Search Results (166)

Metabolic syndrome (MetS) is a major driver of cardiovascular disease, renal injury, and hepatic steatosis, largely through chronic low-grade inflammation and oxidative stress. This study evaluated the cardioprotective, nephroprotective, and hepatoprotective potential of a polyphenol-rich fraction (PP) isolated from Ilex aquifolium leaves in obese Zucker (fa/fa) rats—a well-established model of MetS. Male rats (8 weeks old) were randomly assigned to receive either a standard diet (CTRL, n = 8) or the same diet supplemented with 10 mg/kg body weight/day of the polyphenol fraction (PP, n = 8) for 8 weeks. The fraction was dominated by chlorogenic acid (59.33 mg/g), neochlorogenic acid (35.39 mg/g), and rutin (9.23 mg/g). At the end of the experiment, biochemical markers of oxidative stress, inflammation, and metabolic status were assessed, together with detailed histopathological examination of the heart, kidneys, and liver. Supplementation with Ilex aquifolium polyphenols significantly increased (p < 0.01) total antioxidant status, reduced circulating IL-6 and increased MCP-1 levels. These changes were accompanied by clear cardioprotective effects. However, the intervention also produced organ-specific adverse effects. In the kidneys, polyphenol-treated rats exhibited histopathological features consistent with early-stage nephropathy. In the liver, supplementation exacerbated hepatic steatosis compared to controls. In conclusion, the polyphenol-rich fraction from Ilex aquifolium exerts potent antioxidant and anti-inflammatory effects that translate into substantial cardioprotection in obese Zucker rats. Nevertheless, its capacity to worsen renal injury and hepatic steatosis highlights the need for caution and further dose- and duration-dependent studies before considering therapeutic application in metabolic syndrome. Full article

Background/Objectives: Obesity-associated non-alcoholic fatty liver disease (NAFLD) drives systemic metabolic stress and accelerates chronic kidney disease, yet the mechanistic links remain unclear. Mitochondrial dysfunction has emerged as a central mediator of obesity-induced organ injury. Here, we investigated renal mitochondrial remodeling in a rat model of obesity-associated NAFLD (Ob-NAFLD) and examined the effects of metformin. Methods: Female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for eight weeks, followed by 10 weeks of metformin treatment in designated groups. Kidney tissues were analyzed using biochemical assays, immunoblotting, blue native PAGE, in-gel activity assays, and histological evaluation. Results: In Ob-NAFLD rats, renal ATP levels were elevated despite reduced electron transport chain (ETC) Complex III and increased Complex V expression, reflecting compensatory ATP synthase hyperactivity uncoupled from efficient oxidative phosphorylation. Mitochondrial dynamics were disrupted such that inhibitory phosphorylation of DRP1 was reduced, promoting fission, and total OPA1 expression was decreased with a shift in short-to-long isoform balance, indicating impaired fusion and cristae remodeling. Notably, ATPase inhibitory factor 1 (IF1), a checkpoint that limits ATP synthase overdrive, remained stably expressed, suggesting an adaptive ceiling or failed protective control under chronic metabolic stress. Metformin partially alleviated bioenergetic stress by lowering ATP and modestly restoring Complex III, yet ETC imbalance and structural remodeling persisted, revealing the limitations of metabolic modulation alone. Conclusions: These findings position entrenched mitochondrial dysregulation as a mechanistic bridge linking obesity-driven liver disease to kidney injury. Therapeutic strategies combining metabolic interventions with targeted restoration of ETC coordination, mitochondrial dynamics, and regulatory checkpoints such as IF1 may be required to fully restore renal mitochondrial health and prevent the progression of metabolic kidney disease. Full article

Exercise-induced regulation of cortical GPCR pathways in diabetic obesity remains unclear. This study aimed to investigate exercise-associated GPCR-related transcriptomic pathway changes in the cerebral cortex of diabetic-obese rats. Cerebral cortical samples from male Zucker Fatty Diabetes Mellitus (ZFDM) rats subjected to a 12-week swimming program were examined using RNA sequencing, functional enrichment, GSOAP clustering, and STRING-based protein–protein interaction (PPI) analysis. Exercise training reduced fasting glucose and body weight. RNA sequencing identified 817 exercise-responsive transcripts (403 upregulated and 414 downregulated; p < 0.05), including 48 associated with GPCR signaling. Results showed that these 48 genes mapped to three major GPCR-related networks: cAMP signaling, with increased Adcyap1r1, Gipr, Tshr, and Vipr2 and decreased Vip, Chrm1, Gabbr2, and Sst; calcium signaling, with increased Ntsr1 and Trhr and decreased Chrm1; and neuroactive ligand–receptor interaction, with increased Trh, Trhr, and Crh and decreased Opr-related transcripts. These findings provide hypothesis-generating evidence for interpreting cortical GPCR-related transcriptomic pathway associations in diabetic-obese conditions. Full article

Tenebrio molitor (Coleoptera: Tenebrionidae) is a suitable candidate for use as a biomass resource, recognized for its large-scale breeding and the high nutritional value of its protein content. Feeding obese Zucker rats the cuticle of T. molitor enhances fatty liver metabolism through the mediation of gut microorganisms. Cuticular proteins are demonstrated to be pivotal in the formation of the insect cuticle throughout the developmental stage. The endocuticle structural glycoprotein (Abd) belongs to the RR-1 subclass, a major group of structural cuticular proteins characterized by the conserved Rebers–Riddiford (RR) motif. Nevertheless, there remains a paucity of research into the molecular properties and functions of SgAbd (endocuticle structural glycoprotein) in Coleoptera. In this study, we successfully identified and described the gene TmAbd5 in T. molitor. The coding sequence of TmAbd5 is 306 bp, corresponding to a 101-aa protein. The functional domain predicted that TmAbd5 consists of a signal peptide and a chitin-binding domain 4 (ChtBD4). Motif prediction analysis indicated that TmAbd5 belongs to the CPR (cuticular proteins with Rebers–Riddiford consensus) family with the RR-1 motif. Expression analysis revealed that TmAbd5 is upregulated in the integument, particularly during the first three days of development in the 13th instar stage. Although the RNAi-mediated silencing of TmAbd5 did not cause apparent phenotypic abnormalities and the insects successfully molted into pupae, histological examination revealed a substantial thickening of the endocuticle at 72 h post-pupation, along with a notable increase in lamellar spacing and a disrupted pore canal. In summary, TmAbd5 contributes to the formation and structural organization of the endocuticle, which provides a theoretical basis for the screening of target genes for cuticle development and for the effective utilization of cuticle resources in T. molitor. Full article

Background: Advanced glycation end products (AGEs) and oxidative stress (OS) have been linked to bone complications related to type 2 diabetes mellitus (T2DM). However, the effects of AGEs and OS on bone marrow mesenchymal stromal cells (BMMSCs), which play a key role in bone homeostasis and repair, remain unclear. Objectives: This study aimed to investigate the effects of AGEs on BMMSCs function and the ability of N-acetylcysteine (NAC) to alleviate AGE-induced OS in a T2DM context. Methods: Bone marrow (BM) and BMMSCs were isolated from Zucker diabetic fatty (ZDF) rats, which serve as a T2DM model, and their lean littermates (ZL, controls) at 24 weeks of age. Results: The results show that long-standing T2DM leads to changes in the BM’s cellular composition and BMMSCs function that are distinct from age-related changes. In vitro, AGEs decreased BMMSCs viability, proliferation, and migration. The effects of AGEs were stronger in BMMSCs derived from a T2DM microenvironment. In both T2DM- and ZL-BMMSCs, AGEs induced cytoplasmic ROS, which was differentially reduced by NAC. The effect of NAC on T2DM-BMMSCs was greater when the cells were pre-treated with NAC 24 h before exposure to AGEs, whereas simultaneous exposure to both resulted in a smaller effect. Conclusions: These results show that AGEs impair BMMSCs expansion and functionality. AGE-induced ROS generation may be a critical factor in this impairment, while NAC was able to reduce OS in BMMSCs from a T2DM context. These findings highlight the vicious negative effects of the T2DM microenvironment on BMMSCs and underscore the need for further studies to better understand the underlying mechanisms and to explore strategies aimed at mitigating OS in the T2DM context. Full article

Background: Obesity involves an excessive buildup of adipose tissue and is linked to chronic inflammation and oxidative stress, both of which contribute to immunosenescence. Obesity and aging share common features, including immune system impairment and oxidative and inflammatory states, suggesting that obesity may represent a model for accelerated immunosenescence. Objectives/Methods: The aim of this research was to evaluate in Zucker fatty (fa/fa) rats, a well-established genetic model of obesity, multiple immune function parameters (phagocytic activity, natural killer cell function, lymphocyte proliferation in response to mitogens, and cytokine profiles), as well as redox parameters (total antioxidant capacity, glutathione levels, activities of glutathione peroxidase and reductase, and xanthine oxidase activity) in peritoneal leukocytes, spleen, thymus, and liver at adult age (24 weeks). Comparisons were made with Zucker lean controls (fa/+), commonly used as standard controls, and Wistar rats as an independent control group. Results: Zucker fa/fa rats displayed significant physiological disorders, including increased body and organ weights, premature immunosenescence characterized by impaired innate and adaptive immune responses, reduced IL-2 and IL-10 secretion, elevated TNF-α production upon mitogen stimulation, and oxidative stress evidenced by redox imbalance in the spleen, thymus, and liver. Conclusions: These immune dysfunctions and oxidative imbalances are comparable to those observed during the aging process. Given that the immune parameters analyzed are considered indicators of health, aging rate, and longevity, our findings suggest that adult Zucker fa/fa rats could exhibit features of premature aging. Full article

Background/Objectives: Altered lipid metabolism is a key feature of type 2 diabetes mellitus (T2DM), yet its impact on early spinal cord involvement remains poorly understood. Distinguishing between pathological lipid accumulation and adaptive metabolic responses is essential for interpreting initial stages of neural alteration in T2DM. This study aimed to characterize spinal cord lipid composition and ATPase activities in a rat model of T2DM. Methods: Zucker diabetic fatty (ZDF) rats were used as a model of T2DM and divided into diabetic and obese groups, with lean Zucker rats as controls. ATPase activities in spinal cord tissue were measured spectrophotometrically, and lipid profiling was performed using gas chromatography with flame-ionization detection. Indices of stearoyl-CoA desaturase-1 (SCD1) and delta-5 desaturase activity (D5D) were calculated from specific fatty acid ratios as estimates of enzyme-related activity. Results: Diabetic rats exhibited significantly higher levels of free monounsaturated fatty acids (MUFAs) compared with controls, while the obese group showed a moderate increase. Elevated SCD1 indices were indicative of increased estimated MUFA synthesis. Levels of free polyunsaturated fatty acids (PUFAs), including those crucial for myelin stability, as well as ATPase activities, remained unchanged, suggesting preserved basal membrane-associated enzyme function. Conclusions: This study identifies lipid alterations in the spinal cord preceding overt neurodegenerative changes in T2DM, characterized by increased free MUFA abundance, without evidence of altered ATPase activities. These findings support the interpretation that lipid changes observed at this stage are more consistent with adaptive metabolic remodeling than with overt structural or functional neural impairment. Full article

Background/Objectives: Type 2 diabetes (T2D) and obesity are chronic metabolic disorders associated with cognitive impairment and neuronal damage. The hippocampus, a region sensitive to nutrient excess, is critical for integrating sensory and metabolic signals. This study aimed to determine the early onset of cognitive and motor deficits induced by obesity and/or hyperglycemia and to characterize associated hippocampal alterations in Zucker Diabetic Fatty (ZDF) rats. Methods: Male ZDF rats (13 weeks old) were categorized into three groups: lean control, obese normoglycemic (ZDF-NG), and obese hyperglycemic (ZDF-HG). Assessments included zoometric parameters (weight and adiposity), biochemical assays (glucose tolerance, insulin response, and lipid profile), and behavioral tests (Open Field and Novel Object Recognition). Hippocampal health was evaluated through stereological neuronal density analysis and redox balance markers. Results: Both obese groups exhibited significant visceral adiposity and hyperlipidemia. The ZDF-HG group was further characterized by glucose intolerance, hepatic insulin resistance, and reduced β-cell function. Behavioral results showed that while obesity decreased motor activity, hyperglycemia significantly exacerbated the loss of both short- and long-term recognition memory. Histologically, obesity was associated with decreased neuronal density in the hippocampal DG and CA1 regions. Furthermore, hippocampal ROS was significantly elevated in the ZDF-HG group, and glutathione reductase activity was reduced in both obese phenotypes. Conclusions: The findings demonstrate that obesity initiates hippocampal neurodegeneration and motor decline, and that hyperglycemia severely impairs recognition memory. These results emphasize the critical interplay between metabolic dysfunction and cognitive decline, highlighting the necessity of managing both obesity and T2D to prevent early neurodegenerative changes. Full article

Exercise training reduces metabolic dysfunction and improves neural function; however, its cortical molecular effects in diabetic–obese conditions remain unclear. Here, we aimed to identify transcriptional pathways by integrating physiological evaluation with an in silico analysis of cortical RNA-seq data from Zucker Fatty Diabetes Mellitus rats following a 12-week swimming training program. Exercise training reduced body weight and improved glucose control and blood pressure. RNA-seq analysis revealed 814 differentially expressed genes, with pathway enrichment highlighting glutamatergic synapse, retrograde endocannabinoid signaling, and oxytocin signaling pathways. These coordinated transcriptional shifts involved genes related to excitatory neurotransmission, neuromodulatory feedback, and calcium-dependent regulation. As hypothesis-generating models, these pathway-level patterns suggest that exercise training may modulate cortical signaling properties in diabetic–obese states and provide a conceptual framework for future mechanistic investigation. Full article

Background/Objectives: Obesity and insulin resistance are increasing globally. Emerging evidence suggests that not only the quantity but also the source of dietary protein may improve metabolic health outcomes. This study evaluated the effects of high-protein diets (HPDs) containing animal or plant protein sources on obesity and obesity-related metabolic markers in a rodent model of genetic obesity. Methods: Obese male fa/fa Zucker rats were fed HPDs (35% of energy) containing protein from different sources (casein, egg white protein, soy + pea protein, mixture of egg white + soy + pea proteins) or a normal protein diet (15% of energy) containing casein over 8 weeks. Oral glucose tolerance, weight gain, fat depots, serum biochemistry, adipocyte and pancreatic islet size, and markers of adipose tissue lipolysis, insulin signaling, and immune cells were assessed. Results: Consumption of HPDs containing egg white protein, soy + pea, or their mixture resulted in smaller adipocytes compared to the casein diets, despite greater weight gain, elevated serum NEFA, and more total visceral fat in the HPD plant group. These HPD groups had reduced fasting insulin and no compensatory pancreatic islet enlargement. CD3 levels were elevated in adipose tissue without changes in F4/80, and no differences were observed in ATGL, HSL, Akt or AS160. Conclusions: The source of dietary protein in HPDs significantly influences metabolic outcomes in obese rats, impacting adipocyte and pancreatic islet size, insulinemia, and immune cell markers in adipose tissue. These findings support the potential of employing targeted dietary protein interventions for managing obesity-related metabolic disorders. Full article

Obesity is characterized by low-grade chronic inflammation, similar to the pathophysiology of inflammatory bowel disease (IBD) and colon cancer. IBD, which includes Crohn’s disease and ulcerative colitis, is becoming increasingly common in obese individuals. Our previous research documented that both IBD and obesity involve disrupted NaCl homeostasis in the small intestine. The present study investigated how obesity affects NaCl homeostasis in the distal colon, using the Zucker (Lepr^fa) rat as a genetic model of obesity. The functional and molecular alterations in NaCl homeostasis were evaluated through radioactive uptakes, RT-qPCR, and Western blot studies. We found a significant reduction in Cl absorption via Cl⁻/HCO₃⁻ exchanger, Downregulated in Adenoma (DRA) in the distal colon of obese rats compared to lean controls. This reduction was due to a decrease in the maximum transport capacity (V_max) of DRA, with no change in the affinity of the exchanger for chloride. DRA mRNA and protein levels were also downregulated in obese animals. In contrast, Na absorption via Na⁺/H⁺ exchanger and its expression remained unchanged. These findings are the first to demonstrate that DRA is significantly impaired in the distal colon due to obesity. This suggests that net NaCl absorption in the distal colon is compromised in obesity, potentially increasing the risk for IBD and colon cancer. Full article

The housing of laboratory rats in cages with dimensions according to international standards for research animals can hardly be regarded as a stimulating environment, even when fulfilling the minimum requirements for environmental enrichment. Little is known about whether changes in the housing situations to improve living conditions will affect the phenotypic traits of well-known models for human diseases. The obese Zucker fa/fa rat develops hyperlipidemia, hypertension, and fatty liver, and is widely used for studies on metabolic complications of obesity in humans. Young male obese Zucker fa/fa rats were housed in pairs in standard individually ventilated cages (IVCs: floor area 1500 cm² and maximum height 20 cm), or 4–6 rats were housed in a large open cage (LOC: floor area 7705 cm² and height 75 cm). The LOC provided an environment with more physical, social, auditory, visual, olfactory, and tactile stimuli compared to IVCs. The aims were to compare the development of obesity comorbidities and to assess the well-being of rats housed under different conditions. The rats housed in IVCs and the LOC had similar adiposity, blood pressure, hepatic triacylglycerol content, and similar serum concentrations of cholesterol, triacylglycerol, and alanine transaminase. IVC-housed rats showed some signs of distress, such as less interest in nest-building and signs of apathy compared to LOC-housed rats. To conclude, LOC housing did not affect the typical phenotype of obese Zucker fa/fa rats but did improve the welfare of these rats. Full article

Imbalance in fatty acid (FA) metabolism is a critical factor in the development of type 2 diabetes (T2D). This study examined fatty acid composition and desaturase activities in the liver and spinal cord of male Zucker diabetic fatty (ZDF) rats, a genetic model of T2D. Heterozygous lean ZDF fa/+ animals served as controls, while homozygous obese ZDF fa/fa animals represented the diabetic group. FA profiles were determined by gas chromatography, and the activities of Δ5-desaturase (FADS1), Δ6-desaturase (FADS2), Δ9-desaturase (SCD1), and elongase of very long-chain fatty acids (ELOVL) were estimated. T2D rats displayed significantly elevated levels of monounsaturated fatty acids (MUFAs) and increased SCD1 activity in both the liver and spinal cord. In contrast, polyunsaturated fatty acids (PUFAs), particularly arachidonic acid (AA, C20:4 n-6), were reduced. Since AA plays a fundamental role in neuronal membrane structure and signaling pathways, these alterations have particular relevance to nervous system function. Tissue-specific alterations further suggested impaired FADS1 activity in the liver and reduced elongase/FADS2 activity in the spinal cord. These findings suggest that desaturase imbalance and FA remodeling in the spinal cord might represent characteristic features of T2D and that altered FA metabolism within the nervous system may potentially serve as an early indicator of neuropathy or a predictor of increased susceptibility to diabetes-related complications. Full article

Background: Dicarbonyls and advanced glycation end-products (AGEs) contribute to oxidative stress, inflammation, and complications in type 2 diabetes mellitus (T2DM). Menaquinone-7 (MK-7), a vitamin K2 subtype, has shown benefits for glucose tolerance and vascular health in some studies. We evaluated the impact of MK-7 on dicarbonyls, free AGEs, and protein nitration/oxidation adducts in a rat model of T2DM. Methods: Male heterozygous (fa/+, control) and homozygous (fa/fa, diabetic) Zucker Diabetic Fatty rats were fed a diabetogenic diet without or with MK-7 for 12 weeks. After sacrifice, plasma dicarbonyls as well as plasma and urinary levels of free AGEs and protein nitration/oxidation adducts were quantified by isotope dilution tandem mass spectrometry. Results: Diabetic rats showed significantly increased plasma glyoxal, 3-deoxyglucosone, and fructosyl-lysine with non-significant trends toward increased methylglyoxal-derived hydroimidazolone and methionine sulfoxide, as well as reductions in methylglyoxal and dityrosine. Urinary carboxyethyl-lysine, carboxymethyl-lysine, fructosyl-lysine (all significant), and dityrosine (non-significant) were elevated in diabetic rats; glucosepane (non-significant) was reduced. MK-7 supplementation reduced no measured parameter but was associated with non-significant further increases in plasma glyoxal-derived hydroimidazolone, carboxyethyl-lysine, carboxymethyl-lysine, fructosyl-lysine, 3-nitrotyrosine, and methionine sulfoxide, as well as in urinary glyoxal-derived hydroimidazolone, carboxyethyl-lysine, fructosyl-lysine, and 3-nitrotyrosine, in diabetic rats. Correlation analysis revealed significant associations between glucose, dicarbonyls, AGEs, and oxidative markers. Conclusions: High-dose MK-7 supplementation did not improve dicarbonyl stress, AGE burden, or protein nitration/oxidation. With respect to available scientific evidence and our observations, the combination of glycemia-driven amplification of glycation and oxidative stress, as well as MK-7-induced glutathione depletion, were likely causative. Full article

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness worldwide, primarily due to pathological choroidal neovascularization (CNV). Our study investigates a chemically modified heparin derivative as a novel strategy to selectively modulate angiogenic signaling, offering a reduced anticoagulant risk and preclinical support for AMD treatment. We explored the therapeutic potential of 6-O-desulfated heparin (Hep-6Od) as an antiangiogenic agent with diminished anticoagulant activity. Synthesized via selective 6-O-desulfation and characterized using nuclear magnetic resonance (NMR), Hep-6Od demonstrated safety in retinal pigment epithelial cells with no cytotoxic effects at various concentrations. In vitro, the compound significantly inhibited endothelial cell proliferation, migration, and capillary tube formation. Differential scanning fluorimetry (DSF) assays confirmed molecular interaction between Hep-6Od and fibroblast growth factor 2 (FGF-2), suggesting interference with pro-angiogenic signaling pathways. In vivo, a laser-induced CNV model in lean Zucker rats showed a dose-dependent reduction in neovascular lesion areas after an intravitreal Hep-6Od injection. Compared to unfractionated heparin, Hep-6Od exhibited reduced anticoagulant effects in PT and aPTT assays while maintaining robust antiangiogenic properties. These findings support Hep-6Od as a promising alternative to anti-vascular endothelial growth factor (VEGF) therapies for AMD treatment, potentially expanding current retinal vascular disease interventions. The results underscore its potential to transform AMD management, pending further clinical validation and awaiting confirmation in further studies. Full article