BACKGROUND:High-fat diets activate intestinal inflammasomes, promoting dysbiosis, metabolic dysfunction, and inflammation. The apoptosis speck-like protein with a caspase activation domain (ASC) is a key adaptor for inflammasome activation, but its role in diet-induced metabolic alterations remains unclear. METHODS:We investigated the metabolic and inflammatory consequences of ASC deficiency using Pycard-/- mice fed a high-fat diet. Body weight, glucose tolerance, intestinal and hepatic metabolic profiles, and inflammatory markers were assessed. To evaluate extracellular ASC function, ASC oligomers were administered to Pycard-/- mice. RESULTS:ASC-deficient mice displayed reduced weight gain and improved glucose tolerance compared with wild-type controls. Pycard-/- mice also showed enhanced intestinal and hepatic metabolic profiles and decreased inflammation. Extracellular administration of ASC oligomers partially restored dysbiosis, intestinal metabolic changes, and inflammatory responses in Pycard-/- mice. CONCLUSIONS:ASC contributes to metabolic dysregulation through both its canonical intracellular role in inflammasome activation and an extracellular oligomer-mediated mechanism. These findings identify ASC as a relevant target for interventions aimed at improving obesity-associated metabolic and inflammatory disturbances.
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has emerged as a leading global chronic liver disorder, affecting approximately 30% of the general population. Characterized by the presence of hepatic steatosis along with at least one metabolic comorbidity, MASLD represents a progressive disease spectrum ranging from simple steatosis to hepatocellular carcinoma. The pathogenesis of MASLD involves a complex interplay of metabolic dysregulation, insulin resistance, oxidative stress, and inflammation, which remains incompletely elucidated. Peroxisome proliferator-activated receptors (PPARs) are core lipid and metabolic sensors that orchestrate the transcriptional regulation of glucose homeostasis, lipid metabolism, adipogenesis, and anti-inflammatory responses, making them pivotal therapeutic targets in MASLD. While selective or dual PPAR agonists have reached efficacy plateaus and raised safety concerns in clinical trials, pan-PPAR agonists coordinated activation of all three PPAR isoforms with broader therapeutic efficacy and improved safety profiles. This review delineates the biological rationale for PPAR modulation in MASLD, critically evaluates current preclinical and clinical evidence for pan-PPAR agonists, and discusses emerging strategies for optimizing their development as comprehensive therapeutic interventions for MASLD.
AIM:Despite growing evidence linking better oxidative balance to improved cardiometabolic health, metabolite signatures reflecting oxidative status remain still poorly characterized. We aimed to identify a plasma metabolite signature of the oxidative balance score (OBS) and to examine its association with incident cardiovascular disease (CVD) and type 2 diabetes (T2D). METHODS:The discovery population included 1732 participants at high cardiovascular risk from the PREDIMED study with available plasma metabolomics using LC-MS and OBS data at baseline. The OBS was calculated at baseline and after 1-year of follow-up based on 12 a priori selected pro- and antioxidant dietary and non-dietary lifestyle factors, with higher scores indicating a more favorable antioxidant balance. A set of metabolites predicting OBS was selected from 388 candidate metabolites using elastic net regression. Multivariable Cox models were used to examine the associations between the OBS metabolite signature and incident CVD and T2D. RESULTS:A subset of 21 metabolites was consistently selected (amino acids, vitamins, nucleotides, lipid species, xenobiotics, and others). The metabolite signature was inversely associated with incident CVD in the baseline sample (HR per SD 0.70; 95% CI 0.61-0.81), but not in the 1-year sample (HR 0.94; 95% CI 0.81-1.09). In addition, baseline (HR 0.70; 95% CI 0.60-0.80) and 1-year (HR 0.84; 95% CI 0.72-0.97) OBS metabolite signatures were inversely associated with T2D risk. CONCLUSIONS:A plasma metabolite signature reflecting oxidative balance-related exposures was inversely associated with CVD and T2D risk at baseline. The association with T2D was also observed when the signature was applied to 1-year measurements and in an independent external cohort, whereas the association with CVD was not replicated at 1 year. Most metabolites showed biologically plausible patterns, correlating with specific pro- and antioxidant exposures and including metabolites previously implicated in oxidative stress-related processes. CLINICAL TRIAL REGISTRATION:This trial was registered at controlled-trials.com as ISRCTN35739639.
BACKGROUND:Adipose thermogenesis increases energy expenditure and protects against obesity. However, the endogenous mechanisms that restrain this process are not fully understood. METHODS:Adipose tissue- and adipocyte-specific Asb3-deficient mice were exposed to cold or treated with the β3-adrenergic receptor agonist CL-316,243. Primary thermogenic adipocytes were used to assess adipogenic differentiation and β3-adrenergic/cAMP-PKA responses. Proteomic/phosphoproteomic profiling, co-immunoprecipitation, ubiquitination assays and domain mapping were performed to define the mechanism. Adipose p62 knockdown and high-fat-diet feeding were used to evaluate in vivo relevance. RESULTS:The abundance of ASB3 protein increased in inguinal white adipose tissue (iWAT) following cold exposure or β3-adrenergic stimulation. Conversely, adipose-tissue- or adipocyte-specific deletion of Asb3 enhanced iWAT browning induced by cold exposure and b3-adrenergic receptor agonist CL-316,243, as well as brown adipose tissue activation and thermogenic gene expression. In primary beige adipocytes, ASB3 deficiency potentiated the thermogenic response to activation of the β3-adrenergic/cAMP-PKA pathway. Mechanistically, ASB3 interacted with p62 through its ankyrin-repeat region, promoting p62 ubiquitination involving both K48- and K63-linked ubiquitin chains. Loss of ASB3 was associated with increased p62 abundance and nuclear accumulation. Conversely, local p62 knockdown in iWAT attenuated ASB3 deficiency-induced beiging, thermogenic signaling and whole-body energy expenditure. Furthermore, adipose-tissue-specific ASB3 deficiency protected mice against weight gain, fat accumulation, hepatic steatosis, glucose intolerance and insulin resistance by a high-fat diet. CONCLUSION:These findings indicate the critical role of the ASB3-p62 ubiquitin axis in restricting adipose tissue thermogenic plasticity and suggest that ASB3 may be a promising therapeutic target for obesity and related metabolic disorders.
BACKGROUND & AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health concern, with obesity serving as a primary risk factor. Although Mediator subunit 1 (MED1) plays an important role in lipid metabolism, its specific contribution to obesity-related hepatic steatosis remains unclear. This study aims to elucidate the involvement of MED1 in the pathogenesis of MASLD during obesity. APPROACH & RESULTS:Herein, we found that MED1 expression was upregulated in fatty livers from obese patients with MASLD, a primate MASLD model, genetically obese (ob/ob) mice, and in palmitate-treated HepG2 cells. Hepatocyte-specific knockout of MED1 on an ob/ob background under both chow and high-fat diet feeding ameliorated hepatic steatosis, glucose intolerance, obesity and inflammation of visceral white adipose tissue. Mechanistically, MED1 regulates hepatic lipid metabolism primarily through direct interaction with SREBP1, thereby mediating the expression of key SREBP1 target genes, including ACC, FASN and SCD1. Importantly, therapeutic delivery of AAV8-shMED1 attenuated MASLD progression in ob/ob mice. CONCLUSIONS:These findings establish MED1 as a critical activator of SREBP1-driven lipogenesis and identify hepatic MED1 inhibition as a promising therapeutic strategy for MASLD.
BACKGROUND:Recent genome-wide association studies have identified more than 900 lipid-related loci; however, the specific genes and mechanisms that regulate blood lipid levels remain incompletely understood. This study aimed to identify lipid-associated variants in Koreans and to investigate their potential functional and regulatory mechanisms. METHODS:We performed a genome-wide association study of triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels in 72,298 Korean participants. Genotype data were imputed using the Northeast Asian Reference Database, version 2. We then conducted conditional analysis, statistical fine-mapping, and functional variant-to-gene mapping, and further evaluated the associations of lipid-associated variants with coronary artery disease. Significant variants were subsequently examined using a luciferase reporter assay in HepG2 cells. RESULTS:Our analyses identified 182 independent lipid-associated signals, including 64 previously unreported signals. Integrative fine-mapping and variant-to-gene mapping prioritized 24 variants with evidence of transcriptional regulatory effects and 40 linked genes, including potential lipid metabolism regulators PIP5KL1 and UBE4A. Reporter assays further supported allele-specific regulatory activity for rs10987803 (FAM102A) and rs5130 (APOC3). Several low-frequency protein-altering variants implicated established lipid metabolism pathways. Notably, a Korean-enriched ANGPTL3 missense variant (rs753849210; p.W338C) was associated with markedly lower triglyceride levels. Lipid effects were directionally concordant with coronary artery disease associations for variants in PCSK9 (rs564427867; p.E32K and rs151193009; p.R93C), HIST1H1C (rs12111009; p.G124A), and CELSR2 (rs77619489; p.A2806V). CONCLUSIONS:These findings refine the genetic architecture of lipid traits and nominate candidate genes and regulatory variants for future studies of lipid-related cardiometabolic disease.
Adipose tissue macrophages (ATMs) are a key immune cell population linking obesity, chronic low-grade inflammation, extracellular matrix (ECM) remodeling and systemic metabolic dysfunction. Recent single-cell and spatial omics studies indicate that ATMs cannot be adequately described by the traditional M1/M2 dichotomy. Instead, they form a continuum of states that includes lipid-associated macrophages (LAMs), perivascular macrophages (PVMs), sympathetic neuron-associated macrophages (SAMs), septal adipose tissue macrophages (sATMs) and candidate collagen-expressing macrophages (CEMs). Distinct ATM subsets can exert opposing effects, including inflammation, lipid buffering, tissue repair and fibrosis, depending on adipose depot, species, obesity stage and the mechanical microenvironment. In this review, we discuss adipose tissue fibrosis within a context-dependent framework of ATM-regulated fibro-inflammation. We evaluate the roles of ATMs in ECM deposition, adipose progenitor remodeling, mechano-biochemical positive feedback and the adipose tissue-liver axis. We focus on the interactions among TGF-beta/Smad, Piezo1/YAP, integrin/FAK, MINCLE-OSM, extracellular vesicles and adipocyte-derived signals, particularly adiponectin, and explain how these pathways affect tissue stiffening, ectopic lipid deposition and MASLD/MASH progression. We also stratify the evidence supporting CCR2/CCR5 blockade, macrophage metabolic reprogramming, Piezo1/integrin-targeted mechanotransduction, CAR-M therapy, RNAi and engineered macrophage therapies. This distinction separates strategies with metabolic or preclinical support from emerging approaches that remain at the proof-of-concept stage. Together, this review provides a more precise mechanistic framework for understanding obesity-associated adipose tissue fibrosis and its metabolic consequences.
BACKGROUND:Time-restricted eating (TRE) is a popular dietary strategy for supporting weight loss and immune metabolic health, but the underlying mechanisms are unclear. OBJECTIVE:This narrative mini-review explores the mechanistic associations between TRE, immunomodulation, and ketone body metabolism, focusing on the potential role of ketones in mediating anti-inflammatory responses. Our goals were to synthesize the contemporary literature in humans to identify knowledge gaps that may inform future research directions. KEY FINDINGS:TRE modestly reduced pro-inflammatory markers and increased circulating ketone concentrations, although the magnitude of these effects was variable and often confounded by the metabolic changes associated with weight loss. Studies isolating TRE from caloric restriction remain limited, and no studies directly assessed the relationship between TRE-induced ketogenesis and immune modulation. CONCLUSIONS AND FUTURE DIRECTIONS:Ketone bodies may play a key role in mediating the anti-inflammatory effects of TRE, offering a low-risk, non-pharmacological strategy to managing healthy weight and chronic inflammatory conditions. Future studies should prioritize controlled, isocaloric TRE interventions to better define the contributions of ketogenesis and immunomodulation to TRE's health benefits.
Diabetes mellitus (DM) is a multifactorial metabolic disorder in which chronic hyperglycemia arises alongside adipose-tissue dysfunction, ectopic lipid accumulation, endothelial injury, and progressive multiorgan damage. These processes form an interconnected network, and because lowering glucose or blocking any single pathway leaves the other nodes active, the disease continues to advance even when glycemic targets are met. Therapies that act on several nodes at once are therefore conceptually attractive. Mesenchymal stem cell (MSC) therapy fits this requirement, engaging the immune, vascular, and metabolic arms of the disease at the same time through a shared paracrine program. Here, we analyze 107 registered interventional trials, drawn from 124 screened records, that evaluate MSC-based therapies across type 1 diabetes, type 2 diabetes, and a range of diabetic complications. Autologous bone marrow-derived MSCs (BMMSCs) and adipose-derived MSCs (AdMSCs) featured in the earliest trials, and registration has since shifted toward standardized allogeneic umbilical cord-derived MSCs (UCMSCs) and cell-free derivatives. The strongest and most consistent benefits appear in ischemic and wound-healing complications, particularly diabetic foot ulcers, whereas metabolic outcomes remain variable. Together, current early-phase evidence supports MSC therapy as a safe and potentially disease-modifying adjunct, although larger randomized trials with harmonized endpoints are needed to confirm efficacy.
BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent but heterogeneous condition. How its genetic diversity shapes systemic disease risk remains unclear. We aimed to identify genetically defined MASLD subtypes, assess their effects on extrahepatic diseases, and uncover potential protein-mediated mechanisms. METHODS:We performed a genome-wide association study of MRI-derived hepatic fat content (HFC) in 33,592 UK Biobank (UKBB) participants to identify MASLD-related SNPs. Clustering of associations between MASLD-SNPs and triglyceride-related traits identified distinct genetic subtypes. Phenotypic associations were evaluated in 427,030 UKBB European-ancestry participants and validated in two independent populations. Plasma proteomic profiling and Mendelian randomization/mediation analyses were used to identify protein mediators linking subtypes to disease outcomes. RESULTS:We identified three MASLD polygenic subtypes reflecting hepatic lipid retention, hepatic lipid synthesis, and systemic lipid metabolism. These subtypes exhibited distinct risk profiles across 22 incident diseases spanning multiorgan systems in the UKBB European-ancestry cohort, with partial replication in the UKBB non-European-ancestry populations and the Taizhou Longitudinal Study in China. All three subtypes consistently increased liver disease risk but showed divergent cardiometabolic effects. Proteomic profiling revealed subtype-specific signatures; for instance, systemic lipid metabolism was linked to elevated PCSK9 and higher cardiovascular risk, whereas hepatic lipid retention showed the opposite. Mediation and Mendelian randomization analyses identified both established (e.g., PCSK9, FURIN, APOE) and potentially novel (e.g., CCN1, ASGR1) protein mediators as putative targets for subtype-specific chronic disease prevention. CONCLUSION:Our findings delineate etiologically and clinically distinct MASLD subtypes, reveal protein-mediated pathways to systemic diseases, and inform biologically guided prevention strategies.
BACKGROUND & AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent chronic liver diseases in modern society. Heat shock factor 1 (HSF1) is a transcription factor that orchestrates cellular responses and closely associate with metabolic diseases. However, the specific hepatic function and mechanism of HSF1 in MASLD is not clearly clarified. METHODS:HSF1 expression levels were examined in genetic, diet-induced, and aging-associated murine MASLD models. Hepatocyte-specific HSF1 knockout (LKO) and active HSF1 overexpression mice were challenged with MASLD and metabolic performances were evaluated. Transcriptome sequencing, screening, chromatin-immunoprecipitation, luciferase assay and co-immunoprecipitation were performed to elucidate the transcriptional and post-translational mechanisms. Rescue experiments with celastrol on Pparα-LKO mice, and Uchl1 or fenofibrate on Hsf1-LKO mice were assessed to reveal the regulatory axis. RESULTS:We found that HSF1 levels were reduced in MASLD mice models under the transcriptional regulation of ATF3. Hsf1-LKO mice showed exacerbated diet- or aging-induced MASLD, whereas hepatic overexpression of active HSF1 alleviated MASLD in both diet-induced and genetic MASLD mice models. Interestingly, RNA-seq revealed that Hsf1 regulated Pparα signaling and Pparα is required for Hsf1 agonist celastrol mediated improvement of β-oxidation. Mechanistically, Hsf1 activated the transcription of Uchl1, a deubiquitinating enzyme, to reduce Pparα ubiquitination for enhanced protein stability. Both Uchl1 overexpression or fenofibrate treatment rescued deteriorated MASLD of Hsf1-LKO mice via Pparα protein stabilization. CONCLUSIONS:Our results highlighted the HSF1-UCHL1 transcriptional axis that protects against MASLD through regulation of PPARα protein stability in mice.
