Metabolism[JOURNAL]
Sun
200 papers
Ablation of microglial estrogen receptor alpha predisposes male mice to diet-induced obesity.
Velasco I, Frey JM, Baglaev V … +7 more , Jafari T, Huang T, Schwie S, Santiago OD, Fasnacht RD, Thaler JP, Dorfman MD
Metabolism · 2026 Jul · PMID 42392258 · Publisher ↗
Estrogen receptor alpha (ERα) signaling has metabolic and anti-inflammatory properties in addition to its impact on reproductive function. Compared to females, male mice generally exhibit greater inflammatory activation...
Estrogen receptor alpha (ERα) signaling has metabolic and anti-inflammatory properties in addition to its impact on reproductive function. Compared to females, male mice generally exhibit greater inflammatory activation of microglia and increased susceptibility to diet-induced obesity (DIO). Given the established metabolic protective effects of estrogen, these observations raise the possibility that sex differences in microglial estrogen signaling contribute to this sexual dimorphism. In this study, we assessed metabolic and CNS histopathological properties in a mouse model with inducible microglia-specific ablation of ERα (MG-ERαKO). Male MG-ERαKO mice developed increased weight gain and insulin resistance relative to controls during high-fat diet (HFD) feeding. Indirect calorimetry and food intake analysis revealed that reduced energy expenditure, coupled with an inadequate compensatory reduction in food intake, was the primary driver of the obese phenotype. In contrast, female MG-ERαKO mice fed HFD developed mild insulin resistance, with no change in body weight gain compared to controls, despite a similar reduction in energy expenditure. Immunohistochemical analyses of the microglial activation marker IBA1 in the mediobasal hypothalamus (MBH) revealed that female MG-ERαKO mice had an increased number of microglia without showing morphological signs of activation. In contrast, MBH microglial number was unchanged in MG-ERαKO male mice, but the cells adopted more activated morphological profiles. Finally, HFD-fed MG-ERαKO male mice had increased POMC neuron-microglia interactions but fewer overall hypothalamic POMC neurons, suggesting microglia may disrupt POMC neuron integrity to promote DIO. Together, these findings indicate that sex-specific actions of estrogen in microglia limit the metabolic complications of HFD feeding.
Pathophysiology-based subtypes of individuals at high-risk of type 2 diabetes: multi-omics profiles and lifestyle differences across subtypes.
Deng K, Hameete A, Schrauwen P … +8 more , Wagner R, van Hylckama Vlieg A, Rosendaal FR, Mook-Kanamori DO, le Cessie S, van Dijk KW, de Mutsert R, Li-Gao R
Metabolism · 2026 Jul · PMID 42385855 · Publisher ↗
BACKGROUND: Previous studies identified subtypes among individuals at elevated risk of type 2 diabetes mellitus (T2DM), yet the molecular signatures distinguishing these subtypes remain poorly characterized. We aimed to...
BACKGROUND: Previous studies identified subtypes among individuals at elevated risk of type 2 diabetes mellitus (T2DM), yet the molecular signatures distinguishing these subtypes remain poorly characterized. We aimed to identify and characterize T2DM risk subtypes using routine and non-routine clinical variable lists, and to compare their metabolomic, proteomic, and lifestyle profiles. METHODS: In the Netherlands Epidemiology of Obesity study (median age 56 years; median BMI 29 kg/m), we applied partitioning around medoids (PAM) clustering using two variable lists (routine, N = 5235; non-routine, N = 1510), both including variables derived from a liquid mixed meal challenge. Cox proportional hazards models estimated associations between subtypes and T2DM incidence. Random forest models identified discriminative metabolites and proteins across subtypes. RESULTS: Each variable list yielded four subtypes ranging from an insulin-sensitive and lean profile (subtype 1) to an obese profile with ectopic fat accumulation and insulin resistance (subtype 4), with a graded increase in T2DM risk (hazard ratios ranging from 1.9 [95% confidence interval (CI): 0.4-9.8] to 19.5 [95% CI: 9.1-41.6]). Both subtyping schemes captured metabolic heterogeneity beyond conventional weight-by-glycemia categories, e.g., redistributing overweight or obese but normoglycemic individuals across subtypes with divergent metabolic profiles and T2DM risks. While multi-omics profiling revealed shared metabolic and proteomic markers across higher-risk subtypes (e.g., glycoprotein acetyls, glucose, hepatocyte growth factor), subtype assignment was predominantly driven by fasting glucose and lipoprotein levels (e.g., very-low-density lipoprotein [VLDL]), with additional subtype-specific molecular signatures (e.g., branched-chain amino acids). Individuals in the higher-risk subtypes also exhibited less healthy lifestyle characteristics, including poorer dietary quality. CONCLUSIONS: Four metabolic subtypes with graded T2DM risk were identified in a predominantly overweight or obese, middle-aged population, revealing metabolic heterogeneity among individuals who appear homogeneous under conventional weight-by-glycemia categories. Although subtype differentiation was largely driven by fasting glucose and lipoproteins, multi-omics profiling uncovered additional molecular signatures, suggesting that data-driven subtyping may complement conventional risk markers and inform targeted prevention.
A thermosensitive TET-Parkin epigenetic axis couples mitochondrial quality control to adaptive thermogenesis in adipose tissue.
Byun S, Lee CH, Jang K … +6 more , Pak M, Lee HJ, Ryu S, Jung I, An J, Ko M
Metabolism · 2026 Jul · PMID 42385854 · Publisher ↗
Adipose tissue thermogenesis is a major determinant of energy homeostasis, and its dysregulation contributes to obesity and metabolic disease. Parkin-mediated mitophagy is required for thermogenic adaptation, but the ups...
Adipose tissue thermogenesis is a major determinant of energy homeostasis, and its dysregulation contributes to obesity and metabolic disease. Parkin-mediated mitophagy is required for thermogenic adaptation, but the upstream mechanisms linking thermal cues to this pathway remain poorly defined. Here, we identify the ten-eleven translocation (TET) family of DNA dioxygenases as thermosensitive epigenetic regulators of Prkn transcription in adipocytes. Cold exposure coordinately suppressed TET expression and reduced global 5-hydroxymethylcytosine (5hmC) levels in white and brown adipose tissue through β-adrenergic signaling. Adipose-specific TET triple-knockout mice exhibited enhanced white fat beiging, brown fat activation, increased energy expenditure, and improved cold tolerance. Transcriptomic network analysis identified Parkin as a key mitophagy node in TET-deficient adipose tissue. Consistent with this, loss of adipose TET reduced Parkin expression, impaired mitophagic flux, and promoted accumulation of metabolically active mitochondria with increased respiratory capacity. Mechanistically, TET proteins occupied the Prkn promoter and maintained a transcriptionally permissive state through catalytic conversion of 5-methylcytosine to 5hmC, whereas TET loss increased promoter methylation and suppressed Prkn expression. Re-expression of wild-type, but not catalytically inactive, Parkin largely normalized mitochondrial content and respiratory activity in TET-deficient adipocytes. Together, these findings define a thermosensitive TET-Parkin epigenetic axis that links environmental cold signals to mitochondrial quality control during adaptive thermogenesis.
Raffinose targets the NQO1/NF-κB axis to attenuate DON-driven microglial activation and neuroinflammation via metabolic reprogramming.
Zhang J, Zheng Y, Li H … +5 more , Chen Y, Gao J, Deng X, Dai C, Lv H
Metabolism · 2026 Jul · PMID 42385853 · Publisher ↗
Deoxynivalenol (DON), a prevalent mycotoxin in grain crops, can cross the blood-brain barrier (BBB) and cause neuroinflammation and neurobehavioral deficits in humans and animals. To date, the precise molecular mechanism...
Deoxynivalenol (DON), a prevalent mycotoxin in grain crops, can cross the blood-brain barrier (BBB) and cause neuroinflammation and neurobehavioral deficits in humans and animals. To date, the precise molecular mechanisms remain incompletely understood. Herein, we showed that DON triggers neurotoxicity by reprogramming microglial glycolysis via activation of the NQO1/NF-κB pathway. Raffinose (Raf), a natural trisaccharide, effectively attenuated DON-induced neuroinflammation in vivo and in vitro. Mechanistically, Raf upregulated NQO1 transcription by selectively binding to Nrf2 at Val-514 and Cys-368, thereby reinforcing the NQO1-IκBα interaction, possibly through NQO1-associated regulatory interfaces. This interaction inhibited NF-κB hyperactivation, suppressed glycolysis, and restored oxidative phosphorylation, thereby attenuating DON-induced pro-inflammatory microglial activation. Furthermore, NQO1 knockdown or Nrf2 knockout weakened the inhibitory effect of Raf on the NF-κB signaling pathway and inflammatory activation state of microglia. In conclusion, our findings revealed that Raf supplementation could efficiently alleviate DON exposure-induced neuroinflammation and neurobehavioral deficits by modulating NQO1/NF-κB-associated metabolic remodeling. These findings suggested that Raf may represent a potential therapeutic strategy against DON-induced neuroinflammation.
Endothelial NPR-C promotes insulin resistance via Caveolin-1-mediated insulin transcytosis.
Xu ZQ, Yu XY, Wei JQ … +8 more , Deng QW, Zhai WH, Rong WW, Li MY, Zhang QR, Gao PJ, Li XD, Wang JG
Metabolism · 2026 Jun · PMID 42379496 · Publisher ↗
Obesity-induced insulin resistance contributes to metabolic dysfunction and type 2 diabetes, yet the endothelial mechanisms involved remain incompletely understood. Here, we identify endothelial natriuretic peptide recep...
Obesity-induced insulin resistance contributes to metabolic dysfunction and type 2 diabetes, yet the endothelial mechanisms involved remain incompletely understood. Here, we identify endothelial natriuretic peptide receptor C (NPRC) as a key regulator of insulin transport and insulin sensitivity. NPR-C expression was increased in endothelial cells from adipose tissue and skeletal muscle of obese mice. Endothelial-specific deletion of NPR-C improved insulin sensitivity, whereas endothelial NPR-C overexpression aggravated insulin resistance, as demonstrated by glucose tolerance, insulin tolerance, and hyperinsulinemic-euglycemic clamp. Mechanistically, NPR-C impaired insulin uptake and transendothelial transport by reducing insulin receptor (IR) membrane localization and altering intracellular trafficking. NPR-C directly interacted with Caveolin-1 and promoted Tyr14 phosphorylation-dependent K48-linked ubiquitination and proteasomal degradation of Caveolin-1, disrupting caveolae function and impairing IR trafficking. Importantly, Cdh5 promoter-driven adeno-associated virus-mediated NPR-C knockdown improved insulin sensitivity in mice with established obesity. Together, these findings identify endothelial NPR-C as a regulator of Caveolin-1 stability and IR trafficking and suggest NPR-C as a potential therapeutic target for obesity-associated insulin resistance.
Macrophage-enriched GPR91 aggravates acute liver injury by inhibiting efferocytosis via the AC/cAMP/PPARγ pathway.
Qiu S, Hu J, Guo K … +8 more , Shao S, Zhang Q, He Y, Zheng L, Shi Z, Zhang K, Hong W, Han T
Metabolism · 2026 Jun · PMID 42336269 · Publisher ↗
OBJECTIVE: Acute liver injury is a common precipitating factor in the progression of various liver diseases including liver failure, underscoring the urgent need to identify novel therapeutic targets. G-protein coupled r...
OBJECTIVE: Acute liver injury is a common precipitating factor in the progression of various liver diseases including liver failure, underscoring the urgent need to identify novel therapeutic targets. G-protein coupled receptors (GPCRs) are widely regarded as promising drug targets, however, the roles of non-chemokine GPCRs in acute liver injury remain poorly defined. In this study, we analyzed three GEO datasets related to acute liver injury and identified Sucnr1, encoding GPR91, as a key regulator. We aimed to reveal the role of GPR91 in acute liver injury and to elucidate the underlying mechanism. METHODS: Sucnr1-knockout (Sucnr1-KO) mice were generated and treated by carbon tetrachloride (CCl) with or without succinate co-administration. The role of GPR91 was investigated in the acute and resolution stages of liver injury at 24 h and 72 h after CCl injection, respectively. Confocal microscopy and flow cytometry were conducted to examine the involvement of GPR91 in regulating macrophage efferocytosis, in vitro. RESULTS: Macrophage-enriched Sucnr1 decreased sharply in the acute phase but recovered gradually in the resolution phase. In contrast, succinate, the endogenous GPR91 ligand, surged acutely and, subsequently, exhibited a gradual decline. In vivo data from multiple models demonstrated that Sucnr1 deficiency significantly alleviated CCl-induced inflammation and injury in the acute stage and promoted injury resolution in the resolution stage, while succinate administration itself had no significant effect. Moreover, in vitro data revealed that Sucnr1-knockout (Sucnr1-KO) macrophages manifested lower expression of pro-inflammatory cytokines and higher ability of efferocytosis, accompanied by higher expression of PPARγ. However, the enhanced efferocytosis in macrophages of Sucnr1-KO mice was decreased by in vitro treatment of GW9662, a specific inhibitor of PPARγ. In addition, adenylate cyclase inhibitor SQ22536 could decrease the over-expression of PPARγ, and the enhanced efferocytosis in Sucnr1-KO macrophages. CONCLUSION: Our work has revealed that macrophage-enriched GPR91 plays a vital role in controlling the inflammation and efferocytosis of macrophage, providing a potential therapeutic target for acute liver injury and liver failure.
Corrigendum to "TMEM41B contributes to atherosclerosis by promoting lipid synthesis in vascular smooth muscle cells via fatty acid synthase stabilization" [Metabolism 175 (2026) 156456].
Peng GY, Wei LT, Jing YX … +6 more , Luo HL, Liu ZL, Wei RC, Ning JJ, Chang GQ, Wang M
Metabolism · 2026 Jun · PMID 42335552 · Publisher ↗
Abstract loading — click title to view on PubMed.
Ghrelin predicts food consumption up to three hours prior to eating: A randomised controlled trial.
Hulme OJ, Martinussen C, Andersen BV … +10 more , Svane MS, Holst JJ, Bojsen-Møller KN, Hartmann B, Rehfeld JF, Gregersen S, Hermansen K, Byrne DV, Siebner HR, Madsbad S
Metabolism · 2026 Jun · PMID 42331140 · Publisher ↗
Eating triggers a cascade of metabolic, neural, and subjective signals that unfold and interact over several hours, typically suppressing the motivation to eat until the next meal. Which of these signals predict next-mea...
Eating triggers a cascade of metabolic, neural, and subjective signals that unfold and interact over several hours, typically suppressing the motivation to eat until the next meal. Which of these signals predict next-meal intake is not well understood. In a cross-over, double-blinded, and repeated measures factorial design over four separate test days, we manipulated both the protein and caloric content of four preload meals to experimentally induce differences in satiety. We investigated how the neural, subjective, hormonal, and metabolite states unfolded after a meal and how much each of them predicted the next meal intake 3 h later. Bayesian analysis revealed an extreme level of evidence for the inclusion of the peptide hormone ghrelin as a predictor of next meal energy intake. This predictive effect was consistently found for all time points, including also the time point immediately preceding preload consumption. When measured immediately before the ad libitum test meal, the plasma level of the gut hormone Glucagon-like Peptide-1 (GLP-1) and the subjective report of estimated consumption also predicted next-meal intake. No other measure, including the protein and caloric content of the preload, adequately predicted next-meal intake. Our results link ghrelin levels with the regulation of food intake several hours later.
A translational model of MASLD-associated HFpEF defines mitochondrial dysfunction and cardiac plasticity during disease progression and regression.
Ganguly S, Gunes B, Gu Y … +10 more , Suarez J, Gupta G, Ishizuka K, Murad R, Kisseleva T, Dillmann W, Peterson K, Adler E, Brenner DA, Dhar D
Metabolism · 2026 Jun · PMID 42331139 · Publisher ↗
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced form, MASH, are closely linked to cardiac dysfunction, particularly heart failure with preserved ejection fraction (HFpEF). Ho...
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced form, MASH, are closely linked to cardiac dysfunction, particularly heart failure with preserved ejection fraction (HFpEF). However, the mechanisms underlying MASLD-associated HFpEF and its reversibility remain poorly understood, largely due to the lack of robust preclinical models. Here, we established a translational model of MASLD-associated cardiac dysfunction that recapitulates the key features of human HFpEF. We applied functional and transcriptomic analyses of the left ventricle (LV) to define the pathways associated with cardiac dysfunction and its reversibility. METHODS: Alms1 (Foz/Foz) mice and wild-type littermates were fed normal chow (NC) or Western diet (WD) for up to 36 weeks (wk). Reversibility was modeled by switching WD-fed Foz/Foz mice at 12wk back to NC for 12wk. Cardiac assessment included echocardiography, invasive hemodynamics with dobutamine stimulation, histopathology, electron microscopy and isolated cardiomyocyte contractility. LV transcriptomes were profiled by bulk RNA sequencing and analyzed by differential expression and pathway enrichment. RESULTS: Foz/Foz mice on WD for 24wk developed metabolic syndrome and MASH with advanced liver fibrosis. Cardiac phenotyping showed LV hypertrophy, impaired cardiomyocyte contractility, reduced β-adrenergic reserve, elevated plasma BNP, and increased mortality while the ejection fraction was preserved (>50%), consistent with HFpEF. The progression of cardiac dysfunction was closely associated with liver fibrosis that developed during MASH. Switching WD-fed Foz/Foz mice at 12wk to normal chow diet reversed hepatic fibrosis, restored LV function, and reduced mortality, demonstrating plasticity of the liver-heart axis. LV transcriptomic analysis revealed that cardiac impairment in these mice was associated with mitochondrial dysfunction, altered substrate utilization, extracellular matrix remodeling, and metabolic stress; pathways that are similarly dysregulated in human HFpEF. Cardiac electron microscopy revealed swollen mitochondria with disrupted cristae, which improved following dietary intervention. CONCLUSIONS: Mitochondrial dysfunction and fibroinflammatory remodeling are prominent features of MASLD-associated cardiac dysfunction. Reversal of hepatic and cardiac phenotypes with dietary intervention, together with elucidation of underlying pathways, establish the Foz/Foz model as a useful translational platform for studying liver-heart axis in MASLD.
SUMOylation of HMGCS1 triggers its ubiquitin-dependent degradation to alleviate hepatic steatosis.
Wang M, Wu X, Wang T … +9 more , Liu W, Ma Z, Zhang Y, Zhang X, Yin G, Yang W, Wu Z, Lyu Y, Wu R
Metabolism · 2026 Jun · PMID 42323980 · Publisher ↗
BACKGROUND & AIMS: Despite recent approvals for noncirrhotic MASH with moderate-to-advanced fibrosis, incomplete response rates and the need for mechanistically distinct, durable, and broadly applicable therapies undersc...
BACKGROUND & AIMS: Despite recent approvals for noncirrhotic MASH with moderate-to-advanced fibrosis, incomplete response rates and the need for mechanistically distinct, durable, and broadly applicable therapies underscore an urgent need for additional drug development across the MASLD spectrum. Although SUMOylation regulates hepatic metabolism, its functional role and therapeutic potential in MASLD remain unclear. We aimed to determine whether modulating global hepatic SUMOylation influences MASLD progression and to identify the underlying molecular mechanisms. METHODS: Hepatic SUMOylation was assessed in human MASLD samples spanning simple steatosis to MASH with fibrosis (F1-F3) and in mice fed either a high-fat diet (HFD) or a methionine-choline-deficient (MCD) diet. SUMOylation was enhanced by overexpressing the E2 enzyme UBC9 or administering the activator N106, and inhibited using TAK-981. Proteomic profiling, co-immunoprecipitation, site-directed mutagenesis, and ubiquitination assays were employed to identify and validate downstream effectors. Genetic gain- and loss-of-function studies in vitro and in vivo were used to establish causal relationships. RESULTS: Hepatic SUMOylation was significantly downregulated in human MASLD and in murine models. Enhancing SUMOylation alleviated hepatic steatosis, whereas inhibiting it exacerbated lipid accumulation. Multi-omics analyses identified 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) as a central effector that is inversely regulated by SUMOylation. SUMOylation promotes HMGCS1 ubiquitination and proteasomal degradation, thereby suppressing cholesterol biosynthesis. We further mapped the SUMO2/3 modification to lysine 305 of HMGCS1, catalyzed by the E3 ligase RANBP2. Critically, the small-molecule activator N106 enhanced this pathway and robustly attenuated steatosis in vivo, an effect abolished by a SUMOylation-deficient HMGCS1 mutant. CONCLUSIONS: Our study establishes global hepatic SUMOylation as a druggable regulatory node in MASLD and delineates a SUMO-ubiquitin pathway centered on HMGCS1. Pharmacological activation of this axis via N106 represents a promising preclinical therapeutic strategy, highlighting the potential of targeting the SUMOylation machinery in metabolic liver disease.
Dynamic regulation of circulating endotrophin by changes in fat mass in humans.
Fernández-Verdejo R, Bu D, Zhang N … +3 more , An Z, Ravussin E, Scherer PE
Metabolism · 2026 Jun · PMID 42320555 · Publisher ↗
BACKGROUND AND AIMS: During long-term weight gain, extracellular matrix remodeling in adipose tissue elevates local and systemic endotrophin, potentially contributing to metabolic dysfunction. Whether short-term increase...
BACKGROUND AND AIMS: During long-term weight gain, extracellular matrix remodeling in adipose tissue elevates local and systemic endotrophin, potentially contributing to metabolic dysfunction. Whether short-term increases or reductions in fat mass modulate circulating endotrophin concentrations in humans remains unclear. We aimed to determine the relationship between short-term changes in fat mass (kg and fat percentage points) and circulating endotrophin levels, and to explore whether endotrophin mediates the effects of adiposity on lipid profiles. METHODS: Secondary analysis of the pooled individual participant data from two clinical trials. One trial randomized 42 healthy adults (52.4% women, 26-49 years) to one of the following six-month interventions: (a) weight maintenance, (b) 25% caloric restriction, (c) 12.5% caloric restriction and 12.5% increased energy expenditure, or (d) very low-calorie diet. The other trial enrolled 31 healthy adults (19.4% women, 20-40 years) and exposed them to an eight-week 40% overfeeding. Fat mass, circulating endotrophin, and circulating lipid profile were measured before and after these interventions. RESULTS: Considering all participants, the changes in fat mass ranged from -11.0 to +7.0 kg or -9.6 to +5.7 percentage points. Changes in fat mass were positively associated with changes in circulating endotrophin (unstandardized B-coefficient [95% CI] = 0.76 [0.45, 1.07] ng/mL/kg and 0.89 [0.51, 1.28] ng/mL/percentage point, P < 0.001). Exploratory mediation analyses showed that endotrophin mediated 15% [4, 51] of the effect of fat mass on total cholesterol. CONCLUSION: Changes in fat mass, including loss and gain, are associated with corresponding changes in circulating endotrophin, which may partially mediate metabolic effects. Future studies should test whether endotrophin represents a therapeutic target for metabolic health in humans.
High-intensity interval training and moderate-intensity continuous training are effective, feasible, and safe for patients with metabolic dysfunction-associated steatotic liver disease (MASLD): A systematic review and meta-analysis.
Wang B, Zeng X, Deng H … +20 more , Qiu B, Xu K, Tao M, Zhang Y, Zheng H, Xu Q, Li S, Zhong Y, Zhang X, Li H, Yan H, Song J, Zhang Z, Liang Z, Sun Q, Wu B, Zhang X, Batrakoulis A, Reljic D, Yin M
Metabolism · 2026 Jun · PMID 42297097 · Publisher ↗
PURPOSE: This meta-analysis evaluated the efficacy and feasibility of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) in patients with metabolic dysfunction-associated steatotic...
PURPOSE: This meta-analysis evaluated the efficacy and feasibility of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and identified key moderators. METHODS: Controlled trials were systematically searched (PubMed, Web of Science, CNKI; initially in Feb 2025 and updated Jan 2026). Random-effects meta-analyses used SMDs; risk of bias, methodological quality, and evidence certainty were systematically assessed. RESULTS: Thirty-seven trials (1546 participants, 51% female, moderate quality) showed HIIT significantly improved 12 outcomes vs. controls, including body composition (g - 0.94 to -0.52), cardiometabolic parameters (-1.56 to 1.34), and liver markers (-1.06 to -0.50), while MICT benefited 18 outcomes, including body composition (-0.84 to -0.60), cardiometabolic parameters (-1.42 to 1.79), and liver markers (-0.72 to -0.67). HIIT was superior for total cholesterol reduction (g - 0.44, p < 0.05). Subgroup analyses identified significant moderation by obesity status, training frequency, exercise modality, and progression. Meta-regression revealed MICT effects moderated by age, BMI, and prescription parameters (e.g., session duration, weekly time, program length), with significant associations for body fat, lipids, and glycemic control changes. Exploratory nonlinear meta-regression showed distinct dose-response patterns for liver enzyme biomarker improved emerging beyond baseline, 260-280 MET-min per MICT session. Feasibility was high (adherence 83.4%, completion 83.9%), and safety was relatively high. CONCLUSION: Both HIIT and MICT effectively improve anthropometric, metabolic parameters, and liver function indicators in patients with MASLD, while demonstrating high feasibility and safety. Moderators' analyses identified key moderators and dose-response, informing evidence-based exercise prescription considerations for MASLD management. REGISTERED: PROSPERO (CRD42025646755).
Cytochrome P450 2E1 deficiency alters hepatic mitochondria and impairs liver organoid formation.
Stayer KM, Killingsworth ZK, Unsal KC … +9 more , Thornton MN, Driggers KR, Mendenhall TT, Tomasevich AA, Delaney JR, Sahin O, Helke KL, Engevik MA, Hartman JH
Metabolism · 2026 Jun · PMID 42297096 · Publisher ↗
BACKGROUND: Cytochrome P450 2E1 (CYP2E1) is a liver-expressed monooxygenase that metabolizes low molecular weight pollutants, drugs, and endogenous substrates such as fatty acids and ketones. Germline Cyp2e1 knockout (KO...
BACKGROUND: Cytochrome P450 2E1 (CYP2E1) is a liver-expressed monooxygenase that metabolizes low molecular weight pollutants, drugs, and endogenous substrates such as fatty acids and ketones. Germline Cyp2e1 knockout (KO) mice were developed in the late 1990s and were initially reported to lack an overt phenotype. Subsequent studies showed that these mice are protected from liver injury caused by ethanol, high-fat diet, and chemical exposures. However, most prior work has focused on males. Here, we examined baseline effects of Cyp2e1 deletion in female and male mice. METHODS & RESULTS: Using Cyp2e1-KO (129/Sv-Cyp2e1/J, KO) and wild-type (WT; 129S1/SvImJ) mice, bulk liver mRNA sequencing revealed marked transcriptional changes in female KO liver compared with WT females, including enrichment of mitochondrial pathways. Follow-up studies confirmed that female KO livers exhibited impaired mitochondrial function and decreased mtDNA copy number relative to WT. These effects were less pronounced in males. To assess functional consequences of these mitochondrial alterations, primary liver cells were isolated and used to generate organoids. Cyp2e1 KO liver organoids showed impaired growth, with male KO organoids exhibiting slower growth and most female KO cells failing to form organoids. Histological analysis further revealed biliary and hepatocellular abnormalities in KO livers that were more prevalent and severe in females. CONCLUSIONS: Complete loss of CYP2E1 has important phenotypic consequences in the liver, including striking female-biased abnormalities at baseline. These findings raise caution for therapeutic strategies aimed at broadly suppressing CYP2E1 activity and highlight the importance of incorporating sex as a biological variable in future studies.
Rethinking hypercortisolism screening in obesity and diabetes: A systematic review and meta-analysis.
Ferrari D, Bonaventura I, Tenuta M … +6 more , Pofi R, Al Awadi F, Jamal HF, Pivonello R, Corona G, Isidori AM
Metabolism · 2026 Jun · PMID 42289244 · Publisher ↗
BACKGROUND AND AIM: The growing burden of obesity and diabetes underscores the need for innovative strategies to identify secondary causes. While hypercortisolism is traditionally considered rare, its broader spectrum -...
BACKGROUND AND AIM: The growing burden of obesity and diabetes underscores the need for innovative strategies to identify secondary causes. While hypercortisolism is traditionally considered rare, its broader spectrum - from mild autonomous cortisol secretion to overt Cushing's syndrome (CS) - may be under-recognized in these populations. METHODS: We systematically searched MEDLINE, Scopus and Web of Science for original studies assessing hypercortisolism in obesity or diabetes. We included first-line screening tests for hypercortisolism, particularly the dexamethasone suppression test (DST), and subsequent confirmed CS. Data were pooled using random-effects models and are presented as 95%CIs. Certainty of evidence was assessed with GRADE. RESULTS: Of 3038 articles, 39 (14,995 screened participants) were included. In a pooled cohort of 8705 individuals with obesity (19 studies), the prevalence of an abnormal DST was 4.6% (95%CI: 3.2-6.4), and CS confirmed in 0.8% [0.4-1.5]. Among 6638 patients with diabetes (22 studies), 14.3% (95%CI: 10.9-18.4) had an abnormal DST, increasing to 23.3% (95%CI: 22.2-24.5) after heterogeneity adjustment; 2.1% (95%CI: 1.3-3.3) had confirmed CS. Age, recent weight gain, and diabetes were significant predictors of CS. One in seven abnormal DST led to CS confirmation. Exploratory economic analyses supported broadening screening in selected cohorts. GRADE certainty ranged from low to moderate. CONCLUSIONS: In a clinically relevant subset of patients with obesity and diabetes, underlying hypercortisolism remains undiagnosed. The implications of abnormal DST without confirmed CS warrant further investigation. Screening strategies for secondary causes of obesity and type 2 diabetes might require reassessment, pending confirmation in unbiased cohorts.
SGLT2 inhibitors and GLP-1 receptor agonists in atrial fibrillation treatment: Clinical evidence and mechanistic insights.
Fan Y, Chen X, Cai X … +5 more , Dong Y, Liu C, Chen Y, Lip GYH, Zhu W
Metabolism · 2026 Jun · PMID 42289243 · Publisher ↗
Atrial fibrillation (AF) is the most common sustained arrhythmia globally. Despite certain progress in drug and interventional treatments, AF still presents high morbidity, high mortality, and unsatisfactory clinical out...
Atrial fibrillation (AF) is the most common sustained arrhythmia globally. Despite certain progress in drug and interventional treatments, AF still presents high morbidity, high mortality, and unsatisfactory clinical outcomes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), initially used to treat type 2 diabetes mellitus (T2DM), have demonstrated cardiorenal protective effects beyond glycemic control and have drawn broad attention for their potential in AF management. This narrative review comprehensively synthesizes clinical evidence and underlying mechanisms regarding the effects of SGLT2i and GLP-1 RA on new-onset AF and post-ablation AF recurrence across common comorbidities, including T2DM, heart failure (HF), chronic kidney disease (CKD) and obesity. Available evidence shows that SGLT2i may be associated with reduced new-onset AF risk in patients with T2DM, HF and CKD, and lower post-ablation AF recurrence in high-risk groups. GLP-1 RA show beneficial effects on AF in individuals with obesity or heart failure with preserved ejection fraction. Their protective effects are mainly mediated by upstream metabolic regulation and direct effects on atrial electrophysiology, as evidenced by cellular, animal, and clinical studies. Notably, most clinical evidence comes from post hoc analyses and observational studies, with AF rarely as a primary endpoint and without systematic measurement, leaving the evidence at a hypothesis-generating stage with limited clinical applicability. Overall, SGLT2i and GLP-1 RA serve as potential adjunctive therapies for AF patients with concomitant cardiometabolic comorbidities. Their AF-related outcomes represent exploratory secondary benefits instead of established therapeutic indications. Further specific randomized controlled trials with prespecified AF endpoint and standardized AF monitoring are needed to verify their clinical efficacy and application prospects.
Corrigendum to "PRR14 mediates mechanotransduction and regulates myofiber identity via MEF2C in skeletal muscle" [Metabolism 164 (2025) 156109].
Yang M, Wang J, Liu Z … +1 more , Li Z
Metabolism · 2026 Jun · PMID 42275887 · Publisher ↗
Abstract loading — click title to view on PubMed.
Benefits and harms of antiresorptive therapy in men with non-metastatic prostate cancer on androgen deprivation therapy: A systematic review and meta-analysis of randomized controlled trials.
Bassatne A, El Meski N, Horanieh R … +6 more , Andary F, Rhayem C, Mukherji D, Akl EA, El-Hajj Fuleihan G, Chakhtoura M
Metabolism · 2026 Jun · PMID 42263846 · Publisher ↗
BACKGROUND: Androgen deprivation therapy (ADT) is used as an adjuvant treatment in men with prostate cancer. It is associated with bone loss and increased fracture risk. In this systematic review and meta-analysis, we ev...
BACKGROUND: Androgen deprivation therapy (ADT) is used as an adjuvant treatment in men with prostate cancer. It is associated with bone loss and increased fracture risk. In this systematic review and meta-analysis, we evaluated the effects of antiresorptives on bone health in men with non-metastatic prostate cancer (nmPCa) on ADT. METHODS: We searched four databases until October 14th 2024 for randomized controlled trials (RCTs) of antiresorptives in men with non-metastatic prostate cancer on ADT. FINDINGS: We included 26 RCTs: Intravenous bisphosphonates (N = 17), oral bisphosphonates (N = 5) or denosumab (N = 2). 2 RCTs included both oral bisphosphonate and denosumab. Oral bisphosphonates had no effect on fracture incidence at 12-months (RR = 0.57; 95%CI[0.10, 3.23]; very low certainty). Intravenous bisphosphonates had no effect on the risk of morphometric vertebral fractures at 36-months (RR = 1.06; 95%CI[0.57,1.98]; very low certainty). One trial showed that denosumab probably results in a large reduction in new morphometric vertebral fracture risk at 12 (RR = 0.15), 24 (RR = 0.31) and 36-months (RR = 0.38; 95%CI[0.19-0.78]). Treatment with bisphosphonates or denosumab for 12-months increased BMD at the hip (+1.5 to +3.9%) and lumbar spine (+4.0 to +6.8%) and decreased BTMs (-26 to -78%). Data on mortality is scarce. The most common adverse events were gastrointestinal across all antiresorptives. Acute phase reactions were common with Intravenous bisphosphonates, while jaw osteonecrosis occurred more rarely. INTERPRETATION: Denosumab decreases morphometric vertebral fractures risk in men with nmPCa receiving ADT. Anti-resorptive treatment had a protective effect on BMD and decreased BTMs. Well-designed powered RCTs are needed to assess their effect on fracture risk.
The effects of acute ketone monoester supplementation on brain insulin responsiveness and cognitive performance: Results of a randomized, double-blind, placebo-controlled crossover trial in older men with overweight.
Nijssen KMR, Adam TC, Mensink RP … +1 more , Joris PJ
Metabolism · 2026 Jun · PMID 42263845 · Publisher ↗
INTRODUCTION: Nutritional ketosis may prevent age-related cognitive decline, but underlying mechanisms remain unclear. This study investigated acute ketone monoester (KME) supplementation on brain insulin responsiveness...
INTRODUCTION: Nutritional ketosis may prevent age-related cognitive decline, but underlying mechanisms remain unclear. This study investigated acute ketone monoester (KME) supplementation on brain insulin responsiveness and cognitive performance in older men with overweight. METHODS: In a randomized, double-blind, placebo-controlled crossover trial, 18 men (age: 70.2 ± 3.5 years, BMI: 27.2 ± 1.5 kg/m) consumed KME (395 mg/kg body weight) or a taste-matched placebo. Brain insulin responsiveness (primary outcome) was assessed using pseudo-continuous arterial spin labeling (pCASL)-MRI by measuring cerebral blood flow (CBF) responses to intranasal insulin. Cognitive performance (CANTAB, secondary outcome), resting CBF, cerebral perfusion, and cardiometabolic risk markers were also assessed. RESULTS: KME was well tolerated and rapidly induced nutritional ketosis (peak β-hydroxybutyrate: 2.9 ± 0.4 mmol/L; P < 0.001). Compared with placebo, KME lowered insulin-induced CBF responses in ten brain clusters (all P ≤ 0.05), including five frontal gyri, three parietal/occipital regions, and two subcortical clusters, a pattern opposite to that typically observed in adults with peripheral insulin resistance. KME modestly improved attention and psychomotor speed (reaction time: -9 ms; 95%CI: -18 to -1; P = 0.029), but did not affect memory or executive function. KME ingestion also lowered resting whole-brain CBF (-4.7 mL/100 g/min; 95%CI: -6.4 to -3.0; P < 0.001) and cerebral perfusion (middle cerebral artery velocity: -5.1 cm/s; 95%CI: -9.6 to -0.7; P = 0.028), and induced changes in cardiometabolic markers, including blood pressure, circulating insulin, and glucose. CONCLUSIONS: Acute nutritional ketosis differentially modulates brain insulin responsiveness, reflected by lower insulin-induced CBF responses in insulin-sensitive brain regions, and is accompanied by modest improvements in attention and psychomotor speed in older men with overweight.
GPR84 blockade in macrophages mitigates sepsis-induced liver injury via PPARα-driven metabolic reprogramming and M2 polarization.
Chen Y, Zhou Y, Guo S … +11 more , Zhang K, Wei J, Zhang P, Zhang Y, Bai Z, Lin H, Shi W, Han F, Chen X, Bi H, Xu Y
Metabolism · 2026 Jun · PMID 42263844 · Publisher ↗
BACKGROUND & AIMS: Sepsis-associated liver injury (SLI) is a severe complication that substantially worsens clinical outcomes and increases mortality in patients with sepsis, yet its molecular drivers remain poorly defin...
BACKGROUND & AIMS: Sepsis-associated liver injury (SLI) is a severe complication that substantially worsens clinical outcomes and increases mortality in patients with sepsis, yet its molecular drivers remain poorly defined. Recent meta-analyses identified GPR84, a G protein-coupled receptor activated by saturated medium-chain fatty acids, as markedly upregulated in sepsis, particularly in patients with acute liver injury. This study investigated the functional role of GPR84 in SLI pathogenesis and the mechanisms through which it contributes to disease progression. APPROACH & RESULTS: In murine models of SLI, single-cell RNA sequencing and immunohistochemistry revealed that Gpr84 expression is enriched in hepatic macrophages. Both genetic knockdown and pharmacological inhibition of Gpr84 significantly reduced acute liver inflammation. In vitro, Gpr84 blockade suppressed macrophage pro-inflammatory responses and promoted a shift from the M1 phenotype toward the anti-inflammatory M2 phenotype. Transcriptomic profiling linked these protective effects to enhanced lipid metabolic pathways and activation of peroxisome proliferator-activated receptor-α (PPARα). Mechanistically, Gpr84 suppression restored Pparα activity by reactivating the cAMP-PKA-CREB signaling axis. PKA-mediated phosphorylation of Pparα at Ser179 and Thr200 was essential for its activation, while CREB directly bound to and upregulated the Pparα promoter. These coordinated mechanisms improved mitochondrial fatty acid oxidation in macrophages and strengthened their anti-inflammatory capacity. In Pparα-deficient mice, the hepatoprotective effects of Gpr84 inhibition were largely abolished, confirming that Pparα activation is required for therapeutic benefit. CONCLUSIONS: This study identifies a previously unrecognized GPR84-PPARα regulatory axis as a central driver of SLI and establishes GPR84 as a compelling therapeutic target for mitigating hepatic inflammation in sepsis.
Acacetin ameliorates MASLD by inhibiting the Notch1 pathway in hepatocytes and reprogramming macrophage polarization via Keap1-Nrf2-mediated restraint of ferroptosis.
Xu J, Ying H, Wang Y … +8 more , Zeng Y, Zhao Q, Yu X, Jiang H, Zhu D, Xia Z, Zhou R, Yu F
Metabolism · 2026 Jun · PMID 42259496 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, with macrophage polarization and ferroptosis playing pivotal roles in its progression. Acacetin has...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, with macrophage polarization and ferroptosis playing pivotal roles in its progression. Acacetin has been reported to exert protective effects against MASLD, but its underlying mechanisms remain unclear. Here, male C57BL/6 J mice fed a high-fat diet (HFD) received acacetin by intraperitoneal injection, and RAW264.7, BMDM, and AML12 cells were used for in vitro assays. In our study, acacetin reduced hepatic lipid accumulation, blunted necroptosis, and suppressed the Notch1 pathway in hepatocytes. It also reprogrammed macrophages from an M1-like to an M2-like phenotype while restraining ferroptosis via the Keap1-Nrf2 pathway. Mechanistically, in hepatocytes, N1ICD overexpression attenuated the lipid-lowering effect of acacetin. USP7 was identified as the deubiquitinase for N1ICD, and N1ICD in turn upregulated USP7 transcription, establishing a positive feedback loop. Acacetin disrupted this loop, promoting N1ICD ubiquitination and proteasomal degradation. In macrophages, the ferroptosis activator erastin partially reversed acacetin-induced anti-inflammatory reprogramming, an effect mediated by mitochondrial injury-driven mtDNA release and consequent activation of the cGAS-STING pathway. The Nrf2 inhibitor ML385 also attenuated acacetin-induced protection against macrophage ferroptosis and its promotion of M2-like polarization. Moreover, acacetin enabled Nrf2 nuclear translocation by competitively binding to Keap1 at Arg483. Collectively, this study clarifies a dual-cell mechanism by which acacetin ameliorates MASLD and yields promising insights into MASLD treatment.
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