidation and lipid metabolism. These findings suggest that GT juice mitigates lipidic accumulation and putatively halters oxidative species at the hepatic level through PPAR-α activation. Our study underscores the protective effects of GT juice against MetS, highlighting its future potential as a nutraceutical for improving dysmetabolism and associated alterations. Full article

Among the non-communicable neurological diseases, epilepsy is characterized by abnormal brain activity with several peripheral implications. The role of peripheral inflammation in the relationship between seizure development and nonalcoholic fatty liver disease based on sex difference remains still overlooked. Severe early-life infections lead to increased inflammation that can aggravate epilepsy and hepatic damage progression, both related to increased odds of hospitalization for epileptic patients with liver diseases. Here, we induced a post-natal-day 3 (PND3) infection by LPS (1 mg/kg, i.p.) to determine the hepatic damage in a genetic model of young epileptic WAG/Rij rats (PND45). We evaluated intra- and inter-gender differences in systemic and liver inflammation, hepatic lipid dysmetabolism, and oxidative damage related to mitochondrial functional impairment. First, epileptic rats exposed to LPS, regardless of gender, displayed increased serum hepatic enzymes and altered lipid profile. Endotoxin challenge triggered a more severe inflammatory and immune response in male epileptic rats, compared to females in both serum and liver, increasing pro-inflammatory cytokines and hepatic immune cell recruitment. Conversely, LPS-treated female rats showed significant alterations in systemic and hepatic lipid profiles and reduced mitochondrial fatty acid oxidation. The two different sex-dependent mechanisms of LPS-induced liver injury converge in increased ROS production and related mitochondrial oxidative damage in both sexes. Notably, a compensatory increase in antioxidant defense was evidenced only in female rats. Our study with a translational potential demonstrates, for the first time, that early post-natal infections in epileptic rats induced or worsened hepatic disorders in a sex-dependent manner, amplifying inflammation, lipid dysmetabolism, and mitochondrial impairment. Full article

Background/Objectives: Lipid dysmetabolism seems to contribute to the development and progression of nonalcoholic fatty liver disease (NAFLD). Our aim was to compare serum lipidomic profile between patients with NAFLD having received monotherapy with vitamin E (400 IU/d) and those having received combination therapy with vitamin E (400 IU/d) and low-dose spironolactone (25 mg/d) for 52 weeks. Methods: This was a post hoc study of a randomized controlled trial (NCT01147523). Serum lipidomic analysis was performed in vitamin E monotherapy group (n = 15) and spironolactone plus vitamin E combination therapy group (n = 12). We employed an untargeted liquid chromatography–mass spectrometry lipid profiling approach in positive and negative ionization mode. Results: Univariate analysis revealed 36 lipid molecules statistically different between groups in positive mode and seven molecules in negative mode. Multivariate analysis in negative mode identified six lipid molecules that remained robustly different between groups. After adjustment for potential confounders, including gender, omega-3 supplementation, leptin concentration and homeostasis model assessment—insulin resistance (HOMA-IR), four lipid molecules remained significant between groups: FA 20:5, SM 34:2;O2, SM 42:3;O2 and CE 22:6, all being higher in the combination treatment group. Conclusions: The combination of spironolactone with vitamin E led to higher circulating levels of four lipid molecules than vitamin E monotherapy, after adjustment for potential confounders. Owing to very limited relevant data, we could not support that these changes in lipid molecules may be beneficial or not for the progression of NAFLD. Thus, mechanistic studies are warranted to clarify the potential clinical significance of these findings. Full article

Type 2 diabetes (T2D) is a global public health issue characterized by excess weight, abdominal obesity, dyslipidemia, hyperglycemia, and a progressive increase in insulin resistance. Human population studies of T2D development and its effects on systemic metabolism are confounded by many factors that cannot be controlled, complicating the interpretation of results and the identification of early biomarkers. Aged, sedentary, and overweight/obese non-human primates (NHPs) are one of the best animal models to mimic spontaneous T2D development in humans. We sought to identify and distinguish a set of plasma and/or fecal metabolite biomarkers, that have earlier disease onset predictability, and that could be evaluated for their predictability in subsequent T2D studies in human cohorts. In this study, a single plasma and fecal sample was collected from each animal in a colony of 57 healthy and dysmetabolic NHPs and analyzed for metabolomics and lipidomics. The samples were comprehensively analyzed using untargeted and targeted LC/MS/MS. The changes in each animal’s disease phenotype were monitored using IVGTT, HbA1c, and other clinical metrics, and correlated with their metabolic profile. The plasma and fecal lipids, as well as bile acid profiles, from Healthy, Dysmetabolic (Dys), and Diabetic (Dia) animals were compared. Following univariate and multivariate analyses, including adjustments for weight, age, and sex, several plasma lipid species were identified to be significantly different between these animal groups. Medium and long-chain plasma phosphatidylcholines (PCs) ranked highest at distinguishing Healthy from Dys animals, whereas plasma triglycerides (TG) primarily distinguished Dia from Dys animals. Random Forest (RF) analysis of fecal bile acids showed a reduction in the secondary bile acid glycoconjugate, GCDCA, in diseased animals (AUC 0.76[0.64, 0.89]). Moreover, metagenomics results revealed several bacterial species, belonging to the genera Roseburia, Ruminococcus, Clostridium, and Streptococcus, to be both significantly enriched in non-healthy animals and associated with secondary bile acid levels. In summary, our results highlight the detection of several elevated circulating plasma PCs and microbial species associated with fecal secondary bile acids in NHP dysmetabolic states. The lipids and metabolites we have identified may help researchers to differentiate individual NHPs more precisely between dysmetabolic and overtly diabetic states. This could help assign animals to study groups that are more likely to respond to potential therapies where a difference in efficacy might be anticipated between early vs. advanced disease. Full article

Maternal obesity and gestational diabetes predispose the next generation to metabolic disturbances. Moreover, the lactation phase also stands as a critical phase for metabolic programming. Nevertheless, the precise mechanisms originating these changes remain unclear. Here, we investigate the consequences of a maternal lipid-rich diet during gestation and lactation and its impact on metabolism and behavior in the offspring. Two experimental groups of Wistar female rats were used: a control group (NC) that was fed a standard diet during the gestation and lactation periods and an overnutrition group that was fed a high-fat diet (HF, 60% lipid-rich) during the same phases. The offspring were analyzed at postnatal days 21 and 28 and at 2 months old (PD21, PD28, and PD60) for their metabolic profiles (weight, fasting glycemia insulin sensitivity, and glucose tolerance) and euthanized for brain collection to evaluate metabolism and inflammation in the hypothalamus, hippocampus, and prefrontal cortex using Western blot markers of synaptic dynamics. At 2 months old, behavioral tests for anxiety, stress, cognition, and food habits were conducted. We observed that the female offspring born from HF mothers exhibited increased weight gain and decreased glucose tolerance that attenuated with age. In the offspring males, weight gain increased at P21 and worsened with age, while glucose tolerance remained unchanged. The offspring of the HF mothers exhibited elevated levels of anxiety and stress during behavioral tests, displaying decreased predisposition for curiosity compared to the NC group. In addition, the offspring from mothers with HF showed increased food consumption and a lower tendency towards food-related aggression. We conclude that exposure to an HF diet during pregnancy and lactation induces dysmetabolism in the offspring and is accompanied by heightened stress and anxiety. There was sexual dimorphism in the metabolic traits but not behavioral phenotypes. Full article

Diets(饮食) rich in fat are a major(主要) cause(原因) of metabolic disease(疾病), and nutritional(营养) food has been widely(广泛) used(使用) to counteract the metabolic disorders such(这样) as obesity(肥胖) and fatty(脂肪) liver(肝). The present study investigated the effects of oleuropein-enriched extract(提取物) from Jasminum grandiflorum L. flowers (OLE-JGF) in high-fat diet(饮食) (HFD)-fed mice and oleic acid(酸) (OA)-treated AML-12 cells. Treatment(治疗) of HFD-fed mice with 0.6% OLE-JGF for 8 weeks significantly reduced body and liver(肝) weights, as well as attenuating lipid dysmetabolism and hepatic steatosis. OLE-JGF administration(政府当局) prominently suppressed the mRNA expressions(表达) of monocyte chemoattractant protein(蛋白)-1 (MCP-1) and cluster of differentiation 68 (CD68), and it also downregulated acetyl-CoA carboxylase (ACC) and fatty(脂肪) acid(酸) synthase (FAS) as well as sterol-regulatory-element(元素)-binding protein(蛋白) (SREBP-1c) in the liver(肝). Meanwhile, mitochondrial DNA and uncoupling protein(蛋白) 2 (UCP2) were upregulated along with the increased expression(表达) of mitochondrial biogenic promoters including liver(肝) kinase B1 (LKB1), peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α), nuclear(核) factor(因子)-erythroid-derived 2-like 2 (Nrf2), and mitochondrial transcription factor(因子) A (Tfam), but did not change AMP-activated protein(蛋白) kinase (AMPK) in liver(肝). The lipid droplets were decreased significantly after treatment(治疗) with 80 μM oleuropein for 24 h in OA-induced AML-12 cells. Furthermore, oleuropein significantly inhibited ACC mRNA expression(表达) and upregulated LKB1, PGC-1α, and Tfam mRNA levels, as well as increasing the binding level of LKB1 to PGC-1α promoter in OA-induced cells. These findings indicate(表明) that OLE-JGF reduces hepatic lipid deposition in HFD-fed mice, as well as the fact that OA-induced liver(肝) cells may be partly(部分) attributed to upregulation of the LKB1-PGC-1α axis, which mediates hepatic lipogenesis and mitochondrial biogenesis. Our study provides a scientific(科学) basis(基础) for the benefits and potential(潜在) use(使用) of the J. grandiflorum flower as a food supplement(补充) for the prevention(预防) and treatment(治疗) of metabolic disease(疾病). Full article

The present study evaluated the ability of KlamExtra^®, an Aphanizomenon flos aquae (AFA) extract, to counteract metabolic dysfunctions due to a high fat diet (HFD) or to accelerate their reversion induced by switching an HFD to a normocaloric diet in mice with diet-induced obesity. A group of HFD mice was fed with an HFD supplemented with AFA (HFD-AFA) and another one was fed with regular chow (standard diet—STD) alone or supplemented with AFA (STD-AFA). AFA was able to significantly reduce body weight, hypertriglyceridemia, liver fat accumulation and adipocyte size in HFD mice. AFA also reduced hyperglycaemia, insulinaemia, HOMA-IR and ameliorated the glucose tolerance and the insulin response of obese mice. Furthermore, in obese mice AFA normalised the gene and the protein expression of factors involved in lipid metabolism (FAS, PPAR-γ, SREBP-1c and FAT-P mRNA), inflammation (TNF-α and IL-6 mRNA, NFkB and IL-10 proteins) and oxidative stress (ROS levels and SOD activity). Interestingly, AFA accelerated the STD-induced reversion of glucose dysmetabolism, hepatic and VAT inflammation and oxidative stress. In conclusion, AFA supplementation prevents HFD-induced dysmetabolism and accelerates the STD-dependent recovery of glucose dysmetabolism by positively modulating oxidative stress, inflammation and the expression of the genes linked to lipid metabolism. Full article

Camellia seed oil (CO) is used as edible oil in southern China because of its excellent fatty acid composition and abundant bioactive compounds. Chronic kidney disease (CKD) is one of the most common chronic degenerative diseases in China, and active compounds in vegetable oil, like virgin olive oil, have been demonstrated to be efficacious in the management of CKD. In this study, virgin CO was refined using a standard process. The refining had minimal impact on the fatty acid composition, but significantly reduced the presence of bioactive compounds like polyphenols in CO. Sprague-Dawley (SD) rats fed with high fat diet (Group G) were treated with either virgin (Group Z) or refined CO (Group R). The oral administration of CO alleviated lipid accumulation and decreased body and kidney weight gain. Furthermore, treatment with virgin CO increased the renal ATP content. The renal expression levels of AMPK and key enzymes involved in fatty acid oxidation (CPT-1 and ACOX1) and glycolysis (HK, PFK, PK and GAPDH) were up-regulated in Group Z, thereby enhancing the ATP production. Virgin CO treatment downregulated the expression level of SREBP2 and its downstream target genes, such as ACC, FAS, and HMGCR, which reduced lipid synthesis. These findings indicate that virgin CO improves glycolipid metabolism and restores energy homeostasis in the kidneys of rats fed with a high-fat diet by modulating the AMPK–SREBP-signaling pathway, suggesting the potential of active compounds in virgin CO for managing the renal failure associated with glycolipid dysmetabolism. Full article

The association between obstructive sleep apnea (OSA) and metabolic disorders is well-established; however, the underlying mechanisms that elucidate this relationship remain incompletely understood. Since the liver is a major organ in the maintenance of metabolic homeostasis, we hypothesize that liver dysfunction plays a crucial role in the pathogenesis of metabolic dysfunction associated with obstructive sleep apnea (OSA). Herein, we explored the underlying mechanisms of this association within the liver. Experiments were performed in male Wistar rats fed with a control or high fat (HF) diet (60% lipid-rich) for 12 weeks. Half of the groups were exposed to chronic intermittent hypoxia (CIH) (30 hypoxic (5% O₂) cycles, 8 h/day) that mimics OSA, in the last 15 days. Insulin sensitivity and glucose tolerance were assessed. Liver samples were collected for evaluation of lipid deposition, insulin signaling, glucose homeostasis, hypoxia, oxidative stress, antioxidant defenses, mitochondrial biogenesis and inflammation. Both the CIH and HF diet induced dysmetabolism, a state not aggravated in animals submitted to HF plus CIH. CIH aggravates hepatic lipid deposition in obese animals. Hypoxia-inducible factors levels were altered by these stimuli. CIH decreased the levels of oxidative phosphorylation complexes in both groups and the levels of SOD-1. The HF diet reduced mitochondrial density and hepatic antioxidant capacity. The CIH and HF diet produced alterations in cysteine-related thiols and pro-inflammatory markers. The results obtained suggest that hepatic mitochondrial dysfunction and oxidative stress, leading to inflammation, may be significant factors contributing to the development of dysmetabolism associated with OSA. Full article

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Hyperandrogenism, hyperinsulinism and insulin resistance (IR) are the main drivers of clinical, metabolic and reproductive phenotypes of PCOS. In adolescence, the cornerstones of PCOS treatment are lifestyle and dietary interventions. In particular, the quality and quantity of carbohydrates introduced with the diet play a crucial role in the benefits of diet on PCOS. Recently, the ketogenic diet (KD) has attracted significant interest for the treatment of IR and for the control of carbohydrate metabolism, which has proven to be beneficial for several dysmetabolic conditions, including PCOS. The goal of the KD is to induce a fasting-like metabolism with production of chetonic bodies. Ketosis is a good regulator of calorie intake and mimics the starvation effect in the body, leading to body weight control and consequent metabolism. Additionally, during ketogenesis, insulin receptor sensitivity is also promoted. We proposed a broad overview of the available literature regarding KD indications and considered its metabolic benefits useful for improving PCOS management. The reported data support that a low-calorie ketogenic diet (LCKD) plays a positive role as a regulator of control weight, IR, glucose and lipid homeostasis and hormonal profile. Unfortunately, the evidence concerning the benefits of the very LCKD in adolescents with PCOS and excessive body weight is still numerically scarce. Further studies are necessary to understand whether these effects are due to weight loss or to the nutritional characteristics of this diet. Considering the long-term consequences of PCOS, it is crucial to detect the prospects of nutritional interventions to protect fertility, starting in adolescence. Full article