Search Results (278)

Background/Objectives: Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) analog for type 2 diabetes and obesity, requires sensitive and high-throughput bioanalytical methods to support pharmacokinetic studies. However, previously reported liquid chromatography–tandem mass spectrometry (LC–MS/MS) assays have been limited by lengthy run times (~18 min) and suboptimal sensitivity. This study aimed to develop and validate a rapid, sensitive LC–MS/MS method for quantifying semaglutide in plasma. Methods: Plasma samples (50 μL) were prepared by acetone-mediated protein precipitation followed by solid-phase extraction. Chromatographic separation was performed on a Cadenza CD-C18 MF column within 9 min, using positive electrospray ionization in multiple reaction monitoring mode with the transitions m/z 1029.4 → 110.1 for semaglutide and m/z 938.9 → 109.9 for liraglutide (internal standard). Validation followed the U.S. Food and Drug Administration (FDA) bioanalytical guidelines. Results: The assay showed a lower limit of quantification of 1 ng/mL with linearity across 1–500 ng/mL (R² = 0.9999), with sharp peak shape and no carryover. Intra- and inter-day accuracies were 95.69–103.76% and 94.93–100.08%, with precision ≤4.50% and ≤5.88%. Recovery (93.05–107.95%) and matrix effects (96.34–104.12%) were consistent across quality control levels, and the analyte was stable under all tested conditions. The method was successfully applied to a pharmacokinetic study in Sprague–Dawley rats following subcutaneous administration of 50 μg semaglutide. Conclusions: The validated method offers shorter analysis time, improved sensitivity, and reduced sample volume compared with previously reported assays, supporting its application in preclinical pharmacokinetic studies of semaglutide and related GLP-1 analogs. Full article

Background: Kidney disorders are strongly related to metabolic disturbances, including obesity and type 2 diabetes. Excessive intake of sugar and saturated fats promotes lipid accumulation, cellular energy issues and inflammatory responses. Cannabigerol (CBG), a non-psychotropic phytocannabinoid, has recently gained attention for its metabolic, anti-inflammatory and potential protective properties. Methods: The present study investigated the effect of two weeks of CBG administration (last 14 days of the experiment) on fatty acid (FA) composition, FA metabolic pathways and FA transporters in rats subjected to a high-fat high-sucrose diet (HFHS) for 6 weeks. Male Wistar rats were divided into four groups: Control, CBG, HFHS, and HFHS+CBG. Kidney tissue and urine samples were analyzed by gas–liquid chromatography (GLC) for lipid fractions and FA profiles, while protein expression of FA transporters and metabolic enzymes was assessed by immunoblotting. Polysaccharides and collagen fibers were visualized using Periodic Acid-Schiff (PAS) and AZAN staining, respectively. ELISA and colorimetric kits were used to measure urinary albumin and creatinine contents. Results: HFHS feeding altered renal lipid homeostasis, increasing saturated and monounsaturated fatty acids (SFA and MUFA, respectively) levels and affecting desaturation and elongation ratios. CBG supplementation affected renal lipid metabolism by lowering triacylglycerol (TAG) accumulation, restoring polyunsaturated fatty acids (PUFA) in phospholipid (PL) and altering FA ratios, suggesting an improvement in lipid balance. CBG also increased the expression of carnitine palmitoyltransferase 1 (CPT1) and lipoprotein lipase (LPL) and decreased the expression of stearoyl-CoA desaturase 1 (SCD1) and fatty acid synthase (FAS), suggesting a shift toward enhanced FA oxidation and reduced lipogenesis. Conclusions: Overall, CBG exerted good effects on renal lipid metabolism and may mitigate early lipid-mediated injury associated with metabolic kidney disorders. 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

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to have beneficial effects in T2D, reducing hepatic lipid storage and improving metabolic dysfunction-associated steatotic liver disease. However, sex and reproductive age may influence their effect. We investigated the effect of liraglutide administration (0.2 mg/kg/day subcutaneously for 8 weeks) on metabolic disorders in relation to sex and reproductive age, using male, female and ovariectomized female hereditary hypertriglyceridemic (HHTg) rats as a prediabetic model. Liraglutide improved glucose tolerance in all HHTg rats. Female and ovariectomized (OVX) female rats showed a stronger effect of lipid metabolism and visceral adiposity than males. Moreover, no changes in hepatic triacylglycerol (TAG) accumulation were observed in males. Liraglutide partially reversed ovariectomy effects, such as increased body weight, visceral obesity and impaired glucose tolerance. Compared with males, female and OVX female rats showed more significant changes in hepatic gene expression involved in lipogenesis (Scd-1, Srebp1, Pparγ), fatty acid and lipid metabolism (Pparα, Hmgcr, Srebp2) and fibrosis (Tgfβ), which may improve hepatic lipid metabolism. Females of fertile age showed greater improvements in insulin sensitivity, reductions in ectopic lipid accumulation, and improvements in lipid metabolism. Depending on sex and reproductive status, liraglutide can mitigate fatty liver before diabetes onset. Full article

Background/Objectives: Nobiletin, one of the main components of citrus peel, exhibits potent antioxidant, anti-inflammatory, and metabolic regulatory properties. However, its effect on obesity-associated vasculopathay remains unknown. We aim to investigate the effect of nobiletin in ameliorating oxidative stress and endothelial dysfunction induced by a high-fat diet (HFD). Methods: Male C57BL/6J mice were fed a HFD (60 kcal% fat) or normal chow for four months and orally administered with vehicle or nobiletin (50 mg/kg/day) for 8 weeks. Vasoreactivity in aortas was measured on a wire myograph. Primary rat aortic endothelial cells (RAECs) were isolated from Sprague-Dawley rats for in vitro study. Protein expressions were detected by Western blot. Superoxide production was determined by fluorescence imaging. Results: Exposure to high glucose increased the phosphorylation of JNK (Tyr185) and decreased the protein expressions of Nrf2 and HO-1, as well as downregulated the phosphorylation of AMPK and eNOS (Ser1177) in RAECs. This led to reduced nitric oxide (NO) generation and elevation of oxidative stress. High glucose induction also impaired the endothelium-dependent relaxations (EDRs) in murine aortas. These high glucose-induced impairments were restored by co-treatment of nobiletin (1 μM or 10 μM) whereas effects of nobiletin were abolished by AMPK inhibitor Compound C. The DIO-induced diabetic animal model showed increased body weight and blood pressure, imbalance of glucolipid metabolism, impaired EDRs, and elevated oxidative stress in aortas. AMPK/eNOS and Nrf2/HO-1 pathways were downregulated in aortas from DIO mice. Oral administration of nobiletin could at least partially reverse the above damage. Conclusions: Nobiletin ameliorates endothelial dysfunction by reducing oxidative stress and enhancing NO bioavailability upon activation of AMPK/eNOS and Nrf2/HO-1 pathways in obese diabetic mice. Full article

Chronic wounds are ulcers unable to heal due to vascular insufficiency, diabetes, or obesity. Adipose-derived stromal cells (ASCs) are promising candidates for regenerative therapies owing to their pro-healing and angiogenic properties. Compared with autologous approaches, allogeneic ASC therapies offer the opportunity for off-the-shelf use, enabling immediate availability, standardized qualification, and consistent potency. Gelatin sponges have been shown to reprogram ASCs toward a highly angiogenic phenotype. However, because this activation also modulates some immune-related genes, including MHC, its impact on immunogenicity is unknown and could be critical for allogeneic applications. This study evaluated whether ASCs embedded in a gelatin sponge could be used in an allogeneic setting for ischemic wound repair. To mimic clinical allogeneic conditions, a controlled MHC mismatch was introduced in a rat ischemic wound model: donor ASCs carrying RT1^n or RT1^l haplotypes were implanted into outbred RT1^a recipients. Embedding ASCs within the gelatin sponge upregulated MHC class I but not class II expression, without inducing systemic or local alloreactivity. Serum acute-phase proteins remained unchanged, and no CD3⁺ T-cell infiltration was detected. Histology confirmed efficacy on ischemic wounds, with increased granulation tissue thickness, red blood cell infiltration, and enhanced vessel density versus controls. Allogeneic ASCs activated by a gelatin scaffold promote wound revascularization without eliciting immune rejection, supporting their development as standardized, off-the-shelf therapies for chronic ischemic wounds. Full article

Leptin receptor-deficient WBN/Kob-Lepr fa/fa (WKF) rats spontaneously developed chronic pancreatitis and severe diabetes with obesity. Here, we evaluated the protective effects of diet restriction and chronic exercise against fatty and inflammation-induced disorders in the vulnerable pancreas of WKF rats. Six-week-old male WKF rats were divided into obese control (Obese), diet restriction (DR), and diet restriction + exercise (DR + Ex) groups. WBN/Kob (WK) rats were used as lean control (Lean). Lean and Obese rats had free access to food, whereas food intake for DR and DR + Ex rats was restricted to 69% and 70% of the Obese level, respectively. The DR + Ex rats exercised voluntarily on a wheel ergometer daily. After six weeks, the rats were euthanized with isoflurane after overnight fasting. Obese rats exhibited diabetes, early stages of pancreatitis, diffuse pancreatic islets, and ultrastructural deteriorations in the pancreatic acinar cells, such as lipid droplet accumulation and swollen mitochondria with destroyed cristae, whereas Lean rats did not. DR rats exhibited improved glucose metabolism and serum triglyceride levels, effectively preventing inflammatory processes in the pancreas. However, DR rats exhibited no amelioration in the serum free fatty acids (FFAs) level, and limited improvements in ultrastructural deterioration in pancreatic cells. Chronic exercise combined with diet restriction (DR + Ex) improved serum FFA levels, the boundary of pancreatic islets, and the ultrastructure of subcellular organelles. These results demonstrate that diet restriction suppresses pancreatic inflammation, and further additional exercise effectively improves fatty pancreas-related deterioration by skeletal muscle activity linked through the circulatory network in WKF rats. 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: Individuals with diabetes often experience difficulties in the healing of their alveolar sockets. Furthermore, obesity is strongly associated with the development and progression of type 2 diabetes through complex metabolic and inflammatory mechanisms. The current study provides new insights into the use of Luteolin (LU) and/or chitosan vesicles (CHV) to accelerate bone regeneration, highlighting a biologically and clinically relevant approach that leverages implants as a clinical solution. Methods: Sixty rats were randomly categorized into five groups: Group I (negative control); Group II (positive control), diabetic and obese rats; Group III (LU-treated), diabetic and obese rats with an extraction socket loaded with LU; Group IV (CHV-treated), diabetic and obese rats with an extraction socket loaded with CHV; and Group V (LU-CHV), diabetic and obese rats with an extraction socket loaded with LU-CHV. After 2 and 6 weeks, rats’ mandibles underwent histological, histomorphometric, biochemical, and statistical analyses. Results: The results demonstrated significant differences among the experimental groups. The LU-CHV formulation showed superior therapeutic performance compared with free luteolin and the untreated control group. In vitro release studies revealed sustained, controlled release from LU-CHV, whereas free luteolin exhibited rapid drug release. Additionally, LU-CHV significantly enhanced biological activity, as evidenced by improved anti-inflammatory and/or therapeutic markers compared to the other groups. These findings indicate that encapsulation within chitosan vesicles improved drug stability, bioavailability, and overall therapeutic efficiency. Conclusions: LU-CHV demonstrated superior efficacy compared to free luteolin, highlighting the advantage of chitosan-based vesicular delivery systems. LU-CHV not only enhanced controlled drug release and therapeutic outcomes but also presents a promising platform that could significantly advance targeted drug delivery strategies in inflammatory and metabolic disorders. The findings suggest that LU-CHV represents a transformative approach in improving treatment effectiveness and patient outcomes. 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

Background: Approximately two-thirds of individuals with spinal cord injury (SCI) become overweight or obese. Weight loss surgery, including vertical sleeve gastrectomy (VSG), is one of the most effective long-term treatments for obesity and type 2 diabetes. Introduction: The main objective of this study was to test in our diet induced obesity rat model whether subjects respond to VSG in the same way as subjects with or without SCI. Methods: To address this question, male Wistar rats underwent either T3 contusion injuries or sham spinal surgeries (Sham). Following recovery, all rats were fed a high-energy, high-fat diet (HFD) for six weeks before undergoing VSG. Taste responsivity and preferences were assessed at multiple time points. Results: Prior to HFD exposure, SCI rats exhibited significantly reduced lick responses for sucrose at higher concentrations and increased licking for low concentrations of sodium, although 2BC sucrose preference was unchanged. HFD feeding in SCI rats enhanced salt and sucrose licking overall. Importantly, VSG reduced sucrose licking, with SCI rats showing greater sensitivity to this effect. cFos immunohistochemistry further revealed enhanced neuronal activation to sucrose ingestion in the dorsal vagal complex, including the rostral subnucleus of the nucleus of the solitary tract. Discussion and Conclusions: Together, these findings support the hypothesis that SCI alters taste functions, thereby increasing vulnerability to diet-induced obesity and that VSG may restore sweet taste responsivity even more effectively in SCI-associated obesity than in non-SCI obesity. Future studies are needed to clarify the neural and hormonal mechanisms mediating these effects and to determine their translational relevance to human SCI populations. 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

Growing evidence highlights the links between diabetic neuropathy (DNP), gut dysbiosis, mitochondrial dysfunction and neuroinflammation in colon and bone microstructure deterioration. Geranylgeraniol (GG) shows neuroprotective and osteoprotective capacity. Our study examines GG’s effects on pain-associated behaviors, glucose homeostasis, gut microbiota, mitochondrial homeostasis, and bone microstructure in DNP rats. We randomly assigned 27 male Sprague Dawley rats to three groups (n = 8–10/group): a control group (regular low-fat diet), a DNP group (high-fat diet + a single dose of 35 mg/kg streptozotocin), and a GG-treated DNP group (a single dose of 35 mg/kg streptozotocin + GG at 800 mg/kg in diet) for 6 weeks. Nocifensive response was assessed via the von Frey test and an open field test, and the elevated plus maze was used to assess anxio-depressive behaviors. The mRNA expression levels of tight junction protein, mitochondrial homeostasis, and neuroinflammation were measured in the colon using qRT-PCR. We collected fecal samples for microbiota composition analysis with 16S rRNA gene sequencing and analyzed by QIIME 2. All other data were analyzed via one-way ANOVA followed by post hoc Tukey’s multiple comparison. p < 0.05 was defined as statistical significance. Our study showed GG’s ability to mitigate mechanical hypersensitivity and anxio-depressive behavior in rats with DNP. GG supplementation did not improve glucose homeostasis (i.e., glucose intolerance, insulin sensitivity, pancreatic β-cell dysfunction) and bone microstructure. GG increased alpha-diversity without changing microbial abundance. DNP rats exhibited elevated Clostridium sensu stricto and reduced Eubacterium coprostanoligenes, Lachnospiraceae, Oscillospiraceae, and Peptococcaceae compared with controls. GG did not reverse DNP-induced gut dysbiosis but increased colonic claudin-3 (tight junction), MFN1 (mitochondria fusion), and TFAM (mitochondria biogenesis), while reducing FIS1 (mitochondria fission), GFAP (glial activation), P62 and PINK1 (mitophagy), and TNFα (inflammation). Functionally, GG reduced pain behaviors, improved intestinal integrity and mitochondrial homeostasis, increased alpha-diversity, and suppressed neuroinflammation, but did not improve glucose homeostasis or bone microstructure in obese DNP rats. Full article

Background/Objectives: Thermoregulation is essential for survival, with the hypothalamic preoptic area integrating peripheral signals to maintain core body temperature. While fever enhances immune responses, excessive hyperthermia causes cellular damage. Previous work has shown that central glucagon-like peptide-1 (GLP-1) receptor antagonism intensifies lipopolysaccharide (LPS)-induced fever, suggesting a role for GLP-1 signaling in temperature regulation. However, the direct effects of GLP-1 receptor agonists on fever remained unexplored. This study investigated the effects of liraglutide (LIRA), a GLP-1 analog used to treat diabetes and obesity, on temperature regulation and fever in rats, with a focus on sex-dependent mechanisms. Methods: Male and female Wistar rats received lipopolysaccharide (LPS, i.p.) to induce fever, followed by LIRA treatment (0.3 mg/kg, i.p.) one hour later. Body temperature was monitored for up to six hours post-LPS injection. Results: LIRA reduced body temperature in both euthermic and febrile rats of both sexes. LPS increased PGE₂ concentration in both sexes, with males showing a twofold increase compared to females. LIRA treatment reduced PGE₂ levels in LPS-challenged males (62%, p < 0.01) but not in female rats. LPS elevated interleukin (IL)-6 levels in both sexes, while LIRA treatment decreased IL-6 only in females (45%, p < 0.05). In males, LPS reduced hypothalamic serotonin (5-HT) levels, and LIRA further decreased 5-HT in saline-treated animals. In females, LIRA increased 5-HT levels (84%, p < 0.01) in LPS-challenged animals. Additionally, LIRA exhibited sex-specific effects on hypothalamic JNK phosphorylation, increasing activation in LPS-treated males and reducing it in LPS-treated females. Conclusions: LIRA demonstrates antipyretic properties through distinct, sex-specific mechanisms. In males, temperature reduction correlates with decreased hypothalamic PGE₂, whereas in females, antipyretic effects are associated with reduced IL-6, decreased JNK phosphorylation, and increased 5-HT. These findings reveal sexually dimorphic GLP-1R-mediated thermoregulatory pathways during inflammation. However, the causal relationships between these molecular changes and temperature regulation require further investigation, particularly regarding whether observed biochemical alterations represent primary mechanisms or secondary consequences of temperature modulation. Future studies should investigate the functional significance of the apparent contradiction in serotonergic responses between sexes. Full article

Background: Obesity is a global epidemic and a complex chronic disease affecting more than one billion patients, leading to severe health issues like diabetes, heart disease, and cancer. While lifestyle changes are the first-line treatment, they are often insufficient. Current medications may cause severe side effects, including muscle loss and vision problems. Objectives: This systematic review aims to generalize and evaluate data from preclinical studies on the effect of flavonoid dihydroquercetin (DHQ) on weight loss in experimental animals compared with placebo-treated animals. Methods: This systematic review was conducted in accordance with the PRISMA guidelines. The protocol was registered in the PROSPERO database in August 2025 (CRD420251129793). Risk of bias (RoB) was assessed by using SYRCLE’s tool. Results: In total, eight studies included in the systematic review involved 175 animals (14 treatment groups and 9 control groups). Calculation of correlations between the reported effect on weight change and initial weight showed a strong association between these rates (R −0.9883). The intensity of DHQ effect depended on the condition: There were strong negative correlations between DHQ dose and the observed effect in diabetes mellitus (R −0.9056), hepatic lipid dysmetabolism (R −0.9339), and hepatic fibrosis (R −0.9025) in mice and rats’ data together. Conclusions: Intake of DHQ in the course of one month and three months resulted in a decrease in animals’ weight by 5.24% ± 1.95% and 18.29% ± 1.96% (p < 0.0001), respectively. Taken together, our results suggest the rationality for further research of DHQ as an anorexigenic agent, focusing on the stereochemistry of this flavonoid and its bioavailability optimization. Full article