High-fat Diet-fed Mice Research Articles

Blood circulation effect of fermented citrus bioconversion product (FCBP) in EA.hy926 endothelial cells and high-fat diet-fed mouse model

Background: The escalating global burden of cardiovascular diseases, largely driven by unhealthy lifestyle choices and dietary patterns, has intensified the search for effective and safe interventions. With current treatments often marred by significant side effects, the exploration of natural compounds such as flavonoids presents a compelling alternative. Objective: This study investigated the effects of fermented citrus bioconversion product (FCBP), a fermented citrus bioflavonoid, on various markers of cardiovascular health in the context of a high-fat diet. Design: In vivo, a high-fat diet-induced mouse model was used to assess the effects of FCBP on body weight, serum nitric oxide (NO) levels, activated partial thromboplastin time (aPTT), phosphatidylserine (PS) exposure on red blood cells, and the expression of inflammatory markers Intercellular Adhesion Molecule (ICAM)-1 and Vascular Cell Adhesion Molecule (VCAM)-1 in the thoracic aorta. In vitro, EA.hy926 endothelial cells were used to evaluate the compound’s effects on cell viability, NO production, endothelial nitric oxide synthase (eNOS) expression, and cell adhesion molecule (CAM) levels to further understand the mechanisms behind the in vivo findings. Results: In vivo, FCBP supplementation led to a dose-dependent reduction in weight gain, a significant decrease in serum NO levels at 10 mg/kg, and reduced ICAM-1 and VCAM-1 expressions in the thoracic aorta, indicating anti-inflammatory properties. PS exposure on red blood cells was also reduced, suggesting decreased procoagulant activity, while aPTT remained unchanged. In vitro, FCBP was non-cytotoxic to endothelial cells, showed a trend toward increased NO production and eNOS expression, and reduced the expression of ICAM-1 and VCAM-1, supporting its potential anti-inflammatory effects. Conclusions: FCBP demonstrates potential as a bioactive compound for managing cardiovascular health by reducing inflammation, mitigating weight gain, and influencing blood circulation-related parameters under high-fat diet conditions. Further studies, including diverse models and human trials, are warranted to elucidate its mechanisms and compare its efficacy with established cardiovascular therapeutics.

AS160 is a lipid-responsive regulator of cardiac Ca2+ homeostasis by controlling lysophosphatidylinositol metabolism and signaling

The obese heart undergoes metabolic remodeling and exhibits impaired calcium (Ca2+) homeostasis, which are two critical assaults leading to cardiac dysfunction. The molecular mechanisms underlying these alterations in obese heart are not well understood. Here, we show that the Rab-GTPase activating protein AS160 is a lipid-responsive regulator of Ca2+ homeostasis through governing lysophosphatidylinositol metabolism and signaling. Palmitic acid/high fat diet inhibits AS160 activity through phosphorylation by NEK6, which consequently activates its downstream target Rab8a. Inactivation of AS160 in cardiomyocytes elevates cytosolic Ca2+ that subsequently impairs cardiac contractility. Mechanistically, Rab8a downstream of AS160 interacts with DDHD1 to increase lysophosphatidylinositol metabolism and signaling that leads to Ca2+ release from sarcoplasmic reticulum. Inactivation of NEK6 prevents inhibition of AS160 by palmitic acid/high fat diet, and alleviates cardiac dysfunction in high fat diet-fed mice. Together, our findings reveal a regulatory mechanism governing metabolic remodeling and Ca2+ homeostasis in obese heart, and have therapeutic implications to combat obesity cardiomyopathy.

Epicatechin suppresses the expression of C-C motif chemokine ligand 19 and ameliorates periodontitis

Periodontitis is a prevalent chronic inflammatory disease requiring the development of drug-based therapies. Epicatechin is a major polyphenol in cocoa extract and possesses numerous pharmacological properties. This study aimed to investigate the suppressive effect of epicatechin on C-C motif chemokine ligand 19 (CCL19)-mediated periodontitis using a mouse model. CCL19 expression was high in mouse gingiva with ligature-induced periodontitis. CCL19 expression was increased by lipopolysaccharide stimulation in murine gingival fibroblasts ESK-1 cells, and CCL19 induced the production of tumor necrosis factor alpha and interleukin-1 beta in mouse macrophage-like RAW264.7 cells. Importantly, lipopolysaccharide-enhanced CCL19 expression in ESK-1 cells was significantly suppressed by pretreatment with epicatechin. In addition, epicatechin administration significantly reduced alveolar bone resorption, and expression of Ccl19 and proinflammatory cytokines in the inflamed gingiva in high-fat diet-fed mice. These results demonstrate that epicatechin protects against periodontitis by reducing CCL19 levels, which may be a promising countermeasure for periodontitis in clinical practice.

Variable glucagon metabolic actions in diverse mouse models of obesity and type 2 diabetes

ObjectiveThe study aimed to investigate the effects of glucagon on metabolic pathways in mouse models of obesity, fatty liver disease, and type 2 diabetes (T2D) to determine the extent and variability of hepatic glucagon resistance in these conditions. MethodsWe investigated glucagon's effects in mouse models of fatty liver disease, obesity, and type 2 diabetes (T2D), including male BKS-db/db, high-fat diet-fed, and western diet-fed C57Bl/6 mice. Glucagon tolerance tests were performed using the selective glucagon receptor agonist acyl-glucagon (IUB288). Blood glucose, serum and liver metabolites include lipids and amino acids were measured. Additionally, liver protein expression related to glucagon signalling and a comprehensive liver metabolomics were performed. ResultsWestern diet-fed mice displayed impaired glucagon response, with reduced blood glucose and PKA activation. In contrast, high-fat diet-fed and db/db mice maintained normal glucagon sensitivity, showing significant elevations in blood glucose and phospho-PKA motif protein expression. Acyl-glucagon treatment also lowered liver alanine and histidine levels in high-fat diet-fed mice, but not in western diet-fed mice. Additionally, some amino acids, such as methionine, were increased by acyl-glucagon only in chow diet control mice. Despite normal glucagon sensitivity in PKA signalling, db/db mice had a distinct metabolomic response, with acyl-glucagon significantly altering 90 metabolites in db/+ mice but only 42 in db/db mice, and classic glucagon-regulated metabolites, such as cyclic adenosine monophosphate (cAMP), being less responsive in db/db mice. ConclusionsThe study reveals that hepatic glucagon resistance in obesity and T2D is complex and not uniform across metabolic pathways, underscoring the complexity of glucagon action in these conditions.

Curcuma longa rhizome extract activates brown adipocytes and inhibits lipogenesis in high-fat diet-fed mice

Interactions between the gut, adipose, and liver tissues play important roles in metabolic endotoxemia and gut dysbiosis. This study explored the effectiveness of Curcuma longa rhizome extract (CRE) in improving high-fat diet (HFD)-induced metabolic disorders and modulating gut environments. CRE treatment inhibited lipid accumulation in 3T3-L1 white adipocytes and activated thermogenesis-related genes in T37i brown adipocytes. CRE was administered to HFD-fed mice for 8 weeks, and serum, feces, colon, white adipose, and liver tissue were analyzed. CRE ameliorated the symptoms of metabolic disorders in mice with HFD-induced obesity by suppressing body weight and fat mass gain, adipocyte size, insulin resistance, and hepatic steatosis. CRE regulated gut axis-based mechanisms by inhibiting gut permeability, metabolic endotoxemia, and de novo lipogenesis, and promoting gut barrier integrity. Serum metabolites were negatively correlated with most biomarkers for metabolic disorders. Therefore, CRE could alleviate metabolic disorders by improving the intestinal environment and modulating the gut axis.

Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme alpha subunit to treat obesity in male mice

Obesity and related diseases pose a major health risk, yet current anti-obesity drugs inadequately addressing clinical needs. Here we show AA005, an annonaceous acetogenin mimic, resists obesity induced by high-fat diets and leptin mutations at non-toxic doses, with the alpha subunit of the mitochondrial trifunctional protein (HADHA) as a target identified through proteomics and in vitro validation. Pharmacokinetic analysis shows AA005 enriches in adipose tissue, prompting the creation of adipose-specific Hadha-deficient mice. These mice significantly mitigate diet-induced obesity, echoing AA005’s anti-obesity effects. AA005 treatment and Hadha deletion in adipose tissues increase body temperature and energy expenditure in high-fat diet-fed mice. The beneficial impact of AA005 on obesity mitigation is ineffective without uncoupling protein 1 (UCP1), essential for thermogenesis regulation. Our investigation shows the interaction between AA005 and HADHA in mitochondria, activating the UCP1-mediated thermogenic pathway. This substantiates AA005 as a promising compound for obesity treatment, targeting HADHA specifically.

The deficiency of ALKBH5 contributes to hepatic lipid deposition by impairing VPS11-dependent autophagic flux.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Hepatic lipid deposition is a key factor in the development of NAFLD. N6-methyladenosine (m6A) modification, the most prevalent mRNA modification in eukaryotic cells, plays an important role in regulating hepatic lipid metabolism. However, its potential role in hepatic lipid deposition remains poorly understood. Histological and immunohistochemistry studies were used to investigate lipid deposition in free fatty acids (FFAs)-incubated LO2 cells, high-fat diet-fed mice models and clinical samples. Stable overexpression and knockdown of AlkB homolog 5 (ALKBH5) was manipulated to investigate the effects of ALKBH5 on m6A methylation and lipid metabolism in hepatocytes. RNA-sequencing transcriptome analysis and methylated RNA immunoprecipitation-quantitative-PCR analysis were used to reveal the potential downstream molecular targets of ALKBH5. ALKBH5 was down-regulated in fatty liver compared to normal liver in both humans and mice. Overexpression of ALKBH5 significantly improved FFA-induced lipid accumulation and promoted autophagosome-lysosome fusion in hepatocytes. Meanwhile, knockdown of ALKBH5 significantly increased the expression of microtubule-associated protein 1A/1B-light chain 3B and Sequestosome 1, leading to impaired autophagic flux and further lipid deposition in hepatocytes under FFA incubation. Overexpression of vacuolar protein sorting 11 (VPS11) reversed FFA-induced lipid accumulation in ALKBH5-silenced hepatocytes. Mechanistically, ALKBH5 alleviated hepatic lipid deposition and impaired autophagic flux by removing the m6A modification on VPS11 mRNA to promote its translation. Collectively, our findings revealed an epigenetic mechanism by which ALKBH5 alleviates hepatic lipid deposition by restoring VPS11-dependent autophagic flux, providing a potential target to counteract NAFLD.

Fagopyrum dibotrys extract improves nonalcoholic fatty liver disease via inhibition of lipogenesis and endoplasmic reticulum stress in high-fat diet-fed mice

ObjectiveThe prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing, presenting a treatment challenge due to limited options. Endoplasmic reticulum (ER) stress and associated lipid metabolism disorders are main causes of NAFLD, making it important to inhibit ER stress for effective treatment. Fagopyrum dibotrys has hypolipidemic, anti-inflammatory and hepatoprotective properties, showing promise in treating NAFLD. However, its effects on ER stress in NAFLD remain unclear. This study used a high-fat diet (HFD) to establish NAFLD mouse models and supplemented with Fagopyrum dibotrys extract (FDE) to evaluate its therapeutic effect and underlying mechanisms.ResultsWe showed that FDE supplementation reduced the severity of hepatic steatosis and lowered triglycerides (TG) and total cholesterol (TC) levels in NAFLD mice. At the molecular level, FDE supplementation reduced hepatic lipid deposition by downregulating lipogenic markers (SREBP-1c, SCD1) and upregulating fatty acid oxidase CPT1α expression. Additionally, FDE treatment inhibited the overexpression of ER stress markers (GRP78, CHOP, and P-EIF2α) in NAFLD mice livers, and blocked the activation of the PERK-EIF2α-CHOP pathway, demonstrating its role in maintaining ER homeostasis. Considering that activation of the PERK pathway could exacerbate lipid deposition, our findings suggest that FDE has a protective effect against hepatic steatosis in NAFLD mice by attenuating ER stress, and the potential mechanism is through inhibiting the PERK pathway.

Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes.

Increased plasma creatine concentrations are associated with the risk of type 2 diabetes, but whether this alteration is associated with or causal for impairments in metabolism remains unexplored. Because skeletal muscle is the main disposal site of both creatine and glucose, we investigated the role of intramuscular creatine metabolism in the pathophysiology of insulin resistance in type 2 diabetes. In men with type 2 diabetes, plasma creatine concentrations were increased, and intramuscular phosphocreatine content was reduced. These alterations were coupled to reduced expression of sarcomeric mitochondrial creatine kinase 2 (CKMT2). In C57BL/6 mice fed a high-fat diet, neither supplementation with creatine for 2 weeks nor treatment with the creatine analog β-GPA for 1 week induced changes in glucose tolerance, suggesting that increased circulating creatine was associated with insulin resistance rather than causing it. In C2C12 myotubes, silencing Ckmt2 using small interfering RNA reduced mitochondrial respiration, membrane potential, and glucose oxidation. Electroporation-mediated overexpression of Ckmt2 in skeletal muscle of high-fat diet-fed male mice increased mitochondrial respiration, independent of creatine availability. Given that overexpression of Ckmt2 improved mitochondrial function, we explored whether exercise regulates CKMT2 expression. Analysis of public data revealed that CKMT2 content was up-regulated by exercise training in both humans and mice. We reveal a previously underappreciated role of CKMT2 in mitochondrial homeostasis beyond its function for creatine phosphorylation, independent of insulin action. Collectively, our data provide functional evidence for how CKMT2 mediates mitochondrial dysfunction associated with type 2 diabetes.

Potential Anti-Obesity Effect of Hazel Leaf Extract in Mice and Network Pharmacology of Selected Polyphenols

Background: Obesity is gradually becoming a widespread health problem, and treatment using natural compounds has seen an increasing trend. As a by-product of hazelnut, hazel leaf is usually disposed of as waste, but it is widely used in traditional and folk medicines around the world. Aim of this study: Based on previous studies, the effects of the regulation of lipid metabolism and the mechanism of hazel leaf polyphenol extraction obesity were investigated. Methods: In this study, a high-fat diet-fed mouse model of obesity and 3T3-L1 preadipocytes were established. The ameliorative effects of the hazel leaf polyphenol extract on obesity and the regulating lipid metabolisms were explored based on network pharmacology, gut microbiota, and molecular docking. Results: Network pharmacology showed that hazel leaf polyphenols may play a role by targeting key targets, including PPARγ, and regulating the PPAR signaling pathway. They significantly improved body weight gain, the liver index, and adiposity and lipid levels; regulated the gut microbiota and short-chain fatty acid contents; down-regulated the expression of lipid synthesis proteins SREBP1c, PPARγ, and C/EBP-α; and up-regulated the expression of p-AMPK in obese mice. They inhibited the differentiation of 3T3-L1 cells, and the expression of related proteins is consistent with the results in vivo. The molecular docking results indicated that gallic acid, quercetin-3-O-beta-D-glucopyranoside, quercetin, myricetin, and luteolin-7-O-glucoside in the hazel leaf polyphenol extract had strong binding activities with PPARγ, C/EBP-α, and AMPK. Conclusions: The results demonstrate that the hazel leaf polyphenol extract can improve obesity by regulating lipid metabolism, which provides a valuable basis for developing health products made from hazel leaf polyphenols in the future.

Visceral adiposity in postmenopausal women is associated with a pro-inflammatory gut microbiome and immunogenic metabolic endotoxemia

BackgroundObesity, and in particular abdominal obesity, is associated with an increased risk of developing a variety of chronic diseases. Obesity, aging, and menopause are each associated with differential shifts in the gut microbiome. Obesity causes chronic low-grade inflammation due to increased lipopolysaccharide (LPS) levels which is termed “metabolic endotoxemia.” We examined the association of visceral adiposity tissue (VAT) area, circulating endotoxemia markers, and the gut bacterial microbiome in a cohort of aged postmenopausal women.MethodsFifty postmenopausal women (mean age 78.8 ± 5.3 years) who had existing adipose measurements via dual x-ray absorptiometry (DXA) were selected from the extremes of VAT: n = 25 with low VAT area (45.6 ± 12.5 cm2) and n = 25 with high VAT area (177.5 ± 31.3 cm2). Dietary intake used to estimate the Healthy Eating Index (HEI) score was assessed with a food frequency questionnaire. Plasma LPS, LPS-binding protein (LBP), anti-LPS antibodies, anti-flagellin antibodies, and anti-lipoteichoic acid (LTA) antibodies were measured by ELISA. Metagenomic sequencing was performed on fecal DNA. Female C57BL/6 mice consuming a high-fat or low-fat diet were treated with 0.4 mg/kg diet-derived fecal isolated LPS modeling metabolic endotoxemia, and metabolic outcomes were measured after 6 weeks.ResultsWomen in the high VAT group showed increased Proteobacteria abundance and a lower Firmicutes/Bacteroidetes ratio. Plasma LBP concentration was positively associated with VAT area. Plasma anti-LPS, anti-LTA, and anti-flagellin IgA antibodies were significantly correlated with adiposity measurements. Women with high VAT showed significantly elevated LPS-expressing bacteria compared to low VAT women. Gut bacterial species that showed significant associations with both adiposity and inflammation (anti-LPS IgA and LBP) were Proteobacteria (Escherichia coli, Shigella spp., and Klebsiella spp.) and Veillonella atypica. Healthy eating index (HEI) scores negatively correlated with % body fat and anti-LPS IgA antibodies levels. Preclinical murine model showed that high-fat diet-fed mice administered a low-fat diet fecal-derived LPS displayed reduced body weight, decreased % body fat, and improved glucose tolerance test parameters when compared with saline-injected or high-fat diet fecal-derived LPS-treated groups consuming a high-fat diet.ConclusionsIncreased VAT in postmenopausal women is associated with elevated gut Proteobacteria abundance and immunogenic metabolic endotoxemia markers. Low-fat diet-derived fecal-isolated LPS improved metabolic parameters in high-fat diet-fed mice giving mechanistic insights into potential pro-health signaling mediated by under-acylated LPS isoforms.7yVbQmTTfsF9b4Af3tznWNVideo

Interleukin-2 improves insulin sensitivity through hypothalamic sympathetic activation in obese mice

BackgroundIL-2 regulates T cell differentiation: low-dose IL-2 induces immunoregulatory Treg differentiation, while high-dose IL-2 acts as a potent activator of cytotoxic T cells and NK cells. Therefore, high-dose IL-2 has been studied for use in cancer immunotherapy. We aimed to utilize low-dose IL-2 to treat inflammatory diseases such as obesity and insulin resistance, which involve low-grade chronic inflammation.Main bodySystemic administration of low-dose IL-2 increased Treg cells and decreased inflammation in gonadal white adipose tissue (gWAT), leading to improved insulin sensitivity in high-fat diet-fed obese mice. Additionally, central administration of IL-2 significantly enhanced insulin sensitivity through the activation of the sympathetic nervous system. The sympathetic signaling induced by central IL-2 administration not only decreased interferon γ (IFNγ) + Th1 cells and the expression of pro-inflammatory cytokines, including Il-1β, Il-6, and Il-8, but also increased CD4 + CD25 + FoxP3 + Treg cells and Tgfβ expression in the gWAT of obese mice. These phenomena were accompanied by hypothalamic microgliosis and activation of pro-opiomelanocortin neurons. Furthermore, sympathetic denervation in gWAT reversed the enhanced insulin sensitivity and immune cell polarization induced by central IL-2 administration.ConclusionOverall, we demonstrated that IL-2 improves insulin sensitivity through two mechanisms: direct action on CD4 + T cells and via the neuro-immune axis triggered by hypothalamic microgliosis.

Insights into the modulatory effects of host-gut microbial xanthine co-metabolism on high-fat diet-fed mice.

Gut microbiota-mediated endobiotic and xenobiotic metabolism play crucial roles in disease progression, and drug therapy/toxicity. Our recent study suggested that gut microbiota-mediated xanthine metabolism is correlated with resistance to high-fat diet (HFD)-induced obesity. Here, we explored the role of host-gut microbial xanthine co-metabolism in the prevention and treatment of HFD-induced obesity by orally administration of Bifidobacterium longum, xanthine, and a xanthine oxidase inhibitor (topiroxostat). The findings indicate that xanthine exhibits a significantly protective effect against HFD-induced obesity. While B. longum, xanthine, and topiroxostat did not alleviate the dysbiosis of the weight and glucose metabolism of HFD-induced obesity (DIO) and obesity resistance (DIR) mice. 16S rRNA sequencing analyses revealed that treatments with B. longum significantly altered gut microbiota composition in HFD-fed and DIO mice. Microbial interaction network analysis revealed several Bacteroidetes species, such as Amulumruptor caecigallinarius and Muribaculum intestinale, as keystone taxa that were notably enriched by B. longum. Untargeted metabolomics analysis implied that xanthine might serve as a crucial molecule in regulating body weight, exerting a preventive effect on HFD-induced obesity. This study offers new perspectives on the influence of host-gut microbial xanthine co-metabolism on HFD-fed mice and emphasizes the promising role of xanthine in promoting weight loss.

Black Ginger Extract Suppresses Fat Accumulation by Regulating Lipid Metabolism in High-Fat Diet-Fed Mice.

This study investigated the antiobesity effects of black ginger extract (BGE) in high-fat diet (HFD)-induced obese mice. Mice were divided into six groups: normal diet control (NC, AIN-93G normal diet), 60% HFD control (HFD), HFD containing metformin at 250 mg/kg b.w. (Met, positive control), and HFD containing BGE at 5, 10, or 20 mg/kg b.w. for 15 weeks. BGE administration significantly prevented HFD-induced increases in weight gain, organ weight, and adipose tissue mass. Furthermore, it resulted in decreased adipogenesis and lipogenesis-related factors, including phosphorylated mitogen-activated protein kinase, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding proteins, sterol regulatory element-binding protein 1, phosphorylated cAMP response element-binding protein, glucose-6-phosphate dehydrogenase, fatty acid synthase, dephosphorylated ATP-citrate lyase, dephosphorylated acetyl-CoA carboxylase, and lipoprotein lipase, in white adipose tissues. Moreover, BGE administration enhanced lipolysis in white adipose tissue, as evidenced by elevated levels of adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, and protein kinase A, along with reduced levels of perilipin and phosphodiesterase 3B. BGE induced thermogenesis in brown adipose tissues, as reflected by the increased expression of AMP-activated protein kinase, uncoupling protein 1, and carnitine palmitoyltransferase 1 and decreased levels of fatty acid-binding protein 4. In conclusion, this study provides comprehensive evidence supporting the antiobesity effects of BGE, elucidating the underlying molecular mechanisms involved in preventing weight gain, suppressing adipogenesis, promoting lipolysis, and stimulating thermogenesis. These findings suggest the potential therapeutic utility of BGE in combating obesity and associated metabolic disorders (KHGASP-2023-034).

Growth hormone attenuates obesity and reshapes gut microbiota in high-fat diet-fed mice

Growth hormone (GH) and gut microbiota are key regulators of metabolism and have been linked to the development and treatment of obesity. Although variations in GH levels are associated with changes in gut microbiota composition, the specific effects of GH on gut microbiota and its role in obesity remain unclear. This study explored the effects of various GH doses (0.25, 0.75 and 1.5 IU/kg) on adipose tissue mass and gut microbiota in high-fat diet-induced obese mice. Notably, high-dose GH (1.5 IU/kg) significantly reduced the adipose tissue mass. This dose also reversed high-fat diet-induced gut microbiota dysbiosis, restoring microbial diversity and increasing the abundance of beneficial genera such as Ruminococcaceae and Muribaculaceae. Additionally, high-dose GH normalized several obesity-related gut microbiota pathways, including starch and sucrose metabolism, galactose metabolism, and secondary bile acid biosynthesis. GH therapy also improved intestinal barrier function, a key determinant of gut microbial homeostasis. These findings underscore the therapeutic potential of GH in obesity management through its effects on gut microbiota, providing new avenues for obesity interventions.

Nutritional Composition and Effect of Loquat Fruit (Eriobotrya japonica L. var. Navela) on Lipid Metabolism and Liver Steatosis in High-Fat High-Sucrose Diet-Fed Mice.

Loquat (Eriobotrya japonica L.) is a popular fruit known for its sweet and slightly tangy flavor, which is widely consumed both fresh and in various processed forms. This study aimed to analyze the biochemical composition of loquat juice and investigate its metabolic benefits in mice fed a high-fat/high-sucrose diet (HFSD). Mice were fed either a standard diet or an HFSD and received or not the loquat juice at 4 or 8 mL/kg body weight for 8 weeks. Body weight, food efficiency ratio, plasma lipoprotein profile, plasma glucose, and lipid indices were monitored throughout the experiment. At the end of the experiment, additional assessments were performed, including lipid content measurements in liver, adipose tissue, bile, and feces; hepatic antioxidant enzyme activities (superoxide dismutase and catalase); hepatic malondialdehyde content; plasma biomarkers of liver injury; liver histology; and organ relative weight. Feeding mice with the HFSD resulted in a significant perturbation in lipid and glucose metabolism, obesity, liver steatosis, and oxidative stress-related enzymes. However, the concomitant administration of loquat juice significantly corrected this imbalance. Fresh loquat juice is low in fat and protein, moderately sugary, and energetically light; however, it is rich in minerals, vitamin C, and various phytochemicals compounds, such as phenolic acids, flavonoids, and carotenoids. The loquat juice could be considered a functional food and could be valorized through the extraction of active substances and their use as food supplements to prevent lipid metabolism disorders and the resulting health complications.

Transcriptomic Landscape Analysis Reveals a Persistent DNA Damage Response in Metabolic Dysfunction-associated Steatohepatitis Post-dietary Intervention.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced form, metabolic dysfunction-associated steatohepatitis, have emerged as the most prevalent liver diseases worldwide. Currently, lifestyle modification is the foremost guideline-recommended management strategy for MASLD. However, it remains unclear which detrimental signals persist in MASLD even after disease remission. Thus, we aimed to examine the persistent changes in liver transcriptomic profiles following this reversal. Male C57BL/6J mice were divided into three groups: Western diet (WD) feeding, chow diet (CD) feeding, or diet reversal from WD to CD. After 16 weeks of feeding, RNA sequencing was performed on the mice's livers to identify persistent alterations characteristic of MASLD. Additionally, RNA sequencing databases containing high-fat diet-fed P53-knockout mice and human MASLD samples were utilized. WD-induced MASLD triggered persistent activation of the DNA damage response (DDR) and its primary transcription factor, P53, long after the resolution of the hepatic phenotype through dietary reversal. Elevated levels of P53 might promote apoptosis, thereby exacerbating metabolic dysfunction-associated steatohepatitis, as they strongly correlated with hepatocyte ballooning, an indicator of apoptosis activation. Moreover, P53 knockout in mice led to downregulated expression of apoptosis signaling in the liver. Mechanistically, P53 may regulate apoptosis by transcriptionally activating the expression of apoptosis-enhancing nuclease (AEN). Consistently, P53, AEN, and the apoptosis process all exhibited persistently elevated expression and showed a strong inter-correlation in the liver following dietary reversal. The liver demonstrated upregulation of DDR signaling and the P53-AEN-apoptosis axis both during and after exposure to WD. Our findings provide new insights into the mechanisms of MASLD relapse, highlighting DDR signaling as a promising target to prevent MASLD recurrence.

Oct-B: A derivative of L-BAIBA significantly alleviating high-fat diet-induced obesity in mice

The rising prevalence of obesity is a global health concern. Supplementation with (S)-β-aminoisobutyric acid (L-BAIBA) has shown potential in preventing obesity and related metabolic disorders induced by high-fat diets. However, developing effective and low-toxicity BAIBA derivatives remains a challenging yet promising field. In this study, we introduce Oct-B, a novel BAIBA ester compound, which exhibits 80-fold greater efficacy than L-BAIBA in alleviating obesity in high-fat diet-fed mice. Our results demonstrate that Oct-B significantly reduces serum TG, TC, LDL-C, and the activities of ALT and AST, and also reduces TG and TC in liver, surpassing the effects of L-BAIBA. Histological analysis shows that Oct-B significantly decreases lipid accumulation in liver tissues, normalizes mast cells in white adipose tissue, and upregulates the expression of UCP1 protein in white adipose tissue. The qRT-PCR results indicated Oct-B alleviates obesity by downregulating lipogenic genes (PPARγ, ACC1, FAS), upregulating lipolysis related genes (PPARα, HSL) and thermogenic gene UCP1. Additionally, quantitative mass spectrometry reveals a marked increase in L-BAIBA levels in white fat, brown fat, serum, and muscle following Oct-B administration. These findings suggest that Oct-B is an efficient L-BAIBA substitute, offering a promising therapeutic approach for preventing and treating high-fat diet-induced obesity.

Accelerated BDNF expression in visceral white adipose tissues following high-fat diet feeding in mice.

Brain-derived neurotrophic factor (BDNF) is expressed in the white adipose tissues (WATs), and the expression increases during high-fat diet (HFD) feeding, implicating its role in obesity. Here, we focused on BDNF expression in epididymal WAT (eWAT), a visceral adipose tissue, in mice. During 2 weeks of HFD feeding, Bdnf mRNA expression in eWAT slightly increased, but a robust increase was observed after 8 weeks of HFD feeding. This upregulation of Bdnf mRNA was correlated with significant induction of hypoxia-inducible factor 1α (Hif1α) and platelet-derived growth factor subunit B (Pdgfb) mRNA in eWAT following 8 weeks of HFD feeding. Furthermore, the increased expression of the M1 macrophage markers was strongly correlated with the elevation of Bdnf mRNA in the eWAT. Notably, 8 weeks of HFD feeding significantly elevated Tnfα mRNA expression in eWAT, while no such induction was observed in inguinal WAT (iWAT). In contrast, the expression of Adipoq (adiponectin), implicated in improved insulin sensitivity and anti-inflammatory effects, was significantly upregulated in iWAT, but not in eWAT. Thus, our study may show the role of BDNF in eWAT in obesity models, potentially contributing to the pathological state of visceral adipose tissues.

Oleanolic acid attenuates obesity through modulating the lipid metabolism in high-fat diet-fed mice.

As a natural pentacyclic triterpenoid, oleanolic acid has hepatoprotective, anti-inflammatory, and antioxidant activities. This work performed the invitro experiments and animal assay to explore whether oleanolic acid alleviates lipid accumulation induced by high-fat diet by mediating PPARγ. Oil red O staining showed that oleanolic acid can reduce lipid accumulation in HepG2 cells, which were treated with oleic acid and palmitic acid. Immunofluorescence, western blot analysis, and RT-qPCR showed that oleanolic acid could promote nuclear translocation of PPARγ and reduce the expression level of PPARγ, C/EBP-β, and SREBP-1c. The results of invivo experiments indicated that dietary intervention with oleanolic acid can effectively improve the fat accumulation in liver tissue and attenuate the level of IL-6 and TNF-α in serum caused by high-fat diet. Meanwhile, oleanolic acid did not cause lesions in vital organs at the experimental concentrations. In addition, the computer simulation indicated that oleanolic acid could directly bind to PPARγ with a reasonable and stable docking conformation. The above research results can provide new evidence for oleanolic acid to prevent nonalcoholic fatty liver disease.