Metabolism[JOURNAL]
Sun
200 papers
Folic acid mitigation of alcohol-induced sarcopenia via gut-muscle axis modulation.
Zhang N, Shi J, Zhang H … +8 more , Zhou Z, Liu M, Liang X, Zhou Y, Zhang K, Cui Z, Xue M, Liang H
Metabolism · 2026 May · PMID 41707754 · Publisher ↗
BACKGROUND: Alcohol-related muscle dysfunction is highly prevalent and substantially impairs the quality of life in individuals with alcohol use disorders. Chronic alcohol consumption-induced folic acid (FA) deficiency,...
BACKGROUND: Alcohol-related muscle dysfunction is highly prevalent and substantially impairs the quality of life in individuals with alcohol use disorders. Chronic alcohol consumption-induced folic acid (FA) deficiency, potentially worsening alcohol-related diseases, and has been reported to FA exert protective effects on muscle health. However, the precise mechanisms by which FA may protect skeletal muscle via the gut-muscle axis in alcohol-induced sarcopenia remain insufficiently elucidated. This study aims to investigate whether FA can prevent alcohol-induced sarcopenia and to elucidate the underlying mechanisms of the gut-muscle axis. METHODS: In vivo, eight-week-old male C57BL/6 J mice were given a Lieber-DeCarli alcohol diet for 12 weeks and administered either FA (2.5 or 5 mg/kg) or idebenone (2.5 mg/kg). To further elucidate the role of the gut-muscle axis, we conducted in vivo myostatin (MSTN) manipulation and fecal microbiota transplantation (FMT) experiments. Evaluations included muscle mass and strength, histology, mitochondrial function, markers of oxidative stress and inflammation, gut microbiota, and serum metabolomics. In vitro, C2C12 myoblasts were treated with ethanol or indoxyl sulfate (IS) and then supplemented with FA to assess the mechanism of their action. RESULTS: FA intervention effectively restored muscle mass and strength, reduced homocysteine levels, and improved mitochondrial function (P < 0.05). Mechanistically, FA downregulated MSTN signaling, resulting in decreased protein degradation and increased protein synthesis (P < 0.05). In vivo gain- and loss-of-function experiments, confirming MSTN's critical mediation of FA's protective effects. Concurrently, integrated multi-omic analysis identified that FA rebalanced the gut microbiota-metabolite network, with IS identified as a key gut-derived mediator. FMT from high-dose FA-treated donors replicated the muscle-protective effects, confirming the critical causal role of gut microbiota in FA's therapeutic efficacy. In vitro, FA (40 μM) improved mitochondrial membrane potential and increased the myotube fusion index while suppressing MSTN pathway activation (P < 0.05). CONCLUSIONS: FA significantly attenuated alcoholic sarcopenia by modulating the gut-muscle axis. Specifically, FA corrected the dysregulation of the alcohol-Hcy axis, and enhanced mitochondrial function. Additionally, FA rebalanced to the intestinal microbiota-metabolite network and inhibited MSTN-mediated excessive protein degradation, collectively restoring muscle protein homeostasis.
The early metabolic cardiac targets of empagliflozin during the development of heart failure, independent of SGLT2 inhibition.
Chen S, Hu X, Wang Q … +14 more , Bakker D, van der Made I, Tebbens AM, Guan Y, Lykidou M, van Goor FKJ, Hollmann MW, Weber NC, van Weeghel M, Schomakers BV, Pieper MP, Coronel R, Creemers EE, Zuurbier CJ
Metabolism · 2026 May · PMID 41707753 · Publisher ↗
BACKGROUND & PURPOSE: Cardiac metabolic changes are known early drivers of heart failure (HF). Recent preclinical research showed that protection against HF by sodium glucose transporter 2 inhibitors (SGLT2i) is independ...
BACKGROUND & PURPOSE: Cardiac metabolic changes are known early drivers of heart failure (HF). Recent preclinical research showed that protection against HF by sodium glucose transporter 2 inhibitors (SGLT2i) is independent of SGLT2 inhibition. Here, we unravel the SGLT2-independent metabolic effects of SGLT2i during early HF, to shed light on the early cardiac metabolic mechanisms through which SGLT2i may confer protection against HF. METHODS: Short-term HF was induced through transverse aortic constriction (TAC) and deoxycorticosterone (DOCA) administration in WT and SGLT2 KO mice, in the presence or absence of Empagliflozin (EMPA). Ten days post-surgery, following in vivo echocardiography, hearts were Langendorff-perfused. The SGLT2-independent metabolic effects of EMPA were determined by: 1) performing stable isotope tracer analysis for C-glucose to asses relative glucose contribution to metabolic pathways via fluxomics (C-glucose perfusion), 2) quantifying metabolic intermediates using metabolomics (LC/MS), 3) evaluating metabolic regulators through Western blot analysis, and 4) analyzing gene expression of metabolic pathways via RNA sequencing. RESULTS: Independent of SGLT2 (i.e., being present in both genotypes), TAC/DOCA resulted in in vivo HF (systolic and diastolic dysfunction) that was prevented by EMPA. The early SGLT2-independent cardiac metabolic properties showed: 1) HF hearts used relatively less glucose for energy production through glycolysis and TCA cycle, with more glucose being diverted toward synthesis of glutamine. In contrast, EMPA enhanced glucose labeling of the distal part of glycolysis without affecting relative glucose contribution to acetyl CoA or TCA intermediates, 2) HF led to increased metabolic intermediates (malate, aspartate, 2-hydroxyglutarate) that are known to drive pathology, whereas EMPA reduced pathology-causing metabolic intermediates (malate, glucose-6-P), together with increased lactate release and ATP content, 3) EMPA increased the metabolic regulator SIRT3 and the insulin-sensitive glucose transporter (GLUT4) without affecting AMPK, and 4) HF decreased fatty acid metabolism gene expression, whereas EMPA increased multiple mitochondrial metabolic pathways (TCA cycle, branched-chained amino acid, fatty acid, mitochondrial respiratory chain complexes), possibly through increased ERRα signaling. CONCLUSION: The early, SGLT2-independent, metabolic mechanism marking HF protection by SGLT2i entail 1) decreases in metabolic intermediates that drive hypertrophy (G6P, malate), 2) boosting glycolysis (GLUT4, distal part glycolysis, lactate release) without shifting glucose/fatty acid oxidation ratio, and 3) activating ERRα/SIRT3 pathway associated with increased gene expression of mitochondrial energy pathways and improved cardiac ATP levels.
Mini-review. Vitamin D for the prevention of type 2 diabetes: Evidence and implications.
Amrein K, Kim SH, Brath H … +2 more , Fasching P, Pittas AG
Metabolism · 2026 May · PMID 41707752 · Publisher ↗
Prediabetes is common worldwide and offers a critical opportunity for interventions to prevent type 2 diabetes. Vitamin D has biologically plausible effects on beta cell function, insulin sensitivity, and the immune syst...
Prediabetes is common worldwide and offers a critical opportunity for interventions to prevent type 2 diabetes. Vitamin D has biologically plausible effects on beta cell function, insulin sensitivity, and the immune system, and observational studies consistently associate higher 25-hydroxyvitamin D (25[OH]D) levels with a lower risk of developing diabetes. Three randomized, double-blind, placebo-controlled trials designed specifically for adults with prediabetes tested moderate-to-high doses of vitamin D (Tromsø, D2d) or an active analog (DPVD). Each study showed a modest reduction in progression to type 2 diabetes. An individual participant data meta-analysis of these trials (n = 4190) demonstrated a 15% relative risk reduction, with greater benefit among those with low baseline 25(OH)D levels or a body mass index less than 30 kg/m. Vitamin D supplementation also increased the likelihood of regression to normal glucose regulation. These findings are further supported by multiple aggregate-data meta-analyses showing a consistent benefit of vitamin D supplementation in adults with prediabetes. Compared with intensive lifestyle interventions, metformin, and incretin-based therapies, vitamin D is inexpensive, safe, accessible, and easy to implement, with an estimated number needed to treat of ∼30. The 2024 Endocrine Society Guideline now recommends vitamin D supplementation for adults with prediabetes at doses above the recommended dietary allowance without requiring routine 25(OH)D testing. Achieving and maintaining a blood 25(OH)D level above 40 ng/mL may confer additional benefit, but the hypothesis needs to be tested in clinical trials.
The multifaceted role of GLP-1 in metabolic disorders, chronic inflammation, and aging: Mechanisms and therapeutic potential.
Li M, Xu S, Cai H … +2 more , Xiao J, Qin Y
Metabolism · 2026 May · PMID 41672302 · Publisher ↗
Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells in response to nutrients, regulates glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying,...
Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells in response to nutrients, regulates glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite via hypothalamic signaling. Beyond these canonical actions, emerging evidence reveals GLP-1's pleiotropic functions across multiple systems, with relevance to metabolic disorders, chronic inflammation, and aging-related pathologies. This review summarizes molecular mechanisms underlying GLP-1's protective roles, highlighting its contributions to metabolic balance, inhibition of NF-κB-mediated inflammation, and attenuation of cellular aging through mitochondrial enhancement and autophagy promotion. GLP-1 also influences immune cell function and alleviates hallmarks of senescence, thereby offering therapeutic potential beyond diabetes. We further critically assess the translational potential of GLP-1 receptor agonists (GLP-1RAs), pharmacological agents with superior pharmacokinetics versus native GLP-1, in treating conditions linked to dysregulated metabolism, persistent inflammation, and accelerated aging. Despite demonstrated efficacy in preclinical models and clinical studies, important challenges persist, including inter-individual variability, off-target risks, and uncertainties regarding long-term safety. We conclude by emphasizing the necessity of integrated strategies to target the metabolic-inflammatory-aging axis and by advocating optimization of GLP-1RA formulations, identification of predictive biomarkers, and expansion of their utility for age-associated diseases.
Serum Response Factor (SRF) promotes actin cytoskeletal organization in adipocytes to support adaptive hypertrophic expansion and tissue remodeling during obesity in mice.
So J, Wann J, Kim K … +6 more , Taleb S, Kim HG, Kumari M, Banks AS, Dong XC, Roh HC
Metabolism · 2026 May · PMID 41655957 · Full text
BACKGROUND: Adipocyte hypertrophy, the unique capacity of adipocytes to enlarge in response to energy surplus, is a crucial determinant of metabolic health during obesity. Nonetheless, the molecular mechanisms governing...
BACKGROUND: Adipocyte hypertrophy, the unique capacity of adipocytes to enlarge in response to energy surplus, is a crucial determinant of metabolic health during obesity. Nonetheless, the molecular mechanisms governing this adaptive growth remain incompletely characterized. METHODS: Super-enhancer landscapes in adipocytes were mapped via H3K27ac chromatin immunoprecipitation sequencing analysis of adipocyte nuclei from mice fed either a standard chow diet or high-fat diet (HFD) to identify transcriptional regulators activated under obesogenic conditions. Functional validation was conducted through both in vitro and in vivo experiments, including adipocyte-specific gene deletion mouse models, followed by single-nucleus RNA sequencing. RESULTS: Super-enhancer profiling identified Serum Response Factor (SRF) as a critical driver of actin cytoskeletal remodeling in adipocytes during obesity. SRF was shown to be both necessary and sufficient for regulation of actin cytoskeletal gene expression in 3T3-L1 adipocytes. Adipocyte-specific SRF ablation in mice led to reduced expression of actin cytoskeletal genes, disruption of actin filament organization, and impaired adipocyte enlargement under HFD feeding. Despite comparable body weight, SRF-deficient mice developed exacerbated insulin resistance and ectopic lipid accumulation in the liver and brown adipose tissue, indicative of compromised lipid storage within adipocytes. Single-nucleus RNA-seq further revealed that cell-intrinsic actin cytoskeletal defects in adipocytes propagated to tissue-level dysfunction, impairing vascularization and increasing inflammation. CONCLUSION: These findings establish SRF as a central regulator of actin cytoskeletal organization that promotes healthy adipocyte hypertrophy and adipose tissue remodeling. Enhancing SRF-dependent cytoskeletal remodeling in adipocytes may offer a therapeutic strategy to preserve metabolic health in obesity.
PFKFB3 nuclear translocation improves diabetic retinopathy by attenuating endothelial cell senescence through inhibition of USP7-p53 axis.
Liu P, Shen N, Zhou Y … +12 more , Wu J, Hao M, Zhang S, Wang Y, Wang X, Li H, You Z, Fan H, Xu X, Wang N, Sun D, Wei F
Metabolism · 2026 May · PMID 41655956 · Publisher ↗
BACKGROUND: Endothelial cell (EC) senescence is a key contributor to retinal vascular dysfunction in diabetic retinopathy (DR), yet its molecular mechanisms remain incompletely understood. While PFKFB3 is well recognized...
BACKGROUND: Endothelial cell (EC) senescence is a key contributor to retinal vascular dysfunction in diabetic retinopathy (DR), yet its molecular mechanisms remain incompletely understood. While PFKFB3 is well recognized for its critical function in modulating EC glycolysis and angiogenesis, its contribution to endothelial senescence in DR has not been elucidated. METHODS: Single-cell RNA sequencing was used to profile EC senescence signatures and barrier/tight-junction programs in diabetic retinas. PFKFB3/USP7 abundance and senescence in vivo and in vitro were assessed by Western blotting, SA-β-gal staining, immunofluorescence, and cell-cycle flow cytometry. PFKFB3-USP7 interaction was examined by co-immunoprecipitation, mass spectrometry, and nuclear colocalization. Retinal vascular dysfunction was quantified by Evans blue leakage and PAS-stained retinal trypsin digests. RESULTS: Single-cell analysis identified EC subclusters enriched for senescence transcripts and simultaneously depleted for barrier/tight-junction pathways in diabetic retinas. Hyperglycemia reduced PFKFB3 and impaired its nuclear entry, leading to prominent cellular senescence in vitro and in vivo, and restoration of PFKFB3 effectively reversed this phenotype. By establishing stable endothelial cell lines expressing PFKFB3 only in the nucleus (NLS mutant) or cytoplasm (K472Q mutant), we revealed that anti-senescent activity required PFKFB3 nuclear localization. Nuclear-localized PFKFB3 interacted with USP7, a critical modulator of the p53 pathway, and regulated the USP7-p53 axis by constraining their coupling, thereby promoting proteasomal degradation of p53. As a downstream effector of PFKFB3, USP7 abrogated the protective effect of PFKFB3, whereas its inhibition attenuated hyperglycemia-induced senescence and mitigated retinal vascular dysfunction. CONCLUSIONS: Our findings highlighted the essential role of nuclear PFKFB3 dysfunction and USP7-p53 axis dysregulation in mediating EC senescence under diabetic stress, suggesting that targeting PFKFB3 nuclear translocation may be a novel therapeutic strategy for the prevention of diabetic retinopathy.
A biological-systems-based analysis using proteomic and metabolic network inference reveals mechanistic insights into hepatic steatosis.
Atabaki NN, Coral DE, Pomares-Millan H … +60 more , Smith K, Behjat HH, Koivula RW, Tura A, Miller H, Pinnick KE, Agudelo LZ, Allin KH, Brown AA, Chabanova E, Chmura PJ, Jacobsen UP, Dawed AY, Elders PJM, Fernandez-Tajes JJ, Forgie IM, Haid M, Hansen TH, Jones AG, Kokkola T, Kalamajski S, Mahajan A, McDonald TJ, McEvoy D, Muilwijk M, Tsirigos KD, Vangipurapu J, van Oort S, Vestergaard H, Adamski J, Beulens JW, Brunak S, Dermitzakis ET, Giordano GN, Gupta R, Hansen T, 't Hart LM, Hattersley AT, Hodson L, Laakso M, Loos RJF, Merino J, Ohlsson M, Pedersen O, Ridderstråle M, Ruetten H, Rutters F, Schwenk JM, Tomlinson J, Walker M, Yaghootkar H, Karpe F, McCarthy MI, Thomas EL, Bell JD, Mari A, Pavo I, Pearson ER, Viñuela A, Franks PW
Metabolism · 2026 May · PMID 41655955 · Publisher ↗
OBJECTIVE: To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in...
OBJECTIVE: To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D). METHODS: Bayesian network analyses and complementary two-sample Mendelian randomization were used to quantify causal pathways linking adipose distribution, glycemia, and insulin dynamics with liver fat in the IMI-DIRECT prospective cohort study. Data included frequently sampled metabolic challenge tests, MRI-derived abdominal and hepatic fat content, serological biomarkers, and Olink plasma proteomics from 331 adults with new-onset T2D and 964 adults without diabetes, with harmonized protocols enabling replication. RESULTS: High basal insulin secretion rate (BasalISR), estimated via C-peptide deconvolution, emerged as the primary potential causal driver of liver fat accumulation in both cohorts. BasalISR, a clearance-independent measure of β-cell insulin output distinct from peripheral insulin levels, was independently linked to hepatic steatosis. Visceral adipose tissue exhibited bidirectional associations with liver fat, suggesting a self-reinforcing metabolic loop. Of 446 analyzed proteins, 34 mapped to these metabolic networks (27 in the non-diabetes network, 18 in the T2D network, and 11 shared). Key proteins directly associated with liver fat included GUSB, ALDH1A1, LPL, IGFBP1/2, CTSD, HMOX1, FGF21, AGRP, and ACE2. Sex-stratified analyses identified GUSB in females and LEP in males as the strongest protein predictors of liver fat. CONCLUSIONS: BasalISR may better capture early β-cell-driven disturbances contributing to MASLD. These findings outline a multifactorial, sex- and disease stage-specific proteo-metabolic architecture of hepatic steatosis and identify potential biomarkers or therapeutic targets.
Enduring improvements in hepatic insulin sensitivity predict sustained remission of prediabetes during a 3-year lifestyle intervention: results from the PREVIEW multinational diabetes prevention trial.
Zhu R, Guo J, Huttunen-Lenz M … +13 more , Stratton G, Swindell N, Macdonald IA, Handjieva-Darlenska T, Handjiev S, Navas-Carretero S, Poppitt SD, Silvestre M, Schlicht W, Fogelholm M, Martinez JA, Raben A, Brand-Miller J
Metabolism · 2026 May · PMID 41654010 · Publisher ↗
BACKGROUND: Recent investigation advocates the use of prediabetes remission as a goal of diabetes prevention. We aimed to compare changes in metabolic markers in participants with and without sustained remission of predi...
BACKGROUND: Recent investigation advocates the use of prediabetes remission as a goal of diabetes prevention. We aimed to compare changes in metabolic markers in participants with and without sustained remission of prediabetes during a 3-year lifestyle intervention. METHODS: This post-hoc analysis used data from the PREVIEW trial, a 3-year, multinational, multicenter, randomized controlled trial aiming to examine the effects of lifestyle interventions on prevention of type 2 diabetes among high-risk adults. Adult participants with prediabetes and overweight/obesity underwent 8-weeks of rapid weight loss followed by a 148-week lifestyle intervention for weight loss maintenance. Participants who completed the full protocol and had available data (n = 846) were included in the current analysis. Participants were classified into prediabetes maintainers, relapsers, and non-responders according to blood glucose levels at 1 and 3 years. Changes in metabolic markers over 3 years were compared in those who achieved sustained remission (maintainers, n = 102) vs those who failed (non-responders, n = 618), as well as those who were successful at 1 year but then relapsed (relapsers, n = 126). RESULTS: Only 12% participants experienced sustained remission at 3 years. After adjusting for baseline covariates, compared with non-responders, maintainers achieved greater weight loss (mean difference -4.0 kg; 95% CI -5.8, -2.2 kg) and fat mass loss at 3 years. Maintainers also made further improvements in markers of hepatic insulin sensitivity, regardless of weight change. Compared with relapsers, maintainers had greater decreases in weight and fat mass, but changes in visceral adiposity index were similar. Relapsers gradually reverted to an insulin resistant state at 2 and 3 years compared with maintainers, independent of weight change. CONCLUSIONS: In a long-term lifestyle intervention, sustained remission of prediabetes was associated with enduring improvements in hepatic insulin sensitivity, regardless of weight change. In addition to weight loss, targeting hepatic insulin sensitivity per se may help prevent relapse in prediabetes.
Rising burden of MASLD and CKM syndrome in Asia: A decade of trends and future projections.
Duo T, Wen Y, Bian Y … +7 more , Wang Y, Zhang X, Ju J, Lu Y, Wang Z, Wang J, Yang B
Metabolism · 2026 May · PMID 41643809 · Publisher ↗
OBJECTIVE: To analyze epidemiological trends and project the future burden of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular-kidney-metabolic (CKM) syndrome in Asia using data from th...
OBJECTIVE: To analyze epidemiological trends and project the future burden of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular-kidney-metabolic (CKM) syndrome in Asia using data from the Global Burden of Disease (GBD) Study. This analysis quantifies the substantial co-occurrence of MASLD and CKM syndrome, which together accounted for 50.9% of the total disease prevalence in Asia in 2021, by evaluating incidence, prevalence, deaths, and disability-adjusted life years (DALYs) from 2010 to 2021. METHODS: Data from the GBD 2021 database were used to assess the burden of MASLD and CKM syndrome in Asia. The study analyzed incidence, prevalence, deaths and DALYs for nine metabolic diseases or related conditions: MASLD, atrial fibrillation and flutter (AF/AFL), ischemic heart disease (IHD), hypertension heart disease (HHD), lower extremity peripheral arterial disease (PAD), type 2 diabetes mellitus (T2DM), stroke, and chronic kidney disease (CKD) due to hypertension (HTN) and T2DM. Age-standardized rates (ASRs) and estimated annual percentage changes (EAPCs) were calculated. The autoregressive integrated moving average (ARIMA) model was applied to forecast the trend of MASLD over the next 20 years. This model, widely used in time-series forecasting, identifies trends, cyclical variations, and random fluctuations to provide scientifically grounded projections. RESULTS: In 2021, the collective burden of the nine CKM-related conditions analyzed (including MASLD) accounted for 50.9% of total disease prevalence and 34.4% of all deaths in Asia, with 12.68 million deaths and 306.82 million DALYs. Among the nine metabolic diseases analyzed, MASLD had the highest incidence and prevalence, with MASLD-related liver cirrhosis (MASLD-LC) and MASLD-related steatohepatitis (MASLD-SH) affecting approximately 786.69 million and 786.65 million individuals, respectively. IHD and stroke were the leading causes of death and DALYs. Between 2010 and 2021, the incidence (MASLD-LC/MASLD-SH: +25.4%) and prevalence (MASLD-LC/MASLD-SH: +38.0%) of MASLD increased substantially. T2DM showed the greatest rise in age-standardized incidence rate (EAPC: +1.7%) and age-standardized prevalence rate (EAPC: +2.0%). Geographically, MASLD represented the predominant metabolic burden in most Asian countries, with the exception of Central and South Asia, where IHD prevailed. ARIMA projections suggest that the MASLD burden will continue to grow, with a projected increase in incidence of approximately 34% compared to 1990 levels (MASLD-LC: +34.01%; MASLD-SH: +34.04%), underscoring the need for timely and proactive interventions. CONCLUSION: MASLD and CKM syndrome constitute a major and growing health challenge in Asia. These findings underscore the need for early diagnosis, targeted interventions, and comprehensive public health strategies. Future research should aim to elucidate the mechanisms of disease interactions, enhance diagnostic criteria, and improve data collection to support more accurate burden estimation and inform evidence-based policymaking.
Reply: From liver to vasculature: An integrated view of cardiovascular risk in hepatic steatosis.
Abohashem S, Torpoco Rivera MN, Osborne MT
Metabolism · 2026 Jun · PMID 41621638 · Full text
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From liver to vasculature: An integrated view of cardiovascular risk in hepatic steatosis.
Hu X, Long L
Metabolism · 2026 Jun · PMID 41621637 · Publisher ↗
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Efficacy and safety of sepiapterin versus sapropterin in patients with phenylketonuria: Results from the Phase 3, randomized, crossover, open-label, active-controlled AMPLIPHY trial.
Giżewska M, Inwood A, Tyčová R … +20 more , Vijay S, Fjellbirkeland O, van Spronsen F, Venegas-Moreno EM, Guilder L, Burlina A, Peters H, Potter M, Grošelj U, Chakrapani A, Bélanger-Quintana A, Maillot F, Rutsch F, Arnoux JB, Tchan M, Ingalls K, Zhao Z, Hughes C, Smith N, Muntau AC
Metabolism · 2026 May · PMID 41616812 · Publisher ↗
AIM: AMPLIPHY is the first Phase 3 study comparing sepiapterin versus sapropterin in children and adults with phenylketonuria (PKU). METHODS: AMPLIPHY was an international, Phase 3, two-part, open-label study in particip...
AIM: AMPLIPHY is the first Phase 3 study comparing sepiapterin versus sapropterin in children and adults with phenylketonuria (PKU). METHODS: AMPLIPHY was an international, Phase 3, two-part, open-label study in participants with PKU aged ≥2 years. Participants responsive to sepiapterin (60 mg/kg/day) in Part 1 (≥20% reduction in blood phenylalanine [Phe]) entered Part 2, a crossover treatment period, and were randomized 1:1 to alternative treatment sequences of sepiapterin (60 mg/kg/day, licensed dosage) and sapropterin (20 mg/kg/day, maximum licensed dosage) for 4 weeks each, with a 14-day washout between treatments. The primary endpoint was mean change in blood Phe from baseline to Weeks 3-4 of each treatment period (Part 2). RESULTS: Of 82 participants enrolled, 67 (81.7%) and 62 (75.6%) had reductions in blood Phe ≥20% and ≥30%, respectively, in Part 1. Sixty-two participants were randomized in Part 2 (mean [SD] age, 15.8 [10.8] years). In the primary analysis set (≥30% reduction in blood Phe in Part 1, n = 58), mean (SD) baseline blood Phe before sepiapterin and sapropterin treatment was 725.8 (302.1) and 790.4 (370.0) μmol/L, respectively. Least-squares mean (SE) reduction in blood Phe from baseline was -437.0 (28.0) and -256.6 (28.2) μmol/L, respectively, representing a least-squares mean difference of -180.4 μmol/L (95% CI: -229.5, -131.4; p < 0.0001) and a relative 70% greater reduction with sepiapterin versus sapropterin. Both treatments were well tolerated, with safety profiles consistent with previous reports. CONCLUSIONS: Sepiapterin was superior to the highest approved dose of sapropterin in lowering blood Phe. No new safety signals were observed. The trial was registered in the UK Clinical Study Registry, ISRCTN, on January 29, 2024 (ID number, ISRCTN79102999; https://www.isrctn.com/ISRCTN79102999).
Inter-organ crosstalk in health and cardiovascular-renal-hepatic-metabolic disease: A multidisciplinary perspective.
Jia G, Mantzoros CS, Hill MA
Metabolism · 2026 Jan · PMID 41601324 · Publisher ↗
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HMGCS2 desuccinylation modulates acetoacetate to drive tubule-macrophage inflammatory crosstalk in diabetic kidney disease.
Lin Z, Lv D, Zha H … +7 more , Liu H, Peng R, Yang J, Li W, Liao X, Sun Y, Zhang Z
Metabolism · 2026 Apr · PMID 41580118 · Publisher ↗
Mitochondrial dysfunction in renal tubular epithelial cells (TECs) is a hallmark of diabetic kidney disease (DKD), accompanied by macrophage infiltration, yet how metabolic perturbations in TECs-macrophage driven inflamm...
Mitochondrial dysfunction in renal tubular epithelial cells (TECs) is a hallmark of diabetic kidney disease (DKD), accompanied by macrophage infiltration, yet how metabolic perturbations in TECs-macrophage driven inflammation remains unclear. Here, we identify 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis, as a critical mediator linking tubular mitochondrial stress to macrophage M1 polarization in DKD. In mice subjected to DKD, conditional knockout HMGCS2 in TECs decreases mitochondrial fission of TECs, M1 macrophage infiltration and tubular inflammatory injury. Combining LC-MS/MS and ketone flux detection reveals that desuccinylated HMGCS2 produced more acetoacetate (AcAc) than beta-hydroxybutyrate (β-HB) in TECs of DKD. Mechanistically, Signal Transducer and Activator of Transcription 3 (STAT3) promotes Hmgcs2 transcription and sirtuin 5 (SIRT5) activates HMGCS2 through lysine desuccinylation at K367, which promotes AcAc overload shuttling from TECs to macrophages. AcAc acts as a signaling metabolite to activate the MIF/ERK pathway, driving M1 polarization and amplifying a pro-inflammatory feedback loop of tubular injury. In addition, AAV9-mediated Hmgcs2 silencing therapy improves tubular inflammatory injury and attenuates DKD progression. Taken together, this study unveils a tubule-macrophage metabolic crosstalk axis mediated by HMGCS2-driven AcAc accumulation, which couples mitochondrial stress to immune response in DKD.
Natural polyketide enterocin inhibits ASGR1 to enhance cholesterol efflux and regulate hepatic lipid metabolism.
Liu Y, Pang J, Ma M … +9 more , Xu P, Tang Z, Guo Y, Liu R, Peng X, Lou H, Wang K, Li G, Wang L
Metabolism · 2026 Apr · PMID 41580117 · Publisher ↗
The discovery of novel, targeted cholesterol-lowering agents holds clinical value for cardiovascular disease (CVD) prevention and management. Here, we report the isolation of a naturally occurring polyketide, enterocin,...
The discovery of novel, targeted cholesterol-lowering agents holds clinical value for cardiovascular disease (CVD) prevention and management. Here, we report the isolation of a naturally occurring polyketide, enterocin, from the marine-derived Streptomyces sp. FXY-T25 using a cholesterol-modulating activity-guided assay. Enterocin, with a unique tricyclic caged core skeleton, enhanced cholesterol efflux in Huh-7 and HepG2 liver cells by directly binding to ASGR1 and promoting its proteasomal degradation without transcriptional alteration. This ASGR1 inhibition triggered AMPKα activation and subsequent LXRα-mediated upregulation of cholesterol efflux. The accelerated degradation of ASGR1 was confirmed to be proteasome-dependent, as evidenced by lysosomal or proteasomal inhibitors. In high-fat-diet (HFD)-fed wild-type mice, enterocin significantly reduced visceral and subcutaneous fat, improved serum lipid profiles (decreasing TC, TG, and LDL-C while elevating HDL-C), attenuated hepatic lipid accumulation, and enhanced fecal cholesterol excretion. Consistent with the in vitro findings, enterocin downregulated hepatic ASGR1 protein levels and subsequently activated the AMPKα-LXRα-ABCA1/G1/G5/G8 pathway in mouse liver. In HFD-fed LDLR mice, enterocin exhibited lipid-lowering activity comparable or superior to that of the positive controls atorvastatin and GW3965. Notably, enterocin demonstrated no significant effect on intestinal fat absorption, highlighting its targeted activity in hepatic cholesterol metabolism. These findings establish enterocin as a novel therapeutic candidate that uniquely modulates cholesterol homeostasis, offering potential for the treatment of both hypercholesterolemia and metabolic dysfunction-associated fatty liver disease.
Integrative functional genomics and fine-mapping identify regulatory mechanisms of multivariate obesity GWAS and its cardiometabolic implications.
Wang S, Liu S, Zhang H … +12 more , Sun L, Tan H, Shi Y, Pan L, Geng M, Chen M, Gao B, Wang K, Zhang H, Yue T, Weng J, Zheng X
Metabolism · 2026 Apr · PMID 41570977 · Publisher ↗
BACKGROUND: Obesity is a systemic disorder with heterogeneous fat distribution and complex metabolic complications. Conventional genome-wide association studies (GWAS) typically analyze individual obesity-related traits...
BACKGROUND: Obesity is a systemic disorder with heterogeneous fat distribution and complex metabolic complications. Conventional genome-wide association studies (GWAS) typically analyze individual obesity-related traits separately, limiting the identification of shared genetic architecture and key regulatory mechanisms, particularly those involving non-coding variants. METHODS: We integrated GWAS data for five obesity traits (body mass index, waist circumference, visceral fat, liver fat, and body fat percentage) using genomic structural equation modeling (GSEM) to construct a multivariate phenotype (mvObesity). Functional genomic integration combined adipose chromatin accessibility, enhancer promoter interactions, and expression quantitative trait loci (eQTL) data with transcriptome-wide and proteome-wide (TWAS and PWAS) analyses, fine-mapping, and colocalization. Trait-relevant cell types were identified using single-cell and single-cell polygenic association of GWAS (scPagwas) analyses. RESULTS: Multi-omics integration in adipose tissue identified 799 independent SNPs across 548 loci, including 45 previously unreported signals. Fine-mapping and TWAS defined 150 high-confidence candidate genes enriched for neuronal signaling, synaptic organization, and lipid metabolism pathways. MAGMA-based enrichment further revealed significant overrepresentation in brain regions such as the cerebellum, hippocampus, and hypothalamus, indicating central regulatory involvement. Single-cell analyses highlighted adipocytes, preadipocytes, and smooth muscle cells as major genetically influenced types, while cross-tissue TWAS and scRNA-seq supported coordinated neuro-metabolic transcriptional regulation. Multi-omic prioritization identified key genes such as MED13L, GBE1, CADM2, PIK3R3, ERBB4, and PTK2B and demonstrated significant genome-wide and local genetic overlap between mvObesity and cardiometabolic traits. CONCLUSIONS: This multivariate, multi-omics framework delineates a cross-tissue neuro-adipose regulatory axis underlying obesity, providing mechanistic insight and a genetically informed candidate framework for future precision metabolic intervention research.
Emerging incretin- and multi-agonist-based treatments - the continued refinement and continuous expansion of a potent therapeutic armamentarium for cardio-kidney-liver-metabolic diseases and beyond.
Muzurović E, Katsiki N, Volčanšek Š … +3 more , Plescia F, Rizzo M, Mantzoros CS
Metabolism · 2026 Apr · PMID 41564595 · Publisher ↗
While the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) has achieved a central position in our therapeutic armamentarium, new and innovative incretin- and multi-agonist-based treatment strategies hold fu...
While the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) has achieved a central position in our therapeutic armamentarium, new and innovative incretin- and multi-agonist-based treatment strategies hold further promise as potential game-changers for obesity and cardio-kidney-liver-metabolic diseases. Molecular pathways of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), amylin, glucagon and peptide YY have been consistently involved in improved outcomes associated with obesity and related disorders. Single, dual, and even triple drug combinations are being researched throughout all phases of clinical trials. The similarities in GLP-1, GIP, and glucagon peptide sequences enable the development of unimolecular multi-receptor activating agonists and/or antagonists. Furthermore, subcutaneously administered peptides are being supplemented with oral analogs currently in development. Both well-designed clinical trials and real-world evidence are fuelling the development of incretin and multi-agonist-based therapies, thereby holding the promise to deliver an increasing double-digit percent weight loss in addition to addressing many obesity-related comorbidities and complications. It is increasingly evident that early initiation of incretin-based therapy across a broad spectrum of cardio-kidney-metabolic disorders improves body weight, dysglycemia, and cardiovascular risk factor management and consequently is expected to reduce cardio-kidney-liver-metabolic and vascular morbidity and mortality and soon most probably those from obesity-related malignancies, Alzheimer's, and other neurocognitive diseases. This review explores new incretin- and multi-agonist-based therapies undergoing clinical trials for chronic weight management, type 2 diabetes mellitus with its complications, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease and obstructive sleep apnea; it also highlights areas of uncertainty regarding the potency, safety, tolerability, and sustainability of incretin-based approaches for obesity and cardio-kidney-liver-metabolic disorders and finally, we discuss future directions.
Multi-omics profiling reveals CKM syndrome severity as a gradient risk factor for cancer: A prospective cohort study.
Huang Y, Zhang Y, Zhang Y … +6 more , Ye Z, Yang S, Gan X, Wu Y, Zhang Y, Qin X
Metabolism · 2026 Apr · PMID 41544799 · Publisher ↗
OBJECTIVE: Cardiovascular-Kidney-Metabolic (CKM) syndrome, a multisystem disorder, has been linked to cardiovascular and metabolic morbidity, but its association with cancer risk remains poorly characterized. This study...
OBJECTIVE: Cardiovascular-Kidney-Metabolic (CKM) syndrome, a multisystem disorder, has been linked to cardiovascular and metabolic morbidity, but its association with cancer risk remains poorly characterized. This study aimed to examine the relationship between CKM syndrome severity and the incidence of overall cancer and 18 site-specific cancers, and to identify potential mediating plasma protein and metabolite signatures. METHODS: We analyzed data from 351,239 participants in the UK Biobank, classified into five CKM syndrome stages (0-4). Plasma proteomic (2923 proteins) and metabolomic (168 metabolites) profiles were analyzed. Cox models evaluated associations, and mediation analyses identified biological mediators. RESULTS: Over a median 13.5-year follow-up, 44,840 incident cancer cases were documented. Advancing CKM stages (0-3) showed a dose-response relationship with increased overall (per one-stage increase: adjusted HR, 1.05; 95%CI, 1.03-1.07) and eleven site-specific cancer risks (e.g., digestive, respiratory, urinary tracts) (per one-stage increase: adjusted HR ranging from 1.06 to 1.46). Stage 4 remained associated with elevated risk, though attenuated versus stage 3. Multi-omics mediation analysis identified 22 proteins and 2 metabolites that partially mediated the association between CKM stages 0-3 and overall cancer risk, implicating immune and metabolic pathways. Functional enrichment analysis further highlighted the PI3K-Akt signaling pathway and inflammatory processes as key mechanistic contributors. CONCLUSIONS: CKM syndrome severity is independently associated with increased cancer risk, partially mediated by proteins and metabolites involved in inflammation, proliferation, and lipid metabolism. These findings support CKM staging as a multisystem disorder with significant oncological implications and highlight potential biomarkers for intervention.
Personalizing bariatric metabolic surgery: Predictors of weight-loss success and risk of weight recurrence.
Panunzi S, Russo S, Pompa M … +17 more , De Gaetano A, Verrastro O, Tuccinardi D, Guidone C, Gissey LC, Casella G, Casella Mariolo JR, Angelini G, Pattou F, Sabatini S, Gastaldelli A, Franks PW, Al Ozairi E, Sparso T, Bornstein S, Le Roux CW, Mingrone G
Metabolism · 2026 Apr · PMID 41539472 · Publisher ↗
BACKGROUND: Bariatric metabolic surgery (Roux-en-Y gastric bypass [RYGB] and sleeve gastrectomy [SG]) effectively treats obesity and type 2 diabetes; however, weight loss varies, necessitating predictive factors. METHODS...
BACKGROUND: Bariatric metabolic surgery (Roux-en-Y gastric bypass [RYGB] and sleeve gastrectomy [SG]) effectively treats obesity and type 2 diabetes; however, weight loss varies, necessitating predictive factors. METHODS: We analysed 12- and 24-month weight loss data from 811 patients (RYGB or SG). Factor Analysis of Mixed Data and neural network (NN) modelling identified distinct patient phenotypes and predicted weight-loss patterns. A comparative analysis evaluated weight loss and recurrence between the two procedures. FINDINGS: RYGB showed significantly greater weight loss than SG at both 12 (30.3% vs. 25.4%; p < 0.001) and 24 months (26.3% vs. 21.4%; p < 0.001). SG revealed greater variability with bimodal weight loss distributions. Unsupervised clustering of SG patients highligheted three phenotypes: the highest responders were women with favourable metabolic profiles; the lowest responders were mostly men with insulin resistance and diabetes. A NN achieved an overall accuracy of 72.5% in predicting 12-month weight loss from baseline characteristics. In RYGB, clustering was less distinct, though baseline metabolic health influenced weight trajectories. A NN predicted weight recurrence versus sustained loss with 74% accuracy. Poor outcomes were associated with higher baseline glucose, insulin resistance, and dyslipidemia; younger age and absence of diabetes predicted better responses. RYGB was superior to SG, even for metabolic high-risk individuals. INTERPRETATION: Baseline metabolic health predicts weight-loss outcomes and recurrence risk. RYGB offered greater and more consistent mid-term weight loss, especially benefiting metabolically high-risk patients. Procedure choice must be individualized accounting for specific risk profile and potential complications. These results advocate for a precision-medicine approach in bariatric procedure selection.
Bone inflammation in postmenopausal women with type 2 diabetes or obesity in relation to Wnt signaling and bone strength.
Leanza G, Faraj M, Cannata F … +14 more , Viola V, Pellegrini N, Tramontana F, Pedone C, Vadalà G, Piccoli A, Strollo R, Zalfa F, Nevi L, Carotti S, Civitelli R, Maccarrone M, Papalia R, Napoli N
Metabolism · 2026 Apr · PMID 41519225 · Publisher ↗
BACKGROUND AND AIM: Type 2 diabetes (T2D) and obesity (OB) are associated with chronic inflammation and increased fracture risk. We aimed to study the impact of inflammation and Wnt pathway regulation on bone health in s...
BACKGROUND AND AIM: Type 2 diabetes (T2D) and obesity (OB) are associated with chronic inflammation and increased fracture risk. We aimed to study the impact of inflammation and Wnt pathway regulation on bone health in subjects with T2D or OB. METHODS: This study involved 63 postmenopausal women (aged ≥65 years) undergoing hip arthroplasty, including 19 with T2D, 17 with OB, and 27 controls (CTRL). We assessed body composition using dual-energy X-ray absorptiometry (DXA), bone microarchitecture with microcomputed tomography (μCT), and bone strength through compression tests. Bone tissue was collected for gene and protein expression analysis, and serum samples were obtained for cytokine measurement. RESULTS: Bone gene expression analysis revealed increased tumor necrosis factor-alpha (TNF-α; p < 0.0001) and reduced adiponectin (ADIPOQ; p = 0.0041) in T2D. Secreted frizzled-related protein 5 (SFRP5) was elevated in both T2D (p < 0.0001), whereas the OB group showed only a trend toward higher expression (p = 0.060) after BMI adjustment. Interleukin-10 (IL10) was reduced in both T2D (p = 0.0005), while in the OB group IL10 was not reduced after BMI adjustment. Importantly, the Wnt inhibitor sclerostin (SOST) was elevated in both T2D and OB subjects (p < 0.0001), while wingless-type family member 10B (WNT10B) and lymphoid enhancer-binding factor 1 (LEF1) were reduced in both T2D (WNT10B: p = 0.0070, LEF1: p < 0.0001) and OB (WNT10B: p = 0.0078, LEF1: p = 0.0199), even after BMI adjustment. Protein expression analysis by immunohistochemistry confirmed reduced non-phosphorylated (active) β-catenin in bone tissue of both T2D and OB subjects. Moreover, key inflammatory markers were associated with alterations in Wnt pathway-related genes. Consistently, serum cytokine analysis showed increased inflammation, with higher TNF-α (p = 0.0084) and lower ADIPOQ (p = 0.0402) levels in T2D, and higher interleukin-6 (IL-6; p = 0.0003) in OB compared to CTRL. Finally, serum TNF-α (r = -0.3557, p = 0.0112) and IL-6 (r = -0.3881, p = 0.0194) levels negatively correlated with bone strength. CONCLUSIONS: In conclusion, our results suggest that T2D is associated with increased bone inflammation, and Wnt signaling is downregulated in both T2D and obesity. These observations lay the groundwork for future mechanistic studies on bone fragility in metabolic diseases.
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