Nutrition & 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.
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).
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.
Hepatic TGFβ1 signaling impairs insulin sensitivity via inducing insulin receptor substrate 1 degradation.
Ai W, Pan Q, Shen Z … +4 more , Yang W, Jiang W, Song J, Guo S
Metabolism · 2026 May · PMID 42214482 · Publisher ↗
AIMS/HYPOTHESIS: Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes (T2D), yet the underlying mechanisms remain incompletely defined. We hypothesized that elevated transforming growth...
AIMS/HYPOTHESIS: Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes (T2D), yet the underlying mechanisms remain incompletely defined. We hypothesized that elevated transforming growth factor beta 1 (TGFβ1) level is associated with impaired insulin sensitivity. METHODS: Using primary hepatocytes, and mouse models with hepatic TGFβ1 overexpression or hepatic TGFβ1 signaling disruption, we examined the impact of TGFβ1 signaling on hepatic insulin signaling and glucose metabolism. We performed bulk RNA sequencing of liver samples identify potential mediator of obesity-induced insulin resistance. Immunoprecipitation, in vitro kinase assay, and mass-spec assay were used to explore the mechanisms underlying TGFβ1-induced insulin receptor substrate (IRS1) degradation. We further evaluated the therapeutic potential of targeting TGFβ1 signaling to improve glycemic control using the TGFβ1 signaling inhibitor LY2157299. RESULTS: Prolonged TGFβ1 exposure markedly reduced IRS1 protein abundance and impaired insulin-stimulated Akt activation in hepatocytes. Hepatic TGFβ1 overexpression exacerbated insulin resistance, whereas hepatic TGFβ1 signaling disruption improved insulin sensitivity by increasing IRS1 protein abundance. Mechanistically, TGFβ1 signaling increased Cullin 7 (CUL7) expression and promoted IRS1 phosphorylation at serine 685, leading to ubiquitin-dependent IRS1 degradation. Pharmacological inhibition of TGFβ1 signaling by LY2157299 improved insulin sensitivity in both lean and diabetic db/db mice. CONCLUSIONS/INTERPRETATION: These findings identify TGFβ1 as a key driver of hepatic insulin resistance by promoting CUL7-dependent IRS1 degradation, establishing a mechanistic link between obesity-associated cytokine signaling and impaired insulin action and highlighting the TGFβ1-CUL7-IRS1 axis as a potential therapeutic target for T2D.
Obesity and biological aging across the life course: A geroscience framework for metabolic health.
Correa-Burrows P, Burrows R, Kennedy BK … +1 more , Gonzalez-Billault C
Metabolism · 2026 Aug · PMID 42144183 · Publisher ↗
In this narrative translational review, we propose that obesity and aging are not merely parallel epidemics, but biologically convergent processes with shared metabolic and molecular substrates. We introduce the Obesity-...
In this narrative translational review, we propose that obesity and aging are not merely parallel epidemics, but biologically convergent processes with shared metabolic and molecular substrates. We introduce the Obesity-Accelerated Aging (ObAGE) framework, arguing that excess adiposity functions as a clinically relevant accelerator of biological aging trajectories. Because much of the supporting human evidence is observational, we use acceleration to indicate earlier appearance or increases in aging-related biological signatures and clinical phenotypes, while recognizing that causal strength varies across aging pathways and study designs. By prematurely engaging core aging hallmarks, including dysregulated nutrient sensing, chronic low-grade inflammation, cellular senescence, and epigenetic drift, obesity may intensify aging-related decline without replacing the underlying aging process, progressively eroding physiological resilience before overt cardiometabolic disease becomes clinically manifest. This convergence helps explain why obesity does not simply increase risk for isolated non-communicable diseases but is associated with earlier multimorbidity and functional impairment. Importantly, this biological embedding begins during sensitive life-course windows. Yet, converging evidence from human studies (from lifestyle interventions to incretin-based pharmacotherapy) suggests that several aging-related signatures remain at least partially modifiable through metabolic optimization. Framing obesity within a geroscience paradigm positions metabolic treatment not only as disease management but also as a strategy to preserve physiological capacity and delay aging-related decline.
Postprandial glucose profiles may reflect heterogeneity in insulin secretion and sensitivity in type 2 diabetes.
Giosuè A, Skantze V, Testa R … +8 more , D'Abbronzo G, Costabile G, Vitale M, Corrado A, Jirstrand M, Landberg R, Riccardi G, Bozzetto L
Metabolism · 2026 Aug · PMID 42082049 · Publisher ↗
BACKGROUND: Continuous glucose monitoring (CGM) reveals heterogeneity of postprandial glucose responses (PPGR), a key target for optimizing glycemic control in type 2 diabetes (T2D). We analyzed PPGR patterns to identify...
BACKGROUND: Continuous glucose monitoring (CGM) reveals heterogeneity of postprandial glucose responses (PPGR), a key target for optimizing glycemic control in type 2 diabetes (T2D). We analyzed PPGR patterns to identify subtypes reflecting pathophysiological differences. METHODS: Cross-sectional CGM data from 100 individuals with T2D were collected over 4 h following a standardized meal consumed twice. Dynamic PPGR features-glucose peak, incremental area under the curve (iAUC), rise and fall rates, final vs. fasting glucose-were used for K-Means clustering, with stability assessed using a Random Forest classifier trained on the first meal. In 50 participants, postprandial plasma glucose and insulin were measured, and clinical/metabolic parameters compared across clusters using one-way ANOVA. RESULTS: Three CGM-defined PPGR clusters were identified. Cluster 1 (n = 19) showed the highest peak and iAUC, with post-meal glucose remaining persistently above baseline. Cluster 2 (n = 56) and 3 (n = 25) had lower peaks and iAUCs, but Cluster 3 exhibited higher rise and fall rates than Cluster 2. Clusters did not differ in age, sex, BMI, or diabetes duration, but metformin use was lower in Cluster 3. Cluster 1 showed significantly lower insulin secretion (HOMA2-B%: 77.42 ± 25.64 vs. 104.96 ± 43.94) and higher insulin resistance (HOMA-IR: 7.94 ± 3.27 vs. 4.84 ± 2.78) than Cluster 3, with intermediate values for Cluster 2, confirmed by postprandial indices. Cluster 3 had a higher early insulin response than Cluster 1 and 2 (60-min insulinogenic index: 1.67 ± 1.07, 0.84 ± 0.31, 0.84 ± 0.58, respectively; p < 0.05). CONCLUSIONS: CGM-derived PPGR features could identify T2D subtypes with similar clinical profiles but distinct insulin secretion and sensitivity impairments, supporting targeted interventions.
Metabolomics profiles of type 2 diabetes and insulin resistance and their associations with total mortality.
García-Gavilán JF, Paz-Graniel I, Pérez-Acosta JA … +20 more , Ruiz-Canela M, Li J, Clish C, Razquin C, Yun H, Corella D, Estruch R, Ros E, Fitó M, Wang F, Fiol M, Lapetra J, Gómez-Gracia E, Liang L, Denis C, Babio N, Guasch-Ferré M, Martínez-González MÁ, Hu FB, Salas-Salvadó J
Metabolism · 2026 Jun · PMID 41881293 · Publisher ↗
OBJECTIVE: This study aimed to identify metabolomic profiles associated with type 2 diabetes and insulin resistance (HOMA-IR) and relate them to the risk of total mortality. METHODS: A longitudinal study was conducted in...
OBJECTIVE: This study aimed to identify metabolomic profiles associated with type 2 diabetes and insulin resistance (HOMA-IR) and relate them to the risk of total mortality. METHODS: A longitudinal study was conducted in a subset of participants from a diabetes case-cohort study (mean age, 66.5 years; 62% women; 176/699 with incident T2D) within the PREDIMED trial. Plasma metabolites were analyzed using LC-MS/MS methods at baseline (discovery sample) and 1-year follow-up (validation sample). Multi-metabolite profile scores for type 2 diabetes and HOMA-IR, respectively, were derived using elastic net regression. Cox proportional hazards were fitted to assess the association between metabolomic profiles and total mortality, adjusting for potential confounders. External validation was performed in the NHS/HPFS cohorts. RESULTS: A total of 31 metabolites were associated with type 2 diabetes and 105 with HOMA-IR. Both metabolomic profiles were significantly associated with a higher risk of total mortality (type 2 diabetes HR = 1.52, 95%CI: 1.04-2.25; HOMA-IR HR = 1.33, 95%CI: 1.00-1.75) in the PREDIMED cohort. Shared metabolites between both metabolomic signatures, including glycine, SDMA, DMGV, and phosphocreatine, were associated with mortality. These associations were replicated in a pooled analysis of three independent American cohorts (type 2 diabetes HR = 1.09, 95%CI: 1.05-1.13; HOMA-IR HR = 1.04, 95%CI: 1.00-1.09). CONCLUSIONS: In an older population at high cardiometabolic risk, metabolomic scores of type 2 diabetes and insulin resistance were associated with total mortality risk, potentially explaining some mechanisms behind the increased risk of mortality observed in epidemiological studies for individuals with glycemic dysregulations.
Cardiovascular health factors and altered proteomic landscapes in the progression of cardiovascular-kidney-metabolic syndrome: Evidence from multi-cohorts in China, the UK, and the US.
Xue E, Zhao J, Chen B … +5 more , Ye J, Wu J, Shao J, Li X, Ye Z
Metabolism · 2026 Jun · PMID 41866064 · Publisher ↗
BACKGROUND: The role of cardiovascular health (CVH) factors and their associated proteomic profiles in the progression and prognosis of cardiovascular-kidney-metabolic (CKM) syndrome among individuals at stages 0-3 remai...
BACKGROUND: The role of cardiovascular health (CVH) factors and their associated proteomic profiles in the progression and prognosis of cardiovascular-kidney-metabolic (CKM) syndrome among individuals at stages 0-3 remains unclear. METHODS: This study analyzed data from 10,351 Chinese adults (China Health and Retirement Longitudinal Study [CHARLS]), 224,352 British adults (UK Biobank [UKB]), and 20,726 American adults (National Health and Nutrition Examination Survey [NHANES]). Cox proportional hazards models were used to assess the associations of CVH score and proteomic panel with incident CVD and mortality in CKM stages 0-3 individuals. RESULTS: The median follow-up periods were 13.6 years in UKB, 9.4 years in CHARLS, and 7.5 years in NHANES. Among individuals with CKM stages 0-3, those with optimal CVH had reduced risks of overall CVD compared with those with low CVH (UKB, HR = 0.58, 95% CI: 0.55-0.62; CHARLS, HR = 0.77, 95% CI: 0.64-0.92), and all-cause mortality (UKB, HR = 0.45, 95% CI: 0.42-0.49; CHARLS, HR = 0.60, 95% CI: 0.47-0.76; NHANES, HR = 0.34, 95% CI: 0.26-0.44). These protective associations were similarly observed across CVD subtypes and cause-specific mortality. An ENM-selected panel of 722 proteins was associated with 41% lower overall CVD risk and 54% lower all-cause mortality. Meanwhile, circulating proteins mediated the associations between CVH score and CKM syndrome progression and prognosis, particularly ALPP. CONCLUSIONS: Optimal cardiovascular health behaviors and factors are key to halting the progression and improving the prognosis of CKM syndrome, with the associated proteins potentially serving as biomarkers and molecular targets for interventions.
Adipose tissue catecholamine resistance: a metabolic safeguard that challenges weight control.
Della Guardia L, Shin AC
Metabolism · 2026 Jun · PMID 41833661 · Publisher ↗
Catecholamine resistance in adipose tissue encompasses an articulated network of cellular and molecular adaptations to inflammatory and neuroendocrine signals in obesity. By dampening adrenergic signaling, these adaptati...
Catecholamine resistance in adipose tissue encompasses an articulated network of cellular and molecular adaptations to inflammatory and neuroendocrine signals in obesity. By dampening adrenergic signaling, these adaptations may serve a protective role, shielding tissues from excessive catecholamine stimulation and the metabolic stress induced by inflammatory signals. However, reduced adrenergic responsiveness also constrains lipolysis and thermogenesis in adipose tissue, limiting the ability to mobilize fat during caloric restriction or increased energy demand. Thus, while initially adaptive, catecholamine resistance under conditions of nutrient excess may reinforce energy storage and promote weight persistence in obesity. In this work, we examine the neuro-endocrine framework underlying catecholamine resistance in adipose tissue, with the aim of elucidating its implications for metabolic homeostasis and body weight regulation in obesity.
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.
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).
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.
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.
Consensus statement on vitamin D role in metabolic health.
Giustina A, di Filippo L, Aleksova A … +18 more , Bollerslev J, Colao AM, Dawson-Hughes B, Donini LM, Ebeling PR, Lazaretti-Castro M, Lorusso R, Luzi L, Marcocci C, Minisola S, Napoli N, Pittas AG, Rizzoli R, Rovere Querini P, Santini F, Schafer AL, Virtanen JK, Bilezikian JP
Metabolism · 2026 Mar · PMID 41435994 · Publisher ↗
The 8th International Conference Controversies in Vitamin D, held in September 2024, convened leading experts to address the multifaceted role of vitamin D in human health. Key discussions focused on its influence on met...
The 8th International Conference Controversies in Vitamin D, held in September 2024, convened leading experts to address the multifaceted role of vitamin D in human health. Key discussions focused on its influence on metabolic health, including effects on sarcopenia, muscle function, and energy metabolism, as well as its role in obesity, cardiovascular health, and diabetes. Preclinical evidence was presented, suggesting a pivotal role of vitamin D in regulating muscle function and repair, potentially preventing sarcopenia. A relationship between low vitamin D (25[OH]D) concentrations and increased risk of cardiovascular diseases and diabetes was supported by several preclinical and clinical studies. Vitamin D supplementation was recently demonstrated to help improve glycemia and reduce the progression to diabetes and increase the likelihood of regression to normal glucose regulation in adults with prediabetes. Despite mixed outcomes from large, population-based randomized clinical trials, the conference underscored the critical need for personalized research, through disease-specific clinical trials, to fully elucidate the therapeutic potential of vitamin D supplementation, particularly in chronic conditions such as cardiovascular diseases and diabetes. In conclusion, while vitamin D demonstrates considerable promise in modifying a wide array of metabolic health concerns, rigorous scientific inquiry is essential to deepen our understanding of its mechanisms as well as potential protective effects and establish evidence-based guidelines for supplementation. This growing body of work has the potential to significantly enhance clinical outcomes and improve public health strategies, calling for continued exploration and collaboration in the field of vitamin D research.
Meteorin-like protein inhibits vascular smooth muscle cell-derived foam cell formation and atherosclerosis via KIT- endoplasmic reticulum stress signaling.
Chen X, Jiang X, Hou S … +12 more , Lai F, Hu K, Li J, Yang T, Shen X, Chen H, Chen S, Guo X, Zheng Y, Xu T, Su G, Huang R
Metabolism · 2026 Mar · PMID 41325882 · Publisher ↗
OBJECTIVE: Vascular smooth muscle cell (VSMC)-derived foam cell formation is a major contributor to atherosclerosis progression and plaque instability. Meteorin-like protein (METRNL), a secreted organokine with known met...
OBJECTIVE: Vascular smooth muscle cell (VSMC)-derived foam cell formation is a major contributor to atherosclerosis progression and plaque instability. Meteorin-like protein (METRNL), a secreted organokine with known metabolic and anti-inflammatory effects, has been linked to cardiovascular protection, but its role in atherosclerosis is not well defined. This study investigated the function of METRNL in VSMC-derived foam cell formation and atherosclerosis and explored the underlying signaling mechanisms. METHODS: ApoE mice were used to investigate the role of METRNL in atherosclerosis. VSMC-derived foam cell formation was evaluated in human VSMC treated with oxidized LDL with or without METRNL supplementation. RESULTS: METRNL levels declined during atherosclerosis progression and were restored during regression. METRNL selectively inhibited foam cell formation in VSMCs-but not in macrophages-by downregulating CD36-mediated cholesterol uptake and suppressing endoplasmic reticulum stress through KIT signaling. Deletion of KIT specifically in smooth muscle cells abolished these protective effects. The transcription factor SP1 was found to bind directly to the METRNL promoter and enhance its expression. Clinically, lower serum METRNL levels were independently associated with increased risk and severity of acute coronary syndrome. CONCLUSION: METRNL protects against VSMC foam cell formation and atherosclerosis by enhancing KIT signaling, thereby reducing ER stress and subsequent cholesterol uptake. These findings position METRNL as a potential therapeutic target and biomarker for atherosclerotic cardiovascular disease.
Induction of Yin Yang 1 (YY1) overexpression in mature adipocytes promotes dysfunctional adipose tissue and systemic insulin resistance in mice.
Pedersen L, Gliniak CM, Dale TM … +8 more , Zhu Q, Li C, Funcke JB, Crewe C, Luo J, Palluth L, Zhu Y, Scherer PE
Metabolism · 2026 Feb · PMID 41265559 · Full text
The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been...
The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced weight gain, systemic insulin resistance, and increased liver steatosis in comparison to control littermates. In contrast, brown adipose tissue-specific YY1 overexpression has little effect on mice fed a high-fat diet. In an obesogenic environment, acute ectopic adiponectin promoter-driven YY1 expression promotes weight loss, cell death, and adipose tissue inflammation. Underlying the observed reduction in adipose tissue mass, we find that YY1 controls gene networks related to adipose tissue expansion, lipid anabolic pathways (hypertrophy), and hyperplasia (adipogenesis). Taken together, our results demonstrate novel roles of Yy1 in white adipose tissue. This versatile transcription factor regulates central aspects of white adipose tissue biology that are essential for maintaining whole-body physiology.
Lysine potentiates insulin secretion via AASS-dependent catabolism and regulation of GABA content and signaling.
Muñoz F, Gao Q, Mattanovich M … +8 more , Trost K, Hodek O, Lindqvist A, Wierup N, Fex M, Moritz T, Mulder H, Cataldo LR
Metabolism · 2026 Jan · PMID 41167553 · Publisher ↗
Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane de...
Lysine is an essential amino acid with insulinotropic effects in humans. In vitro, it enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines and rodent islets. While lysine is thought to act via membrane depolarization similar to arginine, the role of its intracellular metabolism in β-cell function remains unexplored. Here, we show that lysine acutely potentiates GSIS and that genes encoding enzymes in the lysine degradation pathway, including AminoAdipate-Semialdehyde Synthase (AASS), a key mitochondrial enzyme catalysing the first two steps of lysine catabolism, were present in human pancreatic islets and INS1 832/13 β cells. Some of these genes including AASS, ALDH7A1, DHTKD1, and HADH, were downregulated in pancreatic islets from type 2 diabetes (T2D) versus non-diabetic (ND) donors. Silencing AASS in human islets and INS1 832/13 β cells led to reduced GSIS. Integrated transcriptomics and metabolomics revealed altered expression of GABA metabolism genes, reduced GABA content and accumulation of glutamate in Aass-KD cells. Mitochondrial TCA cycle and OXPHOS function was impaired, evidenced by decreased ATP/ADP ratio, diminished glucose-stimulated mitochondrial respiration, and elevated lactate/pyruvate ratio. Cytosolic calcium responses to glucose and GABA were also disrupted. Pharmacological analyses demonstrated that inhibition of GABA synthesis or degradation did not account for the reduced GSIS, but providing substrates and activation of GDH partially restored insulin secretion, pointing to a diminished glutamate supply as a contributing factor. Remarkably, exogenous GABA restored insulin secretion in β cells and human islets with suppressed AASS-dependent lysine catabolism, supporting a role for GABA as both a metabolic substrate and signaling effector. Together, these findings identify AASS-mediated lysine catabolism as a critical regulator of β-cell metabolic integrity, linking impaired lysine metabolism to GABA depletion, mitochondrial dysfunction, and secretory failure in T2D islets. They also underscore the nutritional importance of essential amino acids such as lysine in sustaining GSIS and glucose homeostasis, and support therapeutic strategies aimed at restoring lysine catabolism or GABA/glutamate balance to maintain β-cell function.
Pros and cons of different dietary patterns for the treatment of metabolic dysfunction-associated steatotic liver disease.
Palumbo P, Di Betto G, Menozzi R … +2 more , Koek GH, Buzzetti E
Metabolism · 2026 Jan · PMID 41151689 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming the most prevalent hepatic disorder, affecting up to 33 % of the global population. An altered lifestyle, characterized by extended physical in...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming the most prevalent hepatic disorder, affecting up to 33 % of the global population. An altered lifestyle, characterized by extended physical inactivity and increased consumption of highly caloric food, often low in nutritional value, is recognised as one of the main contributing factors for MASLD. Cornerstone for MASLD treatment is a healthy lifestyle, starting from diet. However, the most appropriate dietary pattern for the treatment of MASLD remains a subject of debate. The aims of this narrative review are therefore to explore the mechanisms through which nutrition influences MASLD pathogenesis and to evaluate different dietary patterns for MASLD treatment, highlighting their advantages and limitations. Multiple dietary patterns-including the Mediterranean Diet (MD), the Dietary Approaches to Stop Hypertension (DASH), the Low-Carb Diet (LCD), the Ketogenic Diet (specifically the Very Low-Calorie Ketogenic Diet, VLCKD), the Low-Fat Diet (LFD), Vegetarian Diets (VDs), and Intermittent Fasting (IF)-are reviewed, with a focus on their efficacy on MASLD and the ameliorating of the associated cardiometabolic risks factors (CMRF).
SRSF1 is essential for pancreatic β-cell proliferation and the maintenance of glucose homeostasis in mice.
You X, Peng Q, Qian W … +5 more , Xie Z, Lin Y, Gai Y, Ye J, Feng Y
Metabolism · 2026 Jan · PMID 41138848 · Publisher ↗
BACKGROUND: β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β...
BACKGROUND: β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β-cell proliferation issues and dysfunction is crucial. SRSF1 is a central regulator of cell proliferation and survival, but its influence on β-cell proliferation and glucose control remains unclear. This study aims to investigate the role of SRSF1 in β-cell proliferation and its impact on glucose regulation. By examining the consequences of SRSF1 deficiency in pancreatic β-cells, we seek to elucidate the mechanisms linking SRSF1 to β-cell maintenance and function. METHODS: Mice with pancreatic β-cell-specific deletion of SRSF1 and a Rosa26-tdT lineage reporter were generated. Pancreatic sections were analyzed using immunostaining for insulin, glucagon, somatostatin, Ki67, tdT, proinsulin, TUNEL, and ER stress markers, as well as HE staining. Glucose tolerance tests, glucose and insulin measurements were performed in knockout and control mice. RNA-seq analyzed gene expression changes in 4-month-old islets, while scRNA-seq assessed cellular heterogeneity and gene expression profiles in 10-month-old mice islets. Knockdown assays and puromycin labeling experiments measured new protein synthesis. RESULTS: SRSF1 deficiency resulted in glucose intolerance and impaired insulin secretion, worsening with age. At early stages, knockout islets exhibited reduced β-cell proliferation accompanied by compensatory α-cell expansion. By 4 months, RNA-seq analysis showed downregulation of ribosome biogenesis and cell cycle genes, along with upregulation of α-cell determinants and progenitor-associated factors. Histological examination further revealed a decreased β-cell fraction, an increased α-cell fraction, and a small subset of α-cells co-expressing somatostatin, indicative of transient, stress-associated phenotypic plasticity. scRNA-seq identified ER stress and altered β-cell fate in knockout β-cells from 10-month-old mice. Notably, these changes were absent in 4-month-old knockout islets, indicating ER stress as a secondary response to proliferative defects from SRSF1 deficiency. Mechanistically, SRSF1 employs mechanisms similar to MYC to promote β-cell proliferation, with its effects on β-cells through the regulation of MYC expression. CONCLUSIONS: SRSF1 is essential for β-cell proliferation and function through MYC-mediated pathways. Its deficiency disrupts β-cell homeostasis and contributes to metabolic dysfunction in mice, underscoring its importance in preserving functional β-cells and maintaining glucose balance.
A melanocortin 4- and glucagon-like peptide 1 receptor multiple agonist for the treatment of diabetes and obesity.
Ashlaw EF, Elfers CT, Chichura KS … +9 more , Miranda IC, McGivney A, Chepurny OG, Holz GG, Mullins G, den Hartigh LJ, Liu Y, Roth CL, Doyle RP
Metabolism · 2026 Jan · PMID 41093057 · Full text
Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatmen...
Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatment discontinuation. Such concerns are greater still in children and adolescents. Thus, there remains a clinical unmet need to develop obesity and/or T2D mellitus therapies with significantly improved tolerability. Herein, we examined a polypharmacy approach combining melanocortin (MC) 4-, and GLP-1-receptor agonism in a single monomeric peptide based on α-MSH and Exendin-4 to bind and stimulate different peptide receptors in vitro, and to drive reductions in body weight and food intake in up to 7 weeks of treatment in comparison to semaglutide and tirzepatide as standard of care positive controls in diet-induced obese rats. Despite the monomeric peptide GLP-1-/MC4-receptor multiple agonist (KCEM1) being a non-lipidated, weaker GLP-1R agonist compared to semaglutide and tirzepatide, reductions in calorie intake and body weight were similar in all three groups after daily subcutaneous injections of the three peptides. In addition, KCEM1 offered superior glycemic control during glucose tolerance testing. In gene expression analyses, KCEM1, but not semaglutide or tirzepatide, significantly increased expression of glucose transporter 4 (GLUT4) and key glycolysis enzyme Pgk1 in skeletal muscle, while it reduced genetic markers of inflammation in different tissues, including inflammatory markers IL-6 and TNF-α in liver tissue. Furthermore, KCEM1 lowered hepatic lipid content and improved metabolic dysfunction-associated steatohepatitis (MASH) scoring. Overall, these data extend emerging concepts around the use of multi-receptor polypharmacy to treat metabolic syndrome.
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