Search Results (2,581)

Background: Obesity and mental disorders are associated with gut microbiota dysbiosis and gut–brain axis dysfunction. This secondary analysis evaluated the effects of a 12-week weight loss program (WLP) based on a hypocaloric traditional Mexican diet (TMD) and moderate-intensity exercise on gut microbiota, body composition (BC), and metabolic parameters in Mexican adults with obesity with and without depression and anxiety symptoms. Methods: A total of 106 adults with obesity were classified based on the presence or absence of depressive and anxiety symptoms into an obesity control group without symptoms (OCG), improved symptoms (OIS), and persistent symptoms (OPS). Stool samples were analyzed by sequencing the V3–V4 region of the 16S rRNA gene. Longitudinal changes in serum biochemistry, BC, intestinal permeability markers, and gut microbiota were analyzed using linear mixed-effects models. Differential taxa were identified using linear discriminant analysis effect size (LEfSe), and associations between bacterial genera, biochemical variables, and dietary components were explored using MaAsLin 2. Results: The WLP significantly improved metabolic, inflammatory, intestinal permeability, and BC markers, as well as depressive and anxiety symptoms, although participants remained in WHO grade I obesity. These improvements were accompanied by selective, group-dependent modulation of bacterial genera rather than broad microbiota restructuring. LEfSe identified 22 taxonomic biomarkers: 16 in OPS, 5 in OIS, and 1 in OCG. Conclusions: The culturally adapted WLP, which combined a hypocaloric TMD with exercise, promoted improvements in metabolism and BC in all participants, along with group-specific gut microbiota remodeling that may be associated with differential changes in depressive and anxiety symptoms in the context of persistent obesity. Full article

Background: Pharmacological blockade of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has emerged as an attractive pharmacological strategy for a broad range of inflammatory and metabolic disorders. However, translating preclinical efficacy into clinical success remains a major bottleneck. We previously reported the discovery of a novel, potent NLRP3 inhibitor, KBD3536, but its in vivo efficacy across different pathological conditions remains uncharacterized. Here, we systematically evaluated the in vivo efficacy of KBD3536 across diverse preclinical models of NLRP3-related pathologies. Methods: KBD3536 was evaluated in established rodent models of monosodium urate (MSU)-induced acute inflammation (mouse air pouch and rat gouty arthritis models), radiation-induced dermatitis (RID), and high-fat diet (HFD)-induced obesity. Results: In the MSU models, KBD3536 markedly suppressed local interleukin-1β and interleukin-6 secretion in air pouch exudates and dose-dependently alleviated acute arthritis symptoms, including joint swelling and joint pain. In the RID model, KBD3536 significantly attenuated radiation-induced skin injury and ameliorated radiation-induced systemic weight loss. Under HFD challenge, early intervention with KBD3536 mitigated HFD-induced adiposity, early hepatic steatosis and its associated inflammatory responses, and preserved physical performance. Mechanistically, KBD3536 partially restored AMP-activated protein kinase α1 (AMPKα1) mRNA expression in adipose tissue and restored hepatic Cyp3a11 transcriptional activity. Conclusions: NLRP3 inhibitor KBD3536 exhibited broad-spectrum anti-inflammatory efficacy across multiple preclinical models, supporting its potential as a promising candidate for diverse NLRP3-related disorders. Full article

Background/Objectives: The rates of obesity and binge-eating disorder (BED) have increased markedly over the last few decades. The onset of these conditions has been associated in part with the disruption of neural pathways that regulate food reward. Existing literature has implicated the endogenous opioid system as an important mediator of pleasure and reinforcing behaviors associated with food intake. While the relationship between opioids and food intake has been studied extensively, how dysregulated opioid signaling contributes to compulsive eating still remains unclear. Therefore, the aim of this review is to analyze the role of opioid peptides and receptors, and their interactions with dopamine in hedonic feeding. Methods: We conducted a narrative review of preclinical and clinical trials, incorporating studies that were relevant to opioid-mediated feeding and food reward. Results: β-endorphins appear to modulate the hedonic value of food, but their effects appear to be context-dependent. Enkephalins may influence motivational drive toward food, while nociceptin signaling has been linked to the preferential consumption of palatable foods under binge-like conditions. Consistent with these findings, NOP antagonism has been reported to reduce binge-like intake of a high-fat diet (HFD) without affecting homeostatic eating patterns. Lastly, chronic mu-opioid receptor (MOP) activation by palatable foods may induce neuroadaptive changes, including receptor desensitization, dopamine D2 receptor downregulation, and reward hypofunctionality, which overlap with mechanisms associated with substance use disorders. Conclusions: Altered MOP signaling may disrupt the hedonic and behavioral mechanisms that regulate feeding behavior. Pharmacological therapies targeting opioid and opioid-dopamine interactions may show promise for treating obesity and BED. However, additional research is still needed to clarify peptide-specific mechanisms, sex differences, and long-term neurobiological consequences associated with hedonic and compulsive eating. Full article

Cardiac tamponade in pregnancy is an exceptional maternal–fetal emergency in which physiological tachycardia, hypervolaemia and dependent oedema mask the classical signs of tamponade. Corynebacterium amycolatum is a non-diphtherial, Gram-positive coryneform commensal of human skin and mucosa that is increasingly recognised as a true invasive pathogen, although pericardial infection has rarely, if ever, been reported. We aimed to describe the diagnostic and decompression strategy in such a case. We report a 29-year-old woman at 30 + 4 weeks of gestation with class III obesity (pre-pregnancy body mass index 36 kg/m²), pregnancy-induced hypertension and diet-controlled type 2 diabetes referred after a routine echocardiogram suggested tamponade despite preserved haemodynamic compensation. Transthoracic echocardiography demonstrated a large circumferential pericardial effusion with diastolic right-atrial and right-ventricular collapse, a plethoric inferior vena cava and respiratory mitral-inflow variation. Severe maternal obesity superimposed on advanced gestation degraded the acoustic windows, elevated the diaphragm, displaced the heart anteriorly and brought the gravid uterus into the subxiphoid corridor, rendering percutaneous pericardiocentesis prohibitively hazardous. After multidisciplinary heart-team review, a left anterior mini-thoracotomy with pleuro-pericardial window evacuated approximately 1000 mL of fluid. Aerobic culture yielded C. amycolatum (MALDI-TOF), with histological pericarditis and a consistent antibiogram; autoimmune, viral and neoplastic causes were excluded, although blood cultures and extended viral testing were not performed. Targeted intravenous cefazolin was given, and the patient delivered a healthy term neonate at 39 weeks, with a normal 7-month echocardiogram. To the best of our knowledge, this is among the first reported cases of C. amycolatum pericardial tamponade in pregnancy. Because blood cultures and molecular confirmation of pericardial involvement were not obtained, a contaminant or incidental role for the organism cannot be entirely excluded, and the causal attribution should be regarded as probable rather than definitive. The case highlights heart-team-based individualised decompression and the cautious microbiological interpretation of organisms traditionally regarded as commensals. Full article

Obesity is characterized by pathological adipose tissue expansion and dysregulated energy homeostasis. In this study, we examined whether KBN2201 attenuates high-fat diet (HFD)-induced obesity-associated phenotypes and whether these effects are accompanied by changes in appetite-regulatory markers. C57BL/6J mice were fed a normal chow diet or HFD and orally administered vehicle or KBN2201 (20 mg/kg/day) for 12 weeks. In male mice, KBN2201 reduced HFD-induced body weight gain, adipose tissue accumulation, and adipocyte hypertrophy. KBN2201 was also associated with lower cage-level caloric intake under HFD-fed conditions. In epididymal white adipose tissue (eWAT), KBN2201 suppressed Srebf1 expression and reduced HFD-induced increases in Tnf and Tgfb1 expression. In the colon, KBN2201 further increased Pyy mRNA expression, and a positive mRNA-level association was observed between colonic Pyy and Npy2r expression in NTS-containing brainstem tissue. Behavioral analyses provided no evidence of overt locomotor suppression under the present experimental conditions. These findings suggest that KBN2201 attenuates HFD-induced obesity-associated phenotypes in male mice, accompanied by a lower cage-level food intake pattern, reduced adipose tissue expansion, and changes in the expression of colonic Pyy and NTS-containing brainstem Npy2r. Full article

Background/Objectives: Dietary patterns characterized by excess saturated fat intake contribute to obesity, type 2 diabetes, and cardiac metabolic dysfunction. Ceramides, bioactive sphingolipids synthesized in response to nutrient overload, have emerged as key molecular mediators linking dietary lipid composition to alterations in cardiac metabolic signaling. This review aims to integrate current evidence on diet-induced ceramide remodeling and its impact on intracellular pathways regulating cardiac metabolism. Methods: We analyzed experimental and clinical studies investigating the effects of high-fat and Western-type diets on myocardial ceramide synthesis, lipidomic remodeling, and downstream signaling pathways. Evidence from animal models, genetic and pharmacological interventions, nutritional studies, and circulating biomarker analyses was examined to delineate mechanistic and translational insights. Results: Saturated fatty acid excess, particularly palmitate, activates the de novo ceramide synthesis pathway in the myocardium, promoting accumulation of specific ceramide species. This remodeling impairs insulin signaling through Akt inhibition, protein phosphatase 2A activation, and PKCζ-dependent mechanisms, contributing to cardiac metabolic inflexibility. Ceramides further disrupt mitochondrial function by altering electron transport chain activity, increasing reactive oxygen species production, and modulating mitophagy and apoptotic signaling. Lipidomic studies highlight species-specific effects, with C16-ceramides frequently associated with adverse metabolic and cardiovascular outcomes, whereas very-long-chain ceramides may exert distinct functional roles. Circulating ceramide profiles have also been linked to diet-associated cardiovascular risk. Conclusions: Diet-induced ceramide remodeling represents a central molecular axis connecting dietary lipid excess to altered cardiac metabolic signaling. Targeting sphingolipid metabolism through nutritional or pharmacological strategies may offer novel opportunities for preventing and managing diet-associated cardiac dysfunction. Full article

Apolipoprotein A-IV (ApoA-IV) is a glycoprotein secreted by the small intestine to regulate lipid metabolism and satiety. Its role in insulin-independent glucose homeostasis remains largely unknown. In this study, we demonstrate that intestinal ApoA-IV overexpression significantly attenuates diet-induced obesity and hyperglycemia following severe β-cell loss. Over a 20-week high-fat diet challenge, ApoA-IV transgenic (ApoA-IV-Tg) mice maintained significantly lower adiposity than wild-type controls, driven by elevated energy expenditure and fatty acid oxidation rather than reduced caloric intake. Beyond weight maintenance, ApoA-IV maintained excellent systemic glycemic control and enhanced peripheral insulin sensitivity. Most notably, ApoA-IV significantly attenuated hyperglycemia following streptozotocin (STZ)-induced β-cell ablation, maintaining glucose stability despite severe insulin deficiency. Mechanistically, this protection results from a blunted glucagon response and the subsequent suppression of the hepatic pCREB-G6Pase gluconeogenic signaling pathway. In vitro evidence confirms that ApoA-IV directly inhibits pancreatic α-cell glucagon secretion through an LDL receptor-related protein 1 (LRP1)-dependent pathway, reinforced by the precise co-localization of LRP1 and glucagon in pancreatic islets. Furthermore, ApoA-IV-Tg mice were protected from the STZ-induced corticosterone surge and systemic lipolysis. Collectively, these findings establish the ApoA-IV–LRP1 signaling axis as a potent metabolic switch, providing a promising insulin-independent strategy for managing obesity and diabetes. Full article

Spirulina-derived protein hydrolysates (SPPHs) have attracted considerable attention as bioactive agents due to their potential metabolic and physiological benefits. This study evaluated the therapeutic efficacy of different enzyme-specific SPPHs—Pepsin (SPPH-P), Trypsin (SPPH-T), Chymotrypsin (SPPH-C), and a combined hydrolysate (SPPH-PTC)—in high-fat diet (HFD)-induced male Wister rats, compared with Spirulina platensis protein extract (SPPE, formulated using freeze–thaw cycles and ultrasonication followed by centrifugation) and atorvastatin as a Positive Control. The animals were randomly allocated into seven groups (n = 6 per group) and received their respective treatments orally for 4 weeks. Across treatment groups, significant improvements in obesity-related anthropometric indices were observed, including reductions in BMI, Lee Index, and abdominal circumference to thoracic circumference ratio (AC:TC), with the strongest effects noted in the atorvastatin and SPPH-PTC groups. Protein metabolism markers showed enhanced hepatic and serum protein status, reflected by increased albumin and total protein concentrations. Lipid profile analysis revealed marked decreases in total cholesterol, triglycerides, and LDL in both serum and liver homogenates, while HDL exhibited non-significant but favorable elevations. Liver function markers (bilirubin, ALT, AST) and renal parameters (uric acid, BUN) demonstrated notable improvements, particularly in enzyme-derived hydrolysate groups and Positive Control. Antioxidant assessments indicated substantial reductions in MDA levels and significant increases in SOD, CAT, and GSH activities in serum and liver tissues, confirming enhanced oxidative stress resistance. Among all treatments, SPPH-PTC consistently produced the most robust therapeutic outcomes. Overall, Spirulina protein hydrolysates, especially the combined PTC formulation, exert comprehensive beneficial effects on metabolic regulation, hepatic and renal function, and oxidative balance. These findings support their potential application as functional bioactive agents for managing obesity-associated metabolic disturbances. Full article

Metabolic dysfunction-associated steatohepatitis (MASH; formerly non-alcoholic steatohepatitis, NASH) is characterized by oxidative stress, inflammatory activation, hepatocellular injury, and progressive liver dysfunction. However, the global transcriptomic landscape underlying stress-induced hepatic injury remains incompletely understood. In this study, we employed a methionine–choline-deficient (MCD) diet-induced murine model to characterize the phenotypic and transcriptomic alterations associated with liver injury. Male C57BL/6J mice were fed either a control or MCD diet, and hepatotoxicity was assessed by survival analysis, body and liver weight measurements, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, histopathological examination, RNA sequencing, quantitative real-time PCR (qRT-PCR), and tumor necrosis factor-alpha (TNF-α) enzyme-linked immunosorbent assay (ELISA). MCD feeding markedly reduced survival and body weight while inducing hepatomegaly and significant elevations in serum ALT and AST, indicating severe hepatocellular injury. Histopathological analysis demonstrated hepatic steatosis, hepatocellular ballooning, and lobular inflammation without histological evidence of fibrosis. Transcriptomic profiling revealed extensive gene expression remodeling, characterized by activation of inflammatory pathways, enrichment of MAPK-related signaling, dysregulation of lipid metabolism, suppression of antioxidant defense systems, impairment of cytochrome P450-mediated detoxification, and upregulation of apoptosis-associated genes. qRT-PCR further validated the differential expression of representative genes involved in inflammatory signaling (Tlr4, Nfkb1, Nlrp3, and Casp1), MAPK signaling (Fos), xenobiotic metabolism (Cyp4f18), lipid metabolism (Apoa4 and Lpl), extracellular matrix remodeling (Mmp12), and oxidative stress responses (Sod1 and Gstp1). In addition, elevated serum TNF-α levels provided protein-level evidence supporting activation of the TLR4/NF-κB/TNF-α/NLRP3 inflammatory axis. Although fibrosis-associated transcriptional responses were detected, the absence of histological fibrosis suggests transcriptional priming of fibrogenic pathways rather than established fibrogenesis. Collectively, these findings provide a transcriptomic framework linking oxidative stress, impaired detoxification, inflammatory activation, and stress-responsive signaling to MCD-induced hepatic injury. The MCD model provides a valuable experimental platform for characterizing hepatic stress-response transcriptomes and for generating hypotheses that can subsequently be evaluated in environmentally relevant toxicological models. Nevertheless, caution should be exercised when extrapolating these findings to obesity-associated human MASLD, as the MCD model lacks key metabolic features of the human disease, including obesity and insulin resistance. Therefore, the present findings should be interpreted primarily as transcriptomic signatures of stress-induced hepatic injury rather than as a direct representation of the pathophysiological processes underlying human obesity-associated MASLD. Full article

This study investigated the metabolic regulatory effects and underlying microbial mechanisms of Deinococcus radiodurans extract (DRE), using high-fat diet (HFD)-induced obese mice as the primary mechanistic model and naturally overweight felines. In the mouse model, a 1.5% DRE supplementation mitigated HFD-induced obesity, reduced serum total cholesterol and low-density lipoprotein levels, and markedly ameliorated hepatic steatosis. Fecal 16S rRNA gene sequencing revealed that DRE effectively reversed murine microbial dysbiosis by significantly restoring core commensals depleted by the HFD, notably Ureaplasma and the short-chain fatty acid (SCFA)-producer Odoribacter, while concurrently suppressing the overgrowth of obesity-associated taxa including Alloprevotella and Phascolarctobacterium. As a translational complement, a 28-day DRE intervention in felines under isocaloric maintenance conditions, with no significant change in body weight, body condition score, or fecal score, validated these systemic benefits, significantly enhancing serum total antioxidant capacity by 16.1% and reducing the systemic inflammatory marker serum amyloid A by 27.8%, indicating that the antioxidant and anti-inflammatory effects of DRE are independent of weight change. Concurrently, feline fecal microbiota profiling demonstrated a parallel ecological remodeling, characterized by the enrichment of potent SCFA producers (Oscillibacter and the [Eubacterium]_hallii_group) and the profound suppression of the pro-inflammatory pathogen Fusobacterium. Collectively, by integrating deep mechanistic insights from mice with translational evidence from felines, this study demonstrates that DRE exerts comprehensive anti-obesity and anti-inflammatory effects by regulating lipid metabolism and reshaping the gut microbiota, establishing its robust potential as a novel functional ingredient for metabolic health in companion animals. Full article

Background/Objectives: Overweight and obesity have consistently increased in prevalence. Early exposure to foods high in fats and sugar through maternal conditions may increase vulnerability to developing metabolic diseases and cognitive impairments in adulthood. In this regard, we aim to evaluate the effects that perinatal exposure to cafeteria diet (CAF) and physical activity (PA) has on anxiety-like, depressive-like behavior, memory and diet preference in male and female offspring. Methods: Seventy female and male offspring rats were divided into five groups according to maternal conditions: (1) CONTROL, fed only standard diet (SD) with no voluntary PA, (2) SED+SD, fed only SD with no voluntary PA, (3) SED+CAF, fed SD and CAF with no voluntary PA, (4) PA+SD, fed only SD with voluntary PA, and (5) PA+CAF, fed SD and CAF with voluntary PA. Starting on PND 24, offspring rats were exposed to SD and CAF (except for rats from the CON maternal group) and evaluated for seven weeks for diet preference, and at week seven for anxiety-like, depressive-like behavior and memory. Results: After seven weeks of exposure to CAF, maternal conditions showed significantly different effects on adult male and female offspring for diet preference and memory impairments. Furthermore, maternal PA significantly reduced anxiety-like and depressive-like behaviors in the offspring. Conclusions: Our results suggest that maternal conditions and postweaning CAF exposure have a joint influence on diet preference, anxiety-like and depressive-like behavior. Additionally, perinatal CAF exposure impairs memory in male and female offspring, regardless of maternal PA conditions. However, maternal PA was associated with reduced affective behaviors induced by lifelong CAF, presenting as a promising non-pharmacological intervention to promote favorable long-term behavioral outcomes in offspring. Full article

Pomegranate (Punica granatum), a shrub belonging to the Lythraceae family, has long been recognized for its diverse pharmacological benefits, including potential roles in managing inflammation and diabetes. The present study explored the insulin-secretory and β-cell proliferative properties of the ethanol extract of P. granatum fruit peel (EEPG) and assessed its influence on glucose regulation in high-fat-fed diet-induced obese mice (HFDi-OM) through in vivo and in silico studies. In vitro, EEPG was found to activate cAMP-dependent pathways and regulate K_ATP channels, thereby enhancing glucose-stimulated insulin secretion from BRIN-BD11 β-cells, with partial reliance on extracellular calcium. EEPG promoted β-cell proliferation, as indicated by an increase in Ki-67 positive cells, and displayed inhibitory effects on glucose diffusion and starch hydrolysis, suggesting a capacity to delay carbohydrate digestion and absorption. Furthermore, EEPG demonstrated antioxidant activity by neutralizing free radicals. In an acute test, EEPG (at doses of 150 and 250 mg/5 mL/kg) improved oral glucose tolerance and elevated plasma insulin levels. Long-term oral treatment for 21 days to HFDi-OM led to a significant reduction in fasting blood glucose, body weight, and food and fluid intake. It also enhanced gastrointestinal motility and improved lipid profiles by increasing HDL and lowering total cholesterol, LDL, and triglycerides. The therapeutic properties of EEPG are likely attributed to its rich bioactive components, including flavonoids (quercetin, kaempferol, catechin, and epicatechin) and phenolic acids (ellagic acid), which exhibited strong multi-target binding affinities in in silico molecular docking studies toward SUR1, PDE4, PI3K, and α-amylase, thereby supporting enhanced insulin secretion, β-cell function and glucose homeostasis. Full article

Galectin-3 (Gal-3) is a β-galactoside-binding lectin implicated in metabolic inflammation, cardiovascular and renal dysfunction, neurodegenerative disorders, and obesity-related pathologies. Although Gal-3 is recognized as a clinically relevant biomarker, the mechanisms controlling its tissue expression and circulating abundance remain poorly defined. O-GlcNAcase (Oga; encoded by Mgea5), the enzyme that removes O-linked β-N-acetylglucosamine (O-GlcNAc) from proteins, regulates nutrient-sensitive signaling and transcriptional processes that overlap with Gal-3 associated disease pathways. To investigate the relationship between metabolic status and Gal-3 expression, male mice were fed a high-fat diet (HFD) for eight weeks to induce obesity. HFD-fed mice exhibited significant increases in body weight and fasting and fed blood glucose levels compared with lean controls, confirming metabolic dysregulation. ELISA revealed approximately threefold higher serum and plasma Gal-3 concentrations in obese mice, indicating enhanced Gal-3 production in diet-induced obesity. To determine whether Oga regulates Gal-3 expression, Oga wild-type (WT), heterozygous (HET), and knockout (KO) mice were analyzed. Circulating Gal-3 protein levels were significantly reduced in Oga KO mice, with intermediate levels in Oga HET animals. RT-qPCR revealed genotype-dependent modulation of Gal-3 (Lgals3) mRNA expression across multiple tissues, demonstrating tissue-specific regulation by Oga. These findings establish Oga as a critical regulator of Gal-3 expression and systemic abundance. The data reveal a mechanistic link between O-GlcNAc signaling enzyme Oga, and lectin-mediated metabolic inflammation, suggesting that Oga activity influences Gal-3 homeostasis and may affect its interpretation as a biomarker in metabolic disease. Full article

Background: Obesity is a multifactorial metabolic disorder characterized by excessive adiposity, chronic low-grade inflammation, and dysregulated incretin and energy-sensing pathways, including glucagon-like peptide-1 (GLP-1) and AMP-activated protein kinase (AMPK). Methods: This in vitro and in vivo study evaluated the potential of select phytochemical candidates and botanical formulations to stimulate GLP-1 secretion and activate AMPK signaling. Results: Fourteen phytochemicals and six combinations were screened in human NCI-H716 enteroendocrine cells at 10–20 µg/mL to assess cytotoxicity and GLP-1 secretion. In human adipocytes, selected combinations reduced lipid accumulation and monocyte chemoattractant protein-1 (MCP-1) secretion. Among the tested formulations, combination #4, consisting of ginseng root extract, curcumin, white kidney bean extract, fenugreek extract, capsaicin, and bitter melon extract, significantly increased phosphorylated AMPK levels in vitro. In high-fat diet-induced obese mice, oral administration of combination 4 reduced body weight gain and white adipose tissue mass, improved metabolic biochemical parameters, restored leptin and MCP-1 levels toward normal values, increased GLP-1 level, and normalized GLP-1 receptor expression in subcutaneous adipose tissue. Conclusions: These preclinical findings demonstrate that this multi-component botanical formulation modulates GLP-1 secretion, AMPK phosphorylation, lipid accumulation, and inflammatory markers in cellular and murine models. These data provide a foundational rationale for its further evaluation as a non-toxic candidate for metabolic management. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is closely associated with obesity, insulin resistance, and gut microbiota dysbiosis. This study investigated the effects of a probiotic combination of Lactiplantibacillus plantarum DM083 and Lacticaseibacillus rhamnosus DM163 on glycemic control, insulin resistance, gut microbiota composition, and metabolic parameters in high-fat-diet (HFD)-induced obese mice. Methods: Male C57BL/6 mice were fed a 60% HFD for 8 weeks and subsequently administered DM083/163 (1 × 10⁹, 5 × 10⁹, or 1 × 10¹⁰ CFU/day) or metformin (250 mg/kg/day) for 12 weeks. Glucose metabolism, insulin resistance, hepatic gene expression, gut microbiota composition, and fecal short-chain fatty acids (SCFAs) were evaluated. Results: DM083/163 supplementation at 1 × 10¹⁰ CFU/day significantly reduced fasting blood glucose, HbA1c, oral glucose tolerance test area under the curve, and HOMA-IR compared with the HFD control group (p < 0.05). Hepatic expression of the gluconeogenic genes Pck1 and G6pc was significantly downregulated, accompanied by reduced hepatic and serum TNF-α levels. Gut microbiota analysis revealed significant overall differences in beta diversity across groups (PERMANOVA, R² = 0.262, p = 0.001), driven primarily by diet, with a trend toward a reduced Bacillota/Bacteroidota ratio in the high-dose group. Conclusions: DM083/163 supplementation improved glycemic control and insulin resistance in HFD-induced obese mice. These effects were associated with suppression of hepatic gluconeogenesis, attenuation of inflammation, and increased SCFA production, findings that are consistent with, but do not establish, modulation of the gut–liver axis. These findings support the potential use of DM083/163 as a probiotic intervention for obesity-associated T2DM. Full article