Search Results (1,583)

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

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with early-life origins. Maternal obesity has been associated with increased ASD risk, yet the mechanisms and timing of susceptibility remain unclear. Using a mouse model combining in vitro fertilization (IVF) and embryo transfer, we separated the effects of pre-conception and gestational obesity. We found that maternal high fat diet (HFD) exposure prior to conception alone was sufficient to induce ASD-like behaviors in male offspring—including altered vocalizations, reduced sociability, and increased repetitive grooming—without anxiety-related changes. These phenotypes were absent in female offspring and those exposed only during gestation. Cortical transcriptome analysis revealed dysregulation and isoform shifts in genes implicated in ASD, including Homer1 and Zswim6. Whole-genome bisulfite sequencing of hippocampal tissue showed hypomethylation of an alternative Homer1 promoter, correlating with increased expression of the short isoform Homer1a, which is known to disrupt synaptic scaffolding. This pattern was specific to mice with ASD-like behaviors. Our findings show that pre-conceptional maternal obesity can lead to lasting, isoform-specific transcriptomic and epigenetic changes in the offspring’s brain. These results underscore the importance of maternal health before pregnancy as a critical and modifiable factor in ASD risk. Full article

The kallikrein–kinin system and its B1 and B2 receptors are key regulators in metabolic disorders such as obesity, diabetes, and insulin resistance. Obesity, a chronic and multifactorial condition often associated with comorbidities like type 2 diabetes and dyslipidemia, remains poorly understood at the metabolic level. The kinin B2 receptor (B2R) is involved in blood pressure regulation and glucose metabolism, promoting glucose uptake in skeletal muscle via bradykinin. Studies in B2R-KO mice demonstrate that the absence of this receptor predisposes animals to glucose intolerance under a high-fat diet and impairs adaptive thermogenesis, indicating a protective role for B2R in metabolic homeostasis and insulin sensitivity. In contrast, the kinin B1 receptor (B1R) is inducible under pathological conditions and is activated by kinin metabolites. Mouse models lacking B1R exhibit improved metabolic profiles, including protection against high-fat diet-induced obesity and insulin resistance, enhanced energy expenditure, and increased leptin sensitivity. B1R inactivation in adipocytes enhances insulin responsiveness and glucose tolerance, supporting its role in the development of insulin resistance. Moreover, B1R deficiency improves energy metabolism and thermogenic responses to adrenergic and cold stimuli, promoting the activation of brown adipose tissue and the browning of white adipose tissue. Collectively, these findings suggest that B1R and B2R represent promising therapeutic targets for the treatment of metabolic disorders. Full article

Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder associated with metabolic risk factors such as obesity, type 2 diabetes, and cardiovascular disease. If left untreated, the accumulation of excess hepatic fat can lead to inflammation, fibrosis, cirrhosis, hepatocellular carcinoma, and ultimately liver failure. Capsaicin (CAP), the primary pungent compound in chili peppers, has previously been shown to prevent weight gain in high-fat diet (HFD)-induced obesity models. In this study, we investigated the potential of dietary CAP to prevent HFD-induced MASLD. Methods: C57BL/6 mice were fed an HFD (60% kcal from fat) with or without 0.01% CAP supplementation for 26 weeks. We evaluated CAP’s effects on hepatic fat accumulation, inflammation, and mitochondrial function to determine its role in preventing MASLD. Results: CAP acts as a potent and selective agonist of the transient receptor potential vanilloid 1 (TRPV1) channel. We confirmed TRPV1 expression in the liver and demonstrated that CAP activates hepatic TRPV1, thereby preventing steatosis, improving insulin sensitivity, reducing inflammation, and enhancing fatty acid oxidation. These beneficial effects were observed in wild-type but not in TRPV1 knockout mice. Mechanistically, CAP-induced TRPV1 activation promotes calcium influx and activates AMPK, which leads to SIRT1-dependent upregulation of PPARα and PGC-1α, enhancing mitochondrial biogenesis and lipid metabolism. Conclusions: Our findings suggest that dietary CAP prevents MASLD through TRPV1 activation. TRPV1 signaling represents a promising therapeutic target for the prevention and management of MASLD in individuals with metabolic disorders. Full article

Chrysanthemum × morifolium (Ramat) Hemsl. (Hangbaiju), which has been widely consumed as a herbal tea for over 3000 years, is renowned for its biosafety and diverse bioactivities. This study investigates the impact of polyphenol-rich Hangbaiju extracts (HE) on high-fat diet-induced obesity in mice. HE contains phenolic acids and flavonoids with anti-obesity properties, such as apigenin, luteolin-7-glucoside, apigenin-7-O-glucoside, kaempferol 3-(6″-acetylglucoside), etc. To establish the obesity model, mice were randomly assigned into four groups (n = 8 per group) and administered with either HE or water for 42 days under high-fat or low-fat dietary conditions. Administration of low (LH) and high (HH) doses of HE both significantly suppressed body weight growth (by 16.28% and 16.24%, respectively) and adipose tissue enlargement in obese mice. HE significantly improved the serum lipid profiles, mainly manifested as decreased levels of triglycerides (28.19% in LH and 19.59% in HH) and increased levels of high-density lipoprotein cholesterol (44.34% in LH and 54.88% in HH), and further attenuated liver lipid deposition. Furthermore, HE significantly decreased the Firmicutes/Bacteroidetes ratio 0.23-fold (LH) and 0.12-fold (HH), indicating an improvement in the microecological balance of the gut. HE administration also elevated the relative abundance of beneficial bacteria (e.g., Allobaculum, norank_f__Muribaculaceae), while suppressing harmful pathogenic proliferation (e.g., Dubosiella, Romboutsia). In conclusion, HE ameliorates obesity and hyperlipidemia through modulating lipid metabolism and restoring the balance of intestinal microecology, thus being promising for obesity therapy. 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

Although Hylocereus polyrhizus pulp residues polysaccharides (HPPP) have shown potential in improving metabolic disorders and intestinal barrier function, the mechanism by which they exert their effects through regulating O-glycosylation modifications in the mucus layer remains unclear. Therefore, this study established a HFD-induced obese colitis mouse model (n = 5 per group) and combined nano-capillary liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) technology to quantitatively analyze the dynamic changes in O-glycosylation. Additionally, through quantitative O-glycosylation proteomics and whole-proteome analysis, we identified 155 specifically altered O-glycosylation sites in colon tissue, with the glycosylation modification level of the MUC2 core protein increased by approximately 2.1-fold. The results indicate that HPPP alleviates colonic mucosal damage by regulating interactions between mucus O-glycosylation. Overall, we demonstrated that HPPP increases HFD-induced O-glycosylation sites, improves intestinal mucosal structure in obese mice, and provides protective effects against obesity-induced intestinal mucosal damage. Full article

Background: A high-fat diet has been shown to have an impact on metabolism resulting in changes in arterial wall thickness and degeneration of surviving neural cells of the hippocampus. The present review focuses on the various animal models used to induce high-fat diet conditions for studying obesity-induced atherosclerosis, along with the associated changes observed in surviving neural cells of the hippocampus. It also highlights the limitations of rodent models and discusses their implications for human research. Methods: The sources for the literature search were Scopus, PubMed, Medline and Google Scholar. Both animal and human studies published were considered and are cited. Results: High-fat-diet-induced vascular changes, mainly in the tunica media, has been shown to have more impact on medium-sized arteries and on the Cornu Ammonis three subregions and outer dentatae gyrus of the hippocampus. Conclusions: High-fat-diet-induced neurovascular changes have been studied radically in animal models, and more supporting studies representing preclinical research should be advanced to humans. Full article

The global obesity epidemic and associated metabolic disorders present urgent public health challenges. This study employed a multi-omics approach (lipidomics, metabolomics, and gut microbiome analysis) to investigate how Bletilla striata polysaccharides (BSPs) and composite polysaccharides modulate liver lipid metabolism and gut microbiota in high-fat diet (HFD)-induced obese mice. HFD elevated hepatic phosphatidylcholines, cholesteryl esters (CEs), and acylcarnitines (CARs), alongside increased cecal choline and trimethylamine. BSP interventions reduced hepatic CEs, free fatty acids (FAs), CARs, and cecal sarcosine while restoring gut microbial diversity. Notably, BSP enriched beneficial genera, including Jeotgalicoccus and Atopostipes, and the network analysis revealed negative correlations between these genera and hepatic triglycerides (TGs), implicating the gut–liver axis in lipid metabolism regulation. These findings elucidate the anti-obesity mechanisms of polysaccharides through gut microbiota remodeling and cross-tissue metabolic interactions, providing a foundation for leveraging plant polysaccharides in developing safer, effective obesity therapies. 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

Adipose tissue macrophages (ATMs) play important roles in the progression of obesity-related severe acute pancreatitis (SAP). This study aimed to investigate the alterations of autophagic flux within ATMs, as well as the possible regulatory mechanisms. Obese mice were induced via high-fat diets. SAP was triggered using caerulein and lipopolysaccharide. Inflammatory injuries within pancreatic and adipose tissue were assessed. Autophagic flux, along with the expression of autophagosome-located soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, were examined in ATMs. RNA-sequencing was performed to identify the possible regulatory factor, which was further validated. The results showed that obesity exacerbated inflammatory injuries. ATMs in obesity-related SAP exhibited impaired autophagic flux characterized by reduced autophagosome–lysosome fusion. Expression of autophagosome-located SNARE proteins decreased in ATMs. RNA-sequencing identified Forkhead box as the differentially expressed transcription factor associated with autophagy. The expression and transcriptional activity of Forkhead box O1 (FoxO1) decreased. The inhibition of FoxO1 exacerbated SNARE proteins’ suppression and autophagic flux impairment, while the activation of FoxO1 showed the opposite effect. In conclusion, obesity-induced impaired autophagic flux and autophagosome–lysosome fusion in ATMs are potentially regulated via autophagosome-located SNARE proteins and the transcription factor FoxO1. The impaired autophagic flux in ATMs aggravated inflammatory injuries of obesity-related SAP. Full article

Background/objectives: Being overweight increases the predisposition to obesity and type 2 diabetes (T2D), which significantly elevate stroke risk and the likelihood of severe post-stroke disability. Dietary nitrate (NO₃⁻) supplementation can mitigate obesity and metabolic impairments, making it a promising approach to halt overweight people from developing overt obesity/T2D, thereby potentially also improving stroke outcome. We determined whether NO3⁻ supplementation prevents overweight mice from progressing into obesity and T2D and whether this intervention improves stroke outcome. Methods: An overweight condition was induced via 6 weeks of a high-fat diet (HFD), after which animals were randomized to either a HFD or a HFD with NO₃⁻ supplementation. After 24 weeks, when HFD-mice without NO₃⁻ developed obesity and T2D, all animals were subjected to transient middle cerebral artery occlusion and stroke outcome was assessed via behavioral testing and infarct size. The effect of NO₃⁻ on post-stroke neuroinflammation, neurogenesis, and neovascularization was analyzed by immunohistochemistry. Results: Sustained NO₃⁻ supplementation in overweight mice did not prevent obesity or insulin resistance. However, it attenuated weight gain, prevented hyperglycemia, and significantly improved functional recovery after stroke, without affecting infarct size. Moreover, NO₃⁻ decreased post-stroke neuroinflammation by reducing microglial infiltration. NO₃⁻ did not affect stroke-induced neurogenesis or vascularization. Conclusion: These results highlight the potential of NO₃⁻ supplementation to prevent metabolic impairment in the overweight population and improve stroke prognosis in this large group of people at risk of stroke and severe stroke sequelae. Full article

There are currently no approved therapeutic treatments targeting metabolic dysfunction-associated steatotic liver disease (MASLD). Albumin, a liver-produced plasma protein with anti-inflammatory and antioxidant properties, is reduced in advanced liver disease. Considering the role of chronic obesity-induced inflammation in MASLD pathogenesis, we investigated whether albumin administration could prevent disease progression to metabolic dysfunction-associated steatohepatitis (MASH). MASLD was induced in mice using a high-fat and high-cholesterol (PC) treatment for 8 weeks, followed by treatment with bovine serum albumin (BSA; 0.8 mg/kg) every three days for another 8 weeks. This regimen prevented time-dependent weight gain, regardless of diet, with 57% and 27% reductions in mice fed a standard chow (Std Chow) or PC diet, respectively. Further, supplementation reduced nuclear factor kappa B (NF-κB) activation by 2.8-fold (p = 0.0328) in PC-fed mice, consistent with albumin’s known anti-inflammatory properties. Unexpectedly, albumin also reduced hepatic neutral lipid accumulation and circulating non-esterified fatty acids. While PC-fed mice did not exhibit full progression to MASH, albumin treatment significantly increased hepatic matrix metalloproteinase-2 expression, suggesting the inhibition of early fibrotic signalling. While further studies are needed to elucidate the underlying mechanisms, these findings offer new insight into the potential of albumin, either alone or in combination with other therapies, to reduce hepatic steatosis in MASLD. 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