Search Results (478)

Background: Obesity is a complex disorder with both metabolic and neurocognitive consequences, including impairments in prefrontal cortex (PFC)-dependent learning and memory. Combination pharmacotherapy may offer a more effective approach for addressing obesity-induced cognitive deficits. Objective: This study evaluated the effects of 30-day co-administration of lorcaserin (5-HT₂C agonist) and betahistine (H₁ agonist/H₃ antagonist) in reversing cognitive deficits in a diet-induced obesity (DIO) rat model. Methods: Male Lewis rats were subjected to DIO and administered lorcaserin (2 mg/kg) and betahistine (5 mg/kg), either alone or in combination, via intraperitoneally implanted osmotic minipumps for 30 days. Y-maze, novel object recognition, and object-in-place (OIP) tests were used to assess cognitive functions. In vivo electrophysiological recordings were employed to examine effects of the combination treatment on ventral tegmental area (VTA) dopaminergic neuron activity. Results: Obese Western-diet-fed rats showed lower discrimination scores in the OIP task, a behavioral test that engages PFC functions, while their performance in the Y-maze and novel object recognition tasks was similar to that of non-obese Control-diet-fed rats. Combination treatment with lorcaserin and betahistine significantly improved the OIP scores of obese rats. However, the combination treatment did not reduce body weight or obesity-associated morphometrical parameters. Electrophysiological recordings revealed a reduction in the number of spontaneously active dopaminergic neurons in the VTA of obese rats. Lorcaserin and betahistine co-treatment significantly increased the number of spontaneously active dopaminergic neurons of obese animals. Conclusions: These results demonstrate the potential of combination lorcaserin–betahistine treatment to reverse obesity-related cognitive deficits, possibly through enhancement of mesocortical dopaminergic neuron activity. Full article

Polyphenols have been widely recognized for their potential anti-obesity effects. This study aimed to evaluate the impact of a polyphenol compound-epigallocatechin-3-gallate, quercetin, and rutin (EQR) on obesity-related parameters and gut microbiota composition. After four weeks of high-fat diet (HFD) induction, the obese Wistar male rats received EQR treatment for an additional four weeks. EQR supplementation significantly reduced body weight gain, feed efficiency, adipose tissue accumulation, and liver lipid content in obese rats. Additionally, it enhanced fecal short-chain fatty acid (SCFA) levels and modulated gut microbiota composition. Specifically, EQR treatment significantly induced Fusobacteria, Fusobacteriaceae, Christensenellaceae, Christensenellaceae R-7 group, Lachnoclostridium, Enterorhabdus, and Parvibacter levels and reduced Deferribacteres and Mucispirillum levels. Gene expression analysis in liver, white adipose tissue (WAT), and brown adipose tissue (BAT) revealed that EQR upregulated the expression of liver PPAR-α, WAT SIRT-1, and BAT PGC-1α, while downregulating liver PPAR-γ, liver FATP-1, and WAT FAS, indicating its role in promoting fatty acid oxidation and thermogenesis, as well as suppressing lipid synthesis and transport. In conclusion, EQR demonstrated significant anti-obesity effects by modulating gut microbiota and lipid metabolism, suggesting its potential as a functional ingredient for obesity management. Full article

Honeybee brood biopeptides (HBb-Bps) are a novel source of bioactive compounds with potential health benefits. In this study, HBb-Bps were conjugated with honey via a Maillard reaction and their physicochemical properties, digestive stability, antioxidant capacity, and anti-obesogenic effects were evaluated. Simulated gastrointestinal digestion revealed significantly enhanced resistance after conjugation, with the residual content increasing from 46.99% for native HBb-Bps to 86.12% for the honey-conjugated forms; furthermore, antioxidant activity was largely preserved according to the DPPH and ABTS assays. In the in vivo experiments, 30 male BrlHan: WIST@Jcl (GALAS) (Wistar) rats were fed a high-fat diet (HFD) to induce obesity and orally administered honey-conjugated HBb-Bps at doses of 200, 500, or 1000 mg/kg body weight for 16 weeks. The highest dose led to significant reductions in body weight gain, the Lee index, and body mass index. The serum lipid profiles markedly improved, with decreases in the total cholesterol, triglyceride, and LDL levels, as well as cardiovascular risk indices. Furthermore, fecal analysis showed increased levels of short-chain fatty acids, particularly butyrate. These changes suggest enhanced gut microbial activity; however, the prebiotic effects were inferred from the SCFA profiles, as the gut microbiota composition was not directly analyzed. In conclusion, honey-conjugated HBb-Bps improve gastrointestinal stability and exhibit antioxidant, hypolipidemic, and gut-modulating effects, supporting their potential use as functional ingredients for managing diet-induced metabolic disorders. Full article

Diseases such as obesity and metabolic-dysfunction-associated fatty liver disease (MAFLD) are often associated with changes in gut microbiota composition. The present study aims to investigate the relationship between the potential preventive effects of an Opuntia ficus-indica var. colorada cactus pulp extract on obesity and hepatic steatosis, and changes in gut microbiota composition, in a murine model fed a high-fat high-fructose diet. The low-dose extract was the most effective in reducing hepatic TG (−12.5%) and the weight of subcutaneous and visceral adipose tissue (−18.4% and 11.4%, respectively), while the high dose led to improved serum lipid profile (−74.2% in TG, −37.2% in total cholesterol, −50.5% in non-HDL cholesterol and +71.7% in HDL cholesterol). Opuntia extract supplementation did not prevent the dysbiosis in gut microbiota produced by the high-fat high-fructose diet. However, modifications in its composition, consistent with an increment in both Adlercreutzia muris and Cutibacterium acnes, and a reduction in Massiliimalia timonensis, were observed. It can be proposed that these changes may contribute to the extract effects against obesity and liver steatosis. Nevertheless, further research is required to establish a direct link between the anti-obesity and anti-steatotic effects and the functionality of the bacteria modified by the treatment. Full article

Obesity, a major global health concern, is associated with systemic metabolic dysregulation. Spexin, a peptide implicated in appetite control and energy balance, may represent a biomarker and therapeutic target in obesity management. This study aimed to investigate tissue-specific modulation of spexin expression in obese male rats subjected to aerobic exercise and/or metformin treatment. Thirty-six Sprague–Dawley rats were randomly assigned to six groups (n = 6 per group): (i) control, (ii) obese control, (iii) exercise, (iv) metformin, (v) metformin + exercise, and (vi) a decapitation baseline group. Obesity was induced via a 12-week high-calorie diet. Subsequently, interventions were applied over 4 weeks: treadmill running (30 min/day, 5 days/week) and/or metformin (150 mg/kg/day). Post-intervention, body weight significantly decreased in intervention groups (p < 0.001) exercise (−13.7%), metformin (−14.6%), and metformin + exercise (−21.1%) compared to the obese control group. ELISA revealed tissue-specific effects on spexin expression. In skeletal muscle, spexin levels were highest in controls (628 ± 160.5 pg/mL), with a significant reduction in the metformin + exercise group (349 ± 84.7 pg/mL; p = 0.003, Cohen’s d = 2.17). In the liver, the control group showed the highest expression (443 ± 240.8 pg/mL), while metformin + exercise yielded the lowest (254 ± 20.4 pg/mL). In contrast, heart tissue maintained elevated spexin levels across all intervention groups, with the metformin + exercise group nearly matching control levels (617 ± 25.2 vs. 618 ± 53.2 pg/mL). Immunohistochemistry confirmed these patterns, with the highest cardiac histoscore in the metformin + exercise group (2.34 ± 0.09). Hierarchical clustering underscored distinct tissue-specific expression patterns, separating muscle from liver and heart. Collectively, these findings suggest that spexin is differentially regulated by exercise and metformin, with joint effects and complex, tissue-specific modulation. This highlights spexin’s potential as a biomarker and therapeutic target in precision obesity interventions. Full article

Excess caloric intake and insufficient physical activity are the two major drivers underlying the global obesity and type 2 diabetes mellitus epidemics. However, circadian misalignment of caloric intake and physical activity, as commonly experienced by nightshift workers, can also have detrimental effects on body weight and glucose homeostasis. We have previously reported that combined restriction of eating and voluntary wheel running to the inactive phase (i.e., a rat model for circadian misalignment) shifted liver and muscle clock rhythms by ~12 h and prevented the reduction in the amplitude of the muscle clock oscillation otherwise induced by light-phase feeding. Here, we extended on these findings and investigated how a high-fat diet (HFD) affects body composition and liver and muscle clock gene rhythms in male Wistar rats while restricting both eating and exercise to either the inactive or active phase. To do this, we used four experimental conditions: sedentary controls with no wheel access on a non-obesogenic diet (NR), sedentary controls with no wheel access on an HFD (NR-H), and two experimental groups on an HFD with simultaneous access to a running wheel and HFD time-restricted to either the light phase (light-run-light-fed + HFD, LRLF-H) or the dark phase (dark-run-dark-fed + HFD. DRDF-H). Consumption of an HFD did not alter the daily running distance of the time-restricted groups but did increase the running intensity in the LRLF-H group compared to a previously published LRLF chow fed group. However, no such increase was observed for the DRDF-H group. LRLF-H ameliorated light phase-induced disturbances in the soleus clock more effectively than under chow conditions and had a protective effect against HFD-induced changes in liver clock gene expression. Together with (our) previously published results, these data suggest that eating healthy and being active at the wrong time of the day can be as detrimental as eating unhealthy and being active at the right time of the day. Full article

Obesity remains a major global health challenge with limited therapeutic options. Bromelain, a proteolytic enzyme complex derived from pineapple, has been recognized for its natural anti-inflammatory, anti-edematous, and appetite-suppressing properties. This study aimed to investigate the effects of bromelain on hypothalamic neuropeptides and metabolic markers in a high-fat diet (HFD)-induced obesity model in rats. Thirty-six male Wistar albino rats were randomly divided into four groups: standard diet (SD), standard diet with bromelain (SDBro), high-fat diet (HFD), and high-fat diet with bromelain (HFDBro). Obesity was induced by a 3-month HFD regimen, followed by bromelain supplementation (200 mg/kg/day, orally) for one month. Hypothalamic tissues were analyzed via ELISA for neuropeptide Y (NPY), pro-opiomelanocortin (POMC), glucose transporter 2 (GLUT2), fibroblast growth factor 2 (FGF2), and insulin-like growth factor 1 receptor (IGF1R). While NPY levels showed no significant changes, POMC increased in the HFD and was normalized with bromelain. GLUT2 was downregulated in the HFD and significantly restored by bromelain. FGF2 levels remained unchanged. IGF1R was upregulated in the HFD but reduced by bromelain, with an unexpected increase in SDBro. Overall, bromelain partially reversed HFD-induced disruptions in hypothalamic energy-regulating pathways, particularly affecting GLUT2 and POMC. These findings highlight bromelain’s potential role in central metabolic regulation under dietary stress. Full article

Obesity and metabolic dysfunction are established risk factors for luminal breast cancer, yet current preclinical models inadequately recapitulate the complex metabolic and immune interactions driving tumorigenesis. To develop and characterize an immunocompetent rat model of luminal breast cancer induced by chronic exposure to a cafeteria diet mimicking Western obesogenic nutrition, female rats were fed a cafeteria diet or standard chow from weaning. Metabolic parameters, plasma biomarkers (including leptin, insulin, IGF-1, adiponectin, and estrone), mammary gland histology, tumor incidence, and gene expression profiles were longitudinally evaluated. Gene expression was assessed by PCR arrays and qPCR. A subgroup underwent dietary reversal to assess the reversibility of molecular alterations. Cafeteria diet induced significant obesity (mean weight 426.76 g vs. 263.09 g controls, p < 0.001) and increased leptin levels without altering insulin, IGF-1, or inflammatory markers. Histological analysis showed increased ductal ectasia and benign lesions, with earlier fibroadenoma and luminal carcinoma development in diet-fed rats. Tumors exhibited luminal phenotype, low Ki67, and elevated PAI-1 expression. Gene expression alterations were time point specific and revealed early downregulation of ID1 and COX2, followed by upregulation of MMP2, THBS1, TWIST1, and PAI-1. Short-term dietary reversal normalized several gene expression changes. Overall tumor incidence was modest (~12%), reflecting early tumor-promoting microenvironmental changes rather than aggressive carcinogenesis. This immunocompetent cafeteria diet rat model recapitulates key metabolic, histological, and molecular features of obesity-associated luminal breast cancer and offers a valuable platform for studying early tumorigenic mechanisms and prevention strategies without carcinogen-induced confounders. Full article

Chronic high-fat diet (HFD) feeding in male rats causes significant metabolic as well as inflammatory disturbances, including obesity, insulin resistance, dyslipidemia, liver and kidney dysfunction, oxidative stress, and hypothalamic dysregulation. This study assessed the therapeutic effects of chlorogenic acid (CGA), a natural polyphenol, administered at 10 mg and 100 mg/kg/day for the last 4 weeks of a 12-week HFD protocol. Both CGA doses reduced body weight gain, abdominal circumference, and visceral fat accumulation, with the higher dose showing greater efficacy. CGA improved metabolic parameters by lowering fasting glucose and insulin and enhancing lipid profiles. CGA suppressed orexigenic genes (Agrp, NPY) and upregulated anorexigenic genes (POMC, CARTPT), suggesting appetite regulation in the hypothalamus. In abdominal white adipose tissue (WAT), CGA boosted antioxidant defenses (SOD, CAT, GPx, HO-1), reduced lipid peroxidation (MDA), and suppressed pro-inflammatory cytokines including TNF-α, IFN-γ, and IL-1β, while increasing the anti-inflammatory cytokine IL-10. CGA modulated inflammatory signaling via upregulation of miR-146a and inhibition of IRAK1, TRAF6, and NF-κB. It also reduced apoptosis by downregulating p53, Bax, and Caspase-3, and restoring Bcl-2. These findings demonstrate that short-term CGA administration effectively reverses multiple HFD-induced impairments, highlighting its potential as an effective therapeutic for obesity-related metabolic disorders. Full article

Enteroendocrine cells (EECs) are specialized secretory cells in the gut epithelium that differentiate from intestinal stem cells (ISCs). Mature EECs secrete incretin hormones that stimulate pancreatic insulin secretion and regulate appetite. Decreased EEC numbers and impaired secretion of the incretin glucagon-like peptide-1 (GLP1) have been implicated in obesity-associated metabolic complications. Gut microbial metabolites of dietary tryptophan (TRP) were recently shown to modulate ISC proliferation and differentiation. However, their specific effects on EEC differentiation are not known. We hypothesized that the gut microbial metabolites of dietary tryptophan counteract impaired GLP1 production and function in obesity by stimulating EEC differentiation from ISCs. We utilized complementary models of human and rat intestines to determine the effects of obesity or TRP metabolites on EEC differentiation. EEC differentiation was assessed by the EEC marker chromogranin A (CHGA) levels in the intestinal mucosa of normal versus obese rats. The effects of TRP metabolites on EEC differentiation were determined in human intestinal organoids treated with indole, a primary TRP metabolite, or the culture supernatant of Lactobacillus acidophilus grown in TRP media (LA-CS-TRP). Our results showed that the mRNA and protein levels of CHGA, the EEC marker, were significantly decreased (~60%) in the intestinal mucosa of high-fat-diet-induced obese rat intestines. The expression of the transcription factors that direct the ISC differentiation towards the EEC lineage was also decreased in obesity. In human organoids, treatment with indole or LA-CS-TRP significantly increased (more than 2-fold) CHGA levels, which were blocked by the aryl hydrocarbon receptor (AhR) antagonist CH-223191. Thus, the stimulation of EEC differentiation by colonic microbial metabolites highlights a novel therapeutic role of TRP metabolites in obesity and associated metabolic disorders. Full article

Obesity affects approximately 30% of pregnancies worldwide and is one of the leading metabolic disorders among pregnant women. Maternal obesity is often associated with placental dysfunction and structural alterations, which increase the risk of developing complications. Efflux transporters, including P-glycoprotein (P-gp), may impact placental function and fetal development. Consequently, our research examined the effects of obesity on P-glycoprotein expression in both a rat model and human placental tissue. P-gp expression was measured by RT-PCR and Western blot techniques in human and rat placental tissues. Moreover, we further characterized the high-fat and high-sugar diet (HFHSD)-induced gestational obesity rat model by measuring tissue weights. Significant decreases were observed in fetal, placental, and uterus weights in the obese animals near the end of pregnancy. In obese rats, mRNA and protein expression of placental P-gp showed a reduction on gestation days 15, 20, and 22. A similar P-gp reduction was observed in the term placenta in obese women in mRNA and protein levels. We hypothesize that the reduced expression of P-gp may heighten the susceptibility of both the fetus and placenta to P-gp substrates. This alteration could potentially result in an increased risk of pregnancy complications and obesity-related drug contraindications linked to P-gp transport during pregnancy. Full article

In modern society, obesity and its associated complications have emerged as serious public health concerns, primarily stemming from sedentary lifestyles and carbohydrate-rich diets. Due to the severe side effects often associated with pharmacological anti-obesity agents, emerging global efforts focus on preventive strategies, e.g., dietary modifications and weight gain-suppressing functional foods. In this context, plant-derived metabolites are extensively investigated for their beneficial anti-obesity effects. In this study, we evaluated how Rosa rugosa Thunb. flower bud extract affects fat metabolism in 3T3-L1 preadipocyte cells. The extract significantly inhibited adipocyte differentiation and intracellular triglyceride accumulation in 3T3-L1 cells, enhanced lipolysis, suppressed lipogenesis, and promoted energy metabolism in differentiated adipocytes. In vivo, it reduced body and organ weights and fat mass in high-fat diet-induced obese rats, along with marked adipocyte size and hepatic lipid accumulation reductions. In the epididymal adipose tissue, the extract similarly enhanced lipolytic activity, suppressed lipogenic enzyme expression, and stimulated energy expenditure. Taken together, our results demonstrate the potential of R. rugosa Thunb. flower bud extract in reducing fat accumulation through lipid metabolism modulation both in cellular and animal models. Further studies are warranted to identify the active constituents and evaluate the safety and efficacy of the extract in clinical applications. Full article

Short-chain fatty acids (SCFA), particularly propionate and butyrate, reduce food intake, body weight, and modulate gut microbiota composition. However, it is unclear whether encapsulation of propionate and butyrate enhances their delivery to distal gut to improve energy balance and gut microbiota composition in obesity. Objectives: We determined the effects of microencapsulated propionate and butyrate on energy balance, gut microbiota and metabolite composition in obese rats. Methods: In experiment-1, obese male Sprague-Dawley rats were fed microencapsulated propionate and butyrate (5–10% wt/wt) or control high-fat diet. In experiment-2, obese rats were fed 10% microencapsulated propionate and butyrate, non-encapsulated butyrate (10% wt/wt), and pair-fed to non-capsulated butyrate. Food intake, energy expenditure (EE), sympathetic-mediated EE changes by propranolol, body composition, gut microbiota and fecal and plasma metabolites were analyzed. Results: Microencapsulated propionate decreased caloric intake, weight and fat mass, while microencapsulated butyrate had modest effects. Non-encapsulated butyrate reduced intake and prevented weight gain beyond pair-fed controls. Microencapsulated propionate and non-encapsulated butyrate reduced respiratory quotient suggestive of a shift towards lipid utilization, and enhanced β-adrenergic-mediated EE. Microencapsulated propionate and butyrate altered alpha and beta diversity metrics, microencapsulated propionate increased Verrucomicrobiae, microencapsulated butyrate increased Lactobacillaceae, and microencapsulated propionate and butyrate reduced Erysipelotrichia. Microencapsulated propionate and butyrate increased fecal amino acids and altered select plasma metabolites; microencapsulated propionate increased fecal and plasma propionate, supporting distal gut delivery. Conclusions: Dietary supplementation with microencapsulated propionate and butyrate improved energy balance, enhanced lipid utilization, beneficially modulated gut microbiota composition, and altered metabolite profiles in obese rats. Full article

Background/Objectives: Chronic kidney disease (CKD) is twice as prevalent in individuals with obesity-associated non-alcoholic fatty liver disease (Ob-NAFLD), highlighting the need to determine the link and mechanisms of kidney injury as well as explore therapies. Metformin, a first-line treatment for type 2 diabetes, shows promise in managing NAFLD, but its renal benefits in Ob-NAFLD remain unclear. This study investigates the impact of Ob-NAFLD on kidney injury and assesses the potential protective effects of metformin. Methods: Five-week-old female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for 8 weeks to induce Ob-NAFLD, then fed the diet with Metformin for 10 weeks. Kidneys were collected for histopathological and biochemical analyses. Results: Histopathological studies showed increased tubular injury, mesangial matrix expansion, and fibrosis in kidneys with Ob-NAFLD compared to lean control (LC) rats. Immunohistochemistry further revealed an elevated macrophage and neutrophil infiltration and increased levels of nitrotyrosine and p22phox in Ob-NAFLD kidneys. Furthermore, Ob-NAFLD rat kidneys showed upregulation of TNF-α and CCL2 genes and increased levels of caspase-3 (total and cleaved). Interestingly, metformin treatment significantly decreased TNF-α mRNA and blunted nitrotyrosine levels, and modestly reduced immune cell infiltration in Ob-NAFLD. Conclusions: These findings indicate that Ob-NAFLD promotes CKD as evidenced by tubular injury, oxidative stress, inflammation, and fibrosis. While short-term metformin treatment showed anti-oxidative and anti-inflammatory effects in Ob-NAFLD, its impact on structural kidney damage was limited, highlighting the need for longer treatment or alternative therapeutics such as oxidant scavengers and anti-inflammatory drugs to effectively mitigate renal pathologies. Full article

Background/Objectives: The consumption of fructose-sweetened beverages, especially when combined with a high-fat (HF) diet, substantially contributes to obesity, diabetes, and metabolic dysfunction-associated steatotic liver disease. Ectopic fat accumulation in skeletal muscles is a critical factor in the development of insulin resistance, a key feature of these metabolic disorders. We aimed to investigate the effects of the rare sugar, d-allulose, on fructose-induced insulin resistance. Methods: Male Wistar rats were randomly assigned to fructose-free control diet (CD), HF/fructose-free diet (HF), or HF/fructose diet (HFF) groups. After 4 weeks, an intraperitoneal glucose tolerance test (IPGTT) was performed, followed by a two-step hyperinsulinemic–euglycemic clamp (HE-clamp) test at 5 weeks. Blood, skeletal muscle, and liver samples were collected after 6 weeks, and triglyceride (TG) levels were measured. Additionally, Western blot was performed on skeletal muscle samples. The same protocol was repeated for the HFF group supplemented with either 5% d-allulose or 5% cellulose. Results: Compared to the CD and HF groups, the HFF group exhibited increased blood glucose levels during the IPGTT and greater systemic and skeletal muscle insulin resistance in the HE-clamp. Furthermore, plasma, liver, and muscle TG levels were significantly elevated in the HFF group. However, d-allulose supplementation improved insulin resistance in the HFF group and reduced blood, liver, and muscle TG levels. Additionally, insulin-stimulated AKT phosphorylation and acetyl-CoA carboxylase phosphorylation were enhanced in the skeletal muscle following d-allulose administration. Conclusions: d-allulose may improve insulin resistance by reducing TG accumulation in the skeletal muscle, potentially independent of its anti-obesity properties. Full article