Search Results (1,487)

Primula nutans Georgi, a medicinal herb used in Mongolian and Tibetan medicine for treating respiratory ailments, is a natural agent with antiobesity potential. We investigated the antiobesity and insulin-sensitizing effects of P. nutans Georgi extract (PGE) using in vitro and in vivo models. In 3T3-L1 preadipocytes, PGE inhibited adipocyte differentiation and lipid accumulation without cytotoxicity, accompanied by the reduced expression of adipogenic transcription factors (PPARG, C/EBPA, and adiponectin) and lipogenic genes (FASN, SCD1, and ACC), particularly during the early stages of adipogenesis. Similar effects were observed in primary stromal vascular cells derived from mouse inguinal white adipose tissue. PGE upregulated C/EBP homologous protein and C/EBPB and was associated with altered cell cycle progression, increased G2/M phase distribution, and the potential disruption of mitotic clonal expansion during early adipogenesis. In HFD-induced obese mice, intraperitoneal administration of PGE (10 or 30 mg/kg) significantly reduced body weight gain, white adipose tissue mass, and hepatic steatosis, independent of food intake. PGE downregulated lipogenic and proinflammatory gene expression in adipose and hepatic tissues and increased AMPK phosphorylation in white adipose tissue. PGE improved glucose tolerance and was associated with enhanced insulin sensitivity, as evidenced by reduced areas under the curve in the glucose tolerance and insulin tolerance tests and increased circulating adiponectin levels. Feature-based molecular networking identified 61 compounds from PGE. Network pharmacology analysis revealed several antiobesity targets, including PPARG and AKT1. Molecular docking analyses suggested favorable binding affinities between major compounds and metabolic regulators. Collectively, these findings suggest that PGE may suppress adipogenesis and improve metabolic parameters in obese mice, supporting its potential as a natural candidate for obesity and related metabolic disorders. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a globally prevalent hepatic disorder, characterized by hepatic lipid accumulation and extrahepatic complications, notably intestinal barrier injury, which further exacerbates MASLD progression. The “gut–liver axis” has been identified as a critical contributor to MASLD development, with insulin-like growth factor 1 (IGF-1) serving as a pivotal coupling factor of this axis. However, the specific role and molecular mechanism by which IGF-1 modulates intestinal barrier function in the context of MASLD remains unclear. Methods: This study analyzed the correlations between the GH/IGF-1 axis and intestinal barrier function in MASLD rats, and explored the effects of IGF-1 intervention both in vivo and in vitro. Results: Our results showed that MASLD rats exhibited intestinal barrier impairment, characterized by elevated serum Diamine oxidase (DAO) and D-Lactate (D-LAC) levels, villus damage, and downregulation of tight junction proteins and Mucin (MUC2). These changes were accompanied by suppression of the GH/IGF-1 axis. Correlation analysis uncovered a negative association between IGF-1 levels and markers of barrier dysfunction. IGF-1 intervention effectively repaired the intestinal barrier structure of MASLD rats and significantly upregulated the expressions of IGF-1R, PI3K, and AKT. In vitro, IGF-1 treatment improved transepithelial electrical resistance (TEER), enhanced barrier-related gene expression, promoted cell proliferation, and inhibited apoptosis. Conclusions: These findings suggested that GH/IGF-1 axis suppression, intestinal barrier dysfunction, and IGF-1R/PI3K/AKT signaling were interconnected within the gut–liver axis in MASLD. IGF-1 may contribute to barrier regulation through associated signaling changes, highlighting the GH/IGF-1 axis as a potential complementary target. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, which has recently been found to be closely associated with neuroinflammation. As an anti-inflammatory drug, triptolide (TP), a natural diterpenoid from Tripterygium wilfordii, was selected in the current study for treating PS19 (tau^P301S transgenic) mice, tauopathy AD mice. In addition, we have previously found that TP had the ability to reduce the level of cholesterol. However, the roles and mechanisms of TP in the above processes are not clear. To this end, we found that elevated cholesterol in serum and brain tissues upregulated the expression of apolipoprotein E (APOE) and sialic acid-binding Ig-like lectin 3 (CD33), leading to the activation of SH2-containing protein tyrosine phosphatase 1 (SHP-1). The activation of SHP-1 inhibits the signaling pathways of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6), which results in inhibition of the M2 polarization of microglia, which exacerbates neuroinflammation and cognitive decline in high-cholesterol diet (HCD)-fed mice. Conversely, TP treatment significantly inhibited the hepatic sterol regulatory element-binding protein 2 (SREBP2)/3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) pathway, which reduced the cholesterol levels in the serum and brain. By depressing the levels of cholesterol, the axis of CD33 and SHP-1 was suppressed, which resulted in restoration of the activity of JAK1 and STAT6 pathways, leading to the transition of microglia from the M1 to the M2 phenotype. Of note, these observations demonstrate that TP alleviates the cognitive impairment of PS19 mice via depressing neuroinflammation. Altogether, our results revealed the mechanisms of TP in treating AD via CD33/SHP-1/JAK1/STAT6 pathways in a cholesterol-dependent manner. Full article

Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV’s effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain (p < 0.05), increased abdominal fat content (p < 0.05), and hepatomegaly (p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly (p < 0.05), improving the growth performance of broilers; Effects of RSV on liver function and lipid metabolism of CORT-treated AA broilers: After CORT injection, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) activity and total bile acid (TBA) content significantly increased (p < 0.05). Hepatic total cholesterol (TC) and triglycerides (TG) increased after CORT injection (p < 0.05), causing severe liver damage. RSV supplementation could reverse the increases in serum ALP, ALT, and AST activity (p < 0.05) and reduce TBA content in stressed broilers (p < 0.05). TC and TG levels in the liver decreased under the alleviation of RSV (p < 0.05), and serum TG levels declined (p < 0.05). Microscopic and ultrastructural observations showed that after CORT injection, hepatic tissue cells were swollen, scattered fat vacuoles were present, pores were enlarged, and intracellular lipid droplets appeared. The RSV group significantly alleviated hepatocyte damage, reduced vacuolation, showed uniform chromatin, and decreased lipid droplets. RSV significantly mitigated the CORT-induced increase in SREBP-1 mRNA and protein expression and the decrease in PPARα protein expression; CORT caused a decline in the antioxidant function of AA broiler livers, with significant decreases in SOD and GSH-PX (p < 0.05), and the expression of Nrf2 and its downstream genes also showed a decreasing trend. Compared to the CORT group, the RSV group exhibited significant increases in liver CAT, SOD, and GSH-PX (p < 0.05), and Nrf2 protein expression was elevated (p < 0.05). In summary, resveratrol can alleviate the decline in growth performance, liver steatosis, and hepatic oxidative stress in AA broilers induced by CORT, downregulate lipogenic genes such as SREBP-1c, regulate liver lipid metabolism, and mitigate CORT-induced hepatic oxidative stress in broilers by upregulating the Nrf2 pathway. Full article

Background/Objectives: Exploiting the metabolic properties of postbiotics is a novel strategy for managing metabolic disorders, including diabetes. Inactivated microorganisms, a major class of postbiotics, improve glycemic control in preclinical and clinical studies. Here, we examined whether heat-killed (HK) Mycobacterium aurum (M. aurum) exerts prophylactic or therapeutic anti-hyperglycemic effects in diabetic mice. Methods: Diabetes was induced in male BALB/c mice by streptozotocin (STZ; 150 mg/kg) injection. HK M. aurum (1 mg) was given orally (three prophylactic doses before STZ) or intradermally (six weekly therapeutic doses after STZ). We assessed glycemic parameters, serum C-peptide/insulin (ELISA), and tissue protein expression (Western blot). Results: Neither route altered body weight or glucose homeostasis in non-diabetic mice. In STZ-diabetic mice, oral prophylactic treatment significantly attenuated hyperglycemia (39–60% reduction weeks 5–8 post-STZ) and showed a trend toward improved serum C-peptide, but did not affect dysregulated expression of skeletal muscle (SM), hepatic, pancreatic and renal proteins involved in glucose transport (GLUT2, GLUT4, and SGLT2), glycolysis (α-LDH), mitochondrial uncoupling (UCP2 and UCP3), and antioxidant defense (CAT). Therapeutic intradermal administration significantly decreased blood glucose (~30% at week 5, ~40% at week 6) and modestly enhanced insulin secretion. Hepatic UCP2 and α-LDH and SM UCP3 protein levels were normalized toward non-diabetic levels, whereas hepatic GLUT2 and SM GLUT4 remained largely unchanged. These correlative findings suggest effects independent of insulin-dependent glucose transport, but do not demonstrate direct functional improvement in mitochondrial or redox status. Conclusions: HK M. aurum exerts partial anti-hyperglycemic effects in STZ-induced diabetic mice, but the associated protein changes require functional validation before its role as a postbiotic in β-cell dysfunction can be established. Full article

Non-coding RNAs are pivotal regulators of metabolic disease pathogenesis, yet the role of microRNA-27a (miR-27a) in obesity-associated hepatic steatosis remains incompletely characterized. This study examined the functional contribution and molecular mechanism of miR-27a in regulating hepatocyte mitochondrial homeostasis and lipid metabolism. Utilizing in vivo mouse models, including low-fat diet controls, high-fat diet (HFD)-induced obesity, and gain- and loss-of-function approaches, miR-27a was found to be markedly upregulated in the serum and liver of obese mice, correlating with disrupted glucose and lipid homeostasis as well as hepatic steatosis. Mechanistically, miR-27a overexpression recapitulated HFD-induced mitochondrial dysfunction, manifested by decreased mitochondrial biogenesis and elevated reactive oxygen species (ROS) production. Conversely, genetic silencing of miR-27a restored mitochondrial integrity and mitigated lipid accumulation. In vitro experiments using HepG2 cells confirmed that miR-27a directly suppresses nuclear factor erythroid 2-related factor 2 (NFE2L2), and NFE2L2 overexpression counteracted miR-27a-induced mitochondrial damage and steatosis. Collectively, these results demonstrate that miR-27a promotes hepatic steatosis by targeting NFE2L2, leading to mitochondrial impairment and oxidative stress, highlighting miR-27a as a potential biomarker and therapeutic target for obesity-associated liver metabolic disorders. Full article

The occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related to intestinal flora imbalance, intestinal barrier damage, and gut-liver axis dysfunction. Due to their multi-target regulatory effects and advantages in intestinal microecological intervention, Chinese herbal monomers have shown promising application prospects in the prevention and treatment of MASLD. However, basic research on their toxicity still lags behind, and issues related to safety and clinical translation urgently need attention. This article systematically reviews the research progress on how flavonoids, triterpenoids, alkaloids, and polysaccharides improve hepatic steatosis, inflammatory responses, and metabolic disorders from a toxicological perspective by reshaping the intestinal microbiota, repairing the intestinal mucosal barrier, regulating short-chain fatty acid and bile acid metabolism, and synergistically acting on signaling pathways such as TLR4/NF-kB, FXR, TGR5, SIRT1, and the NLRP3 inflammasome. Furthermore, by combining methods such as 16S rRNA sequencing, metagenomics, metabolomics, and multi-omics integration, the article analyzes their application value and limitations in toxicological mechanism research, and discusses the translational bottlenecks faced by Chinese herbal monomers in pharmacokinetics, bioavailability, quality standardization, targeted delivery, and toxicological safety. Existing evidence indicates that Chinese herbal monomers have a three-in-one intervention advantage of microecological remodeling-metabolic regulation-inflammation inhibition, but their long-term medication safety, toxic target organs, dose-effect/toxicity relationships, and potential drug interactions still need further clarification. This article aims to provide a systematic reference for the safety evaluation and clinical translational research of Chinese herbal monomers in the prevention and treatment of MASLD. Full article

Background/Objectives: Obesity represents a significant global health challenge. Although alternate-day fasting (ADF) has been shown to effectively improve metabolic parameters, long-term adherence to this regimen remains limited. This study aimed to investigate whether highly polymerized persimmon tannin (DP31) could serve as a practical alternative to ADF for the prevention of high-fat diet (HFD)-induced obesity in mice. Methods: Male C57BL/6J mice (n = 10 per group) were subjected to an HFD for 11 weeks, during which they concurrently received either DP31 or ADF. Body weight, fat mass, serum lipid levels, glucose tolerance, fasting glucose, and insulin levels were assessed. Additionally, hepatic transcriptomics, Western blotting, 16S rRNA sequencing, and short-chain fatty acids (SCFAs) analysis were conducted. Results: DP31 demonstrated comparable efficacy to ADF in reducing body weight gain and improving lipid profiles, while exhibiting superior effects on glucose tolerance and fasting glucose levels (p < 0.05). Both interventions effectively reversed HFD-induced hepatic gene dysregulation, leading to the upregulation of genes involved in processes related to steroid metabolism. In addition, both treatments activated the hepatic AMPK-mTORC1-Lpin1 axis, suppressed lipogenesis, upregulated PGC1α, and increased β-hydroxybutyrate levels, indicating enhanced fatty acid oxidation (p < 0.05). Notably, DP31 outperformed ADF in enriching beneficial gut genera, such as Akkermansia, and boosting SCFAs production, which may elucidate its superior glycemic control. Overall, DP31 exhibits comparable effects to ADF in preventing obesity-related metabolic disorders, while demonstrating superior effects on glucose homeostasis. Full article

Obesity development is linked to disturbances in the gut microbiota. Inonotus obliquus polysaccharides (IOPs) have potential therapeutic efficacy in alleviating metabolic disorders. However, the mechanism by which IOP prevents obesity via regulating gut microbiota remains elusive. IOP was extracted and structurally characterized by FT-IR and NMR spectroscopy, confirming typical polysaccharide structures. Structurally, IOP is a 5.4 kDa polysaccharide predominantly composed of glucose, galactose, xylose, mannose, galacturonic acid, glucuronic acid, as well as rhamnose, arabinose, and methyl-galactose. Administration of IOP to high-fat diet (HFD)-fed mice effectively curtailed weight gain and improved serum lipid parameters. Furthermore, it mitigated lipid deposition within hepatic and adipose tissues, while successfully countering HFD-triggered liver damage. Notably, IOP induced significant changes in microbial diversity and composition by selectively increasing the abundance of Streptococcaceae while suppressing Faecalibaculum rodentium at the family and species levels. These findings highlight that IOP is a promising functional food ingredient that regulates gut microbiota for obesity prevention. Full article

Obesity contributes to an increase in the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and is diagnosed when hepatic steatosis is accompanied by at least one of the following factors: obesity or overweight, diabetes mellitus, or signs of metabolic abnormalities. MAFLD is a term that encompasses a wide range of liver disorders, ranging from simple steatosis to metabolic steatohepatitis, which can progress to cirrhosis and eventually, hepatocellular carcinoma (HCC). Lipotoxicity generated by a high-fat diet causes liver inflammation, therefore, blocking inflammatory pathways is considered a promising strategy to prevent MAFLD progression. Inflammatory responses and oxidative stress are linked to endoplasmic reticulum stress, thereby activating the unfolded protein response (UPR) pathway. Although drugs such as resmetirom and semaglutide have recently been approved for the treatment of MAFLD, there is still a need to identify complementary therapies with different mechanisms of action. In this context, the present study evaluated the hepatoprotective effect of ellagic acid through the modulation of mRNAs of proteins in the UPR-Perk pathway in a murine model fed a high-calorie diet. This study revealed that the high-calorie diet activated the UPR pathway in response to stress, increasing the expression of the Grp78, Eif2ak3, Eif2α, Ddit3, Atf4, and Nfe2l2 genes in the liver and epididymal adipose tissue. Ellagic acid modulated the pathway genes and reduced levels of glucose, total cholesterol, HDL and VLDL, triglycerides, insulin, and glycated hemoglobin, and could therefore be considered a hepatoprotective agent. Full article

Background/Objectives: Lipidomics has become a key component of systems biology, enabling comprehensive characterisation of lipid species and their roles in health and disease. As regulators of membrane architecture, energy balance, inflammation, and cellular signalling, lipids offer a powerful framework for understanding metabolic dysfunction. In veterinary medicine, however, lipidomics remains comparatively underdeveloped. In cats, lipid metabolism is central to disorders such as hepatic lipidosis, cystitis, obesity, diabetes mellitus, and chronic inflammatory enteropathies, yet available data remain limited. This systematic review synthesised current evidence on lipidomics and lipid-focused profiling in feline disease and identified lipid alterations with potential clinical relevance. Methods: Following PRISMA 2020 guidelines, PubMed, ScienceDirect, and Scopus were searched for original studies (1994–2026) evaluating lipidomics or lipid-focused profiling in cats. Eligible studies assessed lipid species, fatty acids, lipid mediators, or lipoproteins in disease or physiological states. Owing to methodological heterogeneity, findings were synthesised narratively. Results: Seventeen studies met inclusion criteria, covering hepatic, urinary, gastrointestinal, renal, neurological, oncological, metabolic, and pharmacologically modulated conditions. Recurring alterations involved lipoproteins, triglycerides, phospholipids, sphingolipids, fatty acids, and oxylipins. More consistent patterns emerged in hepatic lipidosis, where lipoprotein disturbances may aid diagnosis; in lower urinary tract disease, where PUFA-derived oxylipins differentiated bacterial from idiopathic cystitis; and in obesity, where phospholipid and triglyceride shifts reflected metabolic risk. Fatty acid remodelling in chronic enteropathies aligned with mucosal inflammation, while sphingolipid changes in neurological disease correlated with severity. Heterogeneity in analytical platforms, dietary control, and study design limited comparability. Conclusions: Feline lipidomics reveals biologically meaningful alterations with emerging diagnostic and prognostic value. Although still developing, lipid-focused approaches may enhance disease characterisation and support translational research. Larger, standardised studies and robust reference datasets are needed to validate lipid signatures for clinical implementation. Full article

Background and Objectives: Hepatic encephalopathy (HE) management becomes particularly challenging in older patients. This study aimed to evaluate the physician-reported diagnostic approaches, therapeutic strategies, and specific challenges in managing HE in older cirrhotic patients across Italy. Methods: A nationwide survey was conducted under the aegis of the Italian Association for the Study of the Liver (AISF). Forty-three hepatology centres participated. Data were analyzed using descriptive statistics. Results: Participating centers followed over 6000 older patients with cirrhosis, nearly one-third of whom experienced overt HE and/or minimal HE episodes in the previous year. Physicians reported that infections were the most frequently reported precipitating factor, followed by constipation and electrolyte disturbances for OHE. Half of patients with HE (50%; IQR 30.0–50.0%) experienced recurrent episodes, while 22% (IQR 10.0–30.0%) were reported to have persistent HE. In this setting, the diagnosis of HE was often complicated by cognitive decline. Treatment primarily consisted of a combination of lactulose and rifaximin, but adherence was often limited. Caregiver support emerged as a critical element in patient management. The management of comorbidities such as diabetes and chronic kidney disease was a major challenge, and nutritional screening was not routinely implemented across centres. Conclusions: This study highlights the need for better multidisciplinary management, improved caregiver support, and more consistent approaches to the diagnosis and treatment of HE in the elderly. The survey also explored how centres approach the differential diagnosis between HE and age-related cognitive disorders, the practical role of caregivers in outpatient management, and the impact of comorbidities, polypharmacy, and nutritional issues on everyday care. Marked heterogeneity emerged in psychometric assessment, multidisciplinary collaboration, and nutritional screening, indicating that several relevant aspects of care remain insufficiently standardized. Overall, the findings suggest that older patients with HE should be regarded as a distinct high-risk subgroup requiring tailored diagnostic pathways and integrated management models. Full article

Background/Objectives: Liver diseases cause more than 2 million annual deaths globally, accounting for 4% of the total global mortality rate. Hepatic fibrosis (HF) acts as an indispensable pathological mediator in the progressive deterioration of chronic liver diseases. Thus, the identification of effective anti-fibrotic targets and rational development of corresponding therapeutic agents are expected to deliver profound clinical value for patients suffering from chronic liver disorders. Methods: An in vivo HF model was established to detect Kupffer cell (KC) polarization and periostin (POSTN) protein expression. In vitro, the CCK-8 (Cell Counting Kit-8) assay was applied to evaluate the regulatory effects of Postn-knockdown macrophages on LX-2 cell activity. Conditional knockout mice with Postn were constructed in vivo, and liver tissue samples were used for single-cell sequencing. Functional enrichment and cell differentiation prediction analyses were performed. CellChat was further utilized to characterize alterations in intercellular communication between Postn-deficient KCs and adjacent liver cells. Finally, POSTN-targeted inhibitors were screened and validated via virtual drug screening and experiments. Results: In the HF model, the M2 polarization of KCs was associated with the upregulated expression of POSTN. In contrast, in vitro Postn knockdown correlated with significantly suppressed LX-2 cell activation. Single-cell profiling suggests that Postn deficiency in Kupffer cells is linked to remodeling of the hepatic microenvironment. In drug repurposing, Rhodiosin exhibited binding affinity to POSTN and was observed to inhibit macrophage M2 polarization. Conclusions: POSTN may contribute to KC M2 polarization and be associated with remodeling of the intercellular interaction network among liver cells. Rhodiosin, as a POSTN-binding compound, shows potential for anti-hepatic fibrotic effects. Full article

Heat stress (HS) has emerged as a major environmental stressor, inducing oxidative stress and hepatic steatosis and impairing production performance and health in laying hens, with limited evidence-based nutritional interventions available. This study investigated the hepatoprotective effects of dietary silibinin (SIL) against chronic HS. In a 10-week trial, 252 43-week-old Hy-Line Brown hens were exposed to daily HS (32 ± 1 °C, temperature–humidity index [THI] > 73) and fed either a basal diet or one supplemented with 100 mg/kg SIL. SIL significantly increased laying rate (p < 0.05) and improved albumen height, Haugh units, and shell strength by week 8 (p < 0.05). Histological analysis showed a 48% reduction in non-alcoholic fatty liver disease (NAFLD) activity score, with significantly decreased hepatic triglyceride content (p < 0.05); Oil Red O staining confirmed reduced lipid droplet accumulation. SIL restored redox balance by increasing plasma, hepatic total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px) (p < 0.05), increasing hepatic catalase (CAT) and glutathione (GSH) levels while decreasing malondialdehyde (MDA) (p < 0.05). Untargeted plasma metabolomics identified 11 key metabolites related to 2-oxoglutarate and purine metabolism, while hepatic transcriptomics revealed 835 differentially expressed genes primarily in the PPAR signaling and fatty acid biosynthesis pathways. SIL suppressed de novo lipogenesis via downregulation of ACACA and FASN, and enhanced β-oxidation through upregulation of CPT1A and ACSL1 (p < 0.05). Molecular docking indicated favorable binding affinities between SIL and these targets, which was further supported by corresponding changes in protein expression via Western blotting. Correlation analysis revealed a consistent alignment between the upregulation of ACSL1/CPT1A and improvement in performance and antioxidant status, suggesting a coordinated metabolic shift. These findings emphasize the potential of SIL as a sustainable animal nutrition antioxidant additive, which can alleviate HS-induced lipid disorders in the liver of laying hens. Importantly, these hepatoprotective effects were demonstrated exclusively under chronic heat stress conditions; further studies incorporating a normothermic baseline are required to distinguish stress-specific mitigation from general metabolic stimulation. Full article

Pancreatic steatosis is closely associated with metabolic disorders, pancreatitis, and pancreatic cancer, yet the underlying mechanisms remain incompletely understood and ideal animal models are lacking. We established and compared four mouse models based on distinct pathogenic mechanisms. In the high-fat diet (HFD)-fed model, pancreatic steatosis occurred later than hepatic steatosis. In ob/ob mice, despite severe obesity and hepatic steatosis, no significant intrapancreatic fat deposition was observed. In the caerulein combined with HFD model, caerulein markedly accelerated HFD-induced intrapancreatic fat accumulation, indicating a synergistic effect of inflammation and metabolic stress. Orthotopic injection of adipogenically differentiated 3T3-L1 cells established a focal model without altering systemic metabolism, enabling investigation of localized fat deposition. Collectively, these four models recapitulate metabolic, genetic, inflammatory, and localized mechanisms, exhibit divergent histological features, and provide a complementary platform for mechanistic studies and drug screening in pancreatic steatosis. Full article