BACKGROUND:Obesity-associated adipose tissue dysfunction is a major contributor to metabolic disease. Although obesity is associated with increased glucocorticoid exposure, the role of glucocorticoid receptor (GR) signaling in mature adipocytes during obesity remains unclear. METHODS AND RESULTS:To investigate the direct effects of dexamethasone (Dex) on mature adipocytes, we established an ex vivo culture model of primary human white adipocytes. Dex-mediated GR activation exerted cytoprotective effects by attenuating stress-associated DNA damage, suppressing aberrant cell-cycle re-entry, and downregulating pro-inflammatory programs, thereby preserving adipocyte function. Similar protective effects were observed in adipocytes exposed to sustained high insulin concentrations. In obese human cohorts, elevated circulating adrenocorticotropic hormone levels and increased adipose expression of 11β-hydroxysteroid dehydrogenase type 1 supported the presence of increased glucocorticoid exposure. However, integrated analysis of human adipose single-nucleus RNA-sequencing datasets revealed a significantly higher proportion of GR- unresponsive adipocytes in obesity. Consistently, key GR pathway components, including glucocorticoid receptor (NR3C1), FK506 binding protein 5, and glucocorticoid-induced leucine zipper were significantly downregulated in adipose tissue and mature adipocytes in obesity. These findings were supported by analyses of bulk sequencing datasets from multiple cohorts of obese human adipose tissue. Dataset analyses showed that suppressed GR signaling in obese adipocytes was reversed following sustained weight loss after bariatric surgery. CONCLUSIONS:GR activation protects human adipocytes by restraining cellular stress responses. Obesity-related adipocyte dysfunction is associated with impaired GR signaling despite increased adipose glucocorticoid exposure. These findings support selective GR activation as a potential therapeutic strategy for obesity-related metabolic syndrome.
Amelioration of the global diabetes pandemic can be effectively achieved by preventing the development of type 2 diabetes (T2D) among individuals with prediabetes. This approach is particularly important in low and middle-income countries (LMIC), especially India and China, that are home to high and rapidly increasing numbers of individuals with T2D. There is sufficient high-quality evidence, albeit mostly from high-income countries, that T2D can be prevented in those with prediabetes by lifestyle intervention, with or without medication. Similar studies in India and China have shown promising results, with growing evidence also emerging from other LMICs, but wider application of these strategies requires a deeper understanding of the pathophysiology of prediabetes, its heterogeneity and the challenges inherent in their implementation in resource-constrained settings. In particular, there is a pressing need to evaluate effective preventive strategies for individuals with impaired fasting glucose, who constitute a large proportion of those with prediabetes in south Asia and in whom lifestyle intervention appears to be less effective in preventing progression to T2D. Clarity is also needed on the best strategy to prevent diabetes in those individuals who do not have obesity, and on the role of newer drugs (such as the incretin-based therapies) and emerging digital technologies. This article mainly addresses the evidence on diabetes prevention in China and India, where the majority of clinical trials have been conducted.
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.
