Molecular Metabolism最新文献

{"title":"Protein kinase C epsilon deletion in AgRP neurons modulates hypothalamic glucose sensing and improves glucose tolerance in mice","authors":"Amanda E. Brandon ,&nbsp;Chenxu Yan ,&nbsp;Xuan Zhang ,&nbsp;Chi Kin Ip ,&nbsp;Zhongmin Gao ,&nbsp;Nicola J. Lee ,&nbsp;Oana C. Marian ,&nbsp;Alex Perez ,&nbsp;Anthony S. Don ,&nbsp;Herbert Herzog ,&nbsp;Lewin Small ,&nbsp;Yan-Chuan Shi ,&nbsp;Carsten Schmitz-Peiffer","doi":"10.1016/j.molmet.2026.102320","DOIUrl":"10.1016/j.molmet.2026.102320","url":null,"abstract":"<div><h3>Objectives</h3><div>Global but not liver-specific deletion of protein kinase C epsilon (PKCε) improves glucose tolerance in fat-fed mice, suggesting that extra-hepatic tissues are involved. AgRP neurons within the arcuate nucleus (ARC) of the hypothalamus can affect glucose homeostasis acutely, in addition to their role in energy homeostasis. We therefore deleted PKCε specifically in AgRP neurons to examine its effects at this site.</div></div><div><h3>Methods</h3><div>Fat-fed AgRP-PKCε^−/− mice were subjected to glucose tolerance tests and euglycaemic-hyperinsulinaemic clamps. c-Fos and tyrosine hydroxylase were used as markers to map neuronal activity in serial brain sections. Transcriptional changes in liver and adipose tissue were examined by qRT-PCR while alterations in protein levels and phosphorylation were determined by immunoblotting and mass spectrometry.</div></div><div><h3>Results</h3><div>Fat-fed AgRP-PKCε^−/− mice exhibited improved glucose tolerance but not insulin sensitivity determined by clamp. c-Fos mapping demonstrated that glucose challenge resulted in greater activation of neurons in the paraventricular nucleus (PVN) in AgRP-PKCε^−/− mice, but reduced expression of tyrosine hydroxylase in the PVN, suggestive of reduced sympathetic outflow. This was associated with a reduction in hormone sensitive lipase phosphorylation and plasma fatty acid levels. Proteomic analysis indicated overlapping alterations in proteins and protein phosphorylation in adipose tissue and liver, consistent with changes in a common, potentially neuronal, cell type.</div></div><div><h3>Conclusions</h3><div>Ablation of PKCε in AgRP neurons improves glucose homeostasis in fat-fed mice. This appears to be mediated through glucose sensing mechanisms, potentially reducing sympathetic outflow from the hypothalamus to tissues such as adipose, reducing lipolysis to indirectly lower hepatic glucose production.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102320"},"PeriodicalIF":6.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycolytic activation of β-cell Na+/K+-ATPases containing β1-subunits accelerates Na+ extrusion, prolonging the duration of Ca2+ oscillations but decreasing insulin secretion","authors":"Matthew T. Dickerson ,&nbsp;Prasanna K. Dadi ,&nbsp;Reagan P. McDevitt ,&nbsp;Jordyn R. Dobson ,&nbsp;Soma Behera ,&nbsp;Spencer J. Peachee ,&nbsp;Shannon E. Gibson ,&nbsp;Tenzin Wangmo ,&nbsp;David A. Jacobson","doi":"10.1016/j.molmet.2025.102296","DOIUrl":"10.1016/j.molmet.2025.102296","url":null,"abstract":"<div><div>Electrogenic Na⁺/K⁺ ATPases (NKAs) control β-cell Ca²⁺ influx and insulin secretion by integrating the signal strength of stimulatory G protein (G_s)-coupled ligands (e.g., GLP-1, glucagon) and inhibitory G protein (G_i)-coupled ligands (e.g., somatostatin, epinephrine). However, there is a significant gap in our understanding of how specific NKA subunits contribute to β-cell function. Here, we demonstrate that the NKA β1-subunit (NKAβ1) is highly expressed and functional at the plasma membrane of mouse and human β-cells. β-cell-specific NKAβ1 knockout improves glucose tolerance and hepatic insulin sensitivity, coinciding with enhanced first- and second-phase glucose-stimulated insulin secretion (GSIS). Electrophysiological studies reveal that β-cell NKAβ1 enhances somatostatin-induced NKA currents, increases action potential afterhyperpolarization amplitude, and accelerates action potential frequency. Loss of NKAβ1 delays glucose-stimulated Ca²⁺ entry by impairing glycolysis-dependent NKA activation and reduces Na⁺ clearance efficiency during Ca²⁺ oscillations, resulting in prolonged silent phases. Thus, glycolytic stimulation of Na⁺ influx dictates silent phase duration via the kinetics of Na⁺ clearance by NKA, which is diminished in β-cells without NKAβ1. Furthermore, NKAβ1 differentially modulates β-cell G protein-coupled receptor (GPCR) signaling by attenuating G_i-GPCR effects and augmenting G_s-coupled GLP-1 receptor-mediated cAMP production and Ca²⁺ entry. β-cell NKAβ1 knockdown in human pseudoislets led to tonically elevated intracellular Ca²⁺ and increased insulin secretion. These findings establish NKAβ1-containing NKA complexes as critical regulators of β-cell electrical activity, Ca²⁺ oscillations, and secretory patterns, with direct consequences for systemic glucose homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102296"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation","authors":"Giulia Milan ,&nbsp;Olga A. Mareninova ,&nbsp;Marco Fantuz ,&nbsp;Martina Spacci ,&nbsp;Carlotta Paoli ,&nbsp;Jerik A. Pineda ,&nbsp;Roberta Noè ,&nbsp;Beatrice Calciolari ,&nbsp;Roberto Zoncu ,&nbsp;Anna S. Gukovskaya ,&nbsp;Alessandro Carrer","doi":"10.1016/j.molmet.2025.102292","DOIUrl":"10.1016/j.molmet.2025.102292","url":null,"abstract":"<div><div>Pancreatitis is a common cause of hospitalization that necessitates attentive clinical management. Affected individuals are at risk for pancreatic cancer due to aberrant signaling and empowered cell plasticity. Yet, molecular and cellular dynamics that govern epithelial cell behavior in response to inflammation remain largely elusive.</div><div>Here we found that inflammation induces Endoplasmic Reticulum-Associated Degradation protein (ERAD)-mediated downregulation of Niemann-Pick type C protein 1 (NPC1), which leads to the sequestration of free cholesterol within acinar cells’ lysosomes. Reducing intra-pancreatic cholesterol levels through genetic ablation of <em>Acly</em> ameliorates cerulein-induced pancreatitis, while pharmacological targeting of NPC1 exacerbates tissue damage.</div><div>Mechanistically, the accumulation of lysosomal cholesterol is sensed by the mechanistic Target of Rapamycin Complex 1 (mTORC1) that promotes metaplasia of pancreatic acinar cells, an event commonly associated to pancreatitis and tissue regeneration. Indeed, cholesterol supplementation or NPC1 inhibition facilitate acinar-to-ductal metaplasia (ADM) both <em>ex vivo</em> and <em>in vivo</em>, in an mTORC1-dependent manner.</div><div>These results identify a metabolic/signaling axis driving the reprogramming of pancreatic epithelial cells in response to inflammation. This hinges on a nutrient sensing paradigm, previously documented exclusively in pathological conditions.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102292"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145677682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-fat diet induces senescence in ADSCs via CDK4 ubiquitination-mediated cell cycle disruption, contributing to impaired glucose tolerance","authors":"Zheng Ge ,&nbsp;Zitian Liu ,&nbsp;Shuohui Dong ,&nbsp;Xiang Zhao ,&nbsp;Guangwei Yang ,&nbsp;Ao Yu ,&nbsp;Wei Guo ,&nbsp;Xiang Zhang ,&nbsp;Qunzheng Wu ,&nbsp;Kexin Wang","doi":"10.1016/j.molmet.2025.102293","DOIUrl":"10.1016/j.molmet.2025.102293","url":null,"abstract":"<div><div>High-fat diet (HFD) promotes adipose tissue senescence, which in turn disrupts insulin-mediated glycemic homeostasis. The underlying mechanisms remain unclear. Through clinical survey data, animal models, and primary adipose-derived mesenchymal stem cells (ADSC), we investigated how dietary patterns influence adipocyte senescence. We found that elevated fatty acid levels enhance the interaction between the E3 ubiquitin ligase TRIP12 and Cyclin-dependent kinase 4 (CDK4) in ADSCs, triggering CDK4 ubiquitination and degradation. As a process associated with this disruption in cell cycle progression, cellular senescence may represent a key outcome. Consequently, senescent ADSC-derived mature adipocytes (ADSC-MA) exhibit impaired insulin-stimulated GLUT4 membrane translocation and reduced glucose uptake. In contrast, within an HFD setting, dietary fiber supplementation is associated with the reversal of cellular senescence. The gut microbiota–short-chain fatty acids (SCFAs) axis may be involved in the restoration of cell cycle progression and the amelioration of ADSC senescence, correlating with a partial recovery of glucose uptake capacity in ADSC-MAs. Our study highlights potential strategies to reverse cellular senescence and identifies promising therapeutic targets for impaired glucose tolerance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102293"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut hormone signaling drives sex differences in metabolism and behavior","authors":"Olga Kubrak ,&nbsp;Alina Malita ,&nbsp;Nadja Ahrentløv,&nbsp;Stanislav Nagy,&nbsp;Michael J. Texada,&nbsp;Kim Rewitz","doi":"10.1016/j.molmet.2025.102312","DOIUrl":"10.1016/j.molmet.2025.102312","url":null,"abstract":"<div><div>Males and females have different physiological and reproductive demands and consequently exhibit widespread differences in metabolism and behavior. One of the most consistent differences across animals is that females store more body fat than males, a metabolic trait conserved from flies to humans. Given the central role of gut hormones in energy balance, we asked whether gut endocrine signaling underlies these sex differences. We therefore performed a multidimensional screen of enteroendocrine cell (EEC)-derived signaling across a broad panel of metabolic and behavioral traits in male and female <em>Drosophila</em>. Here, we uncover extensive sex-biased roles for EEC-derived signals – many of which are conserved in mammals – in energy storage, stress resistance, feeding, and sleep. We find that EEC-derived amidated peptide hormones sustain female-typical states, including elevated fat reserves, enhanced stress resilience, and protein-biased food choice. In contrast, the non-amidated peptide Allatostatin C (AstC) promotes male-like traits by stimulating energy mobilization, thereby antagonizing amidated-peptide function. Female guts contain more AstC-positive EECs. Disruption of peptide amidation by eliminating peptidylglycine α-hydroxylating monooxygenase – the enzyme required for maturation of most gut peptide hormones – abolished female-typical physiology and behavior, shifting females toward a male-like state. Among individual amidated peptides, Diuretic hormone 31 (Dh31) and Neuropeptide F (NPF) emerged as key mediators of female physiology. These findings establish gut hormone signaling as a determinant of sex-specific metabolic and behavioral states.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102312"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein kinase D deficiency induces a senescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions","authors":"Wolfgang S. Lieb ,&nbsp;Carlos O. Oueslati Morales ,&nbsp;Kornelia Ellwanger ,&nbsp;Claudia Koch ,&nbsp;Sylke Lutz ,&nbsp;Stephan A. Eisler ,&nbsp;Annika M. Möller ,&nbsp;Veronika Leiss ,&nbsp;Angelika Hausser","doi":"10.1016/j.molmet.2025.102297","DOIUrl":"10.1016/j.molmet.2025.102297","url":null,"abstract":"<div><div>Insulin secretion from pancreatic β-cells is essential for maintaining glucose homeostasis and preventing type 2 diabetes, a condition closely associated with aging. Although previous studies in mice have shown that both basal and glucose-stimulated insulin secretion increase with age, the underlying mechanisms remained poorly understood. In this study, we identify protein kinase D (PKD) as a critical regulator of β-cell function during aging through its control of cellular senescence. Using β-cell–specific expression of dominant-negative PKDkd-EGFP and the selective PKD inhibitor CRT0066101, we demonstrate that inhibition of PKD activity in mature adult mice induced a senescent-like β-cell phenotype characterized by enlarged cell size and elevated β-galactosidase activity. These changes were associated with decreased expression of the antioxidant enzyme superoxide dismutase 2 and increased levels of reactive oxygen species. Surprisingly, despite promoting a senescent-like phenotype, PKD inhibition significantly improved glucose tolerance, enhanced glucose-stimulated insulin secretion, and protected against high-fat diet–induced glucose and insulin intolerance. These findings highlight the importance of PKD in preserving β-cell function under aging and metabolic stress conditions.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102297"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cold exposure induces the constitutively active thermogenic receptor, GPR3, via ERRα and ERRγ","authors":"Olivia Sveidahl Johansen ,&nbsp;Rebecca L. McIntyre ,&nbsp;Janane F. Rahbani ,&nbsp;Qiaoqiao Zhang ,&nbsp;Charlotte Scholtes ,&nbsp;Damien Marc Lagarde ,&nbsp;Cyrielle Billon ,&nbsp;Isabelle Côté ,&nbsp;Maria Delgado-Martin ,&nbsp;David Tandio ,&nbsp;Astrid Linde Basse ,&nbsp;Elodie Eury ,&nbsp;Anastasia Kralli ,&nbsp;Thomas P. Burris ,&nbsp;Vincent Giguère ,&nbsp;Lawrence Kazak ,&nbsp;Zachary Gerhart-Hines","doi":"10.1016/j.molmet.2025.102277","DOIUrl":"10.1016/j.molmet.2025.102277","url":null,"abstract":"<div><h3>Objectives</h3><div>Despite transformative advances in obesity pharmacotherapy, safely increasing energy expenditure remains a key unmet need. Exploiting thermogenic adipocytes represents a promising target given their capacity for significant catabolic activity. We previously showed that G protein-coupled receptor 3 (GPR3) can drive energy expenditure in brown and white mouse and human adipocytes. GPR3 is a unique GPCR because it displays high intrinsic activity and leads to constitutive cAMP signaling upon reaching the cell surface. Therefore, the transcriptional induction of GPR3 is analogous to ligand-binding activation of most GPCRs. <em>Gpr3</em> expression is physiologically induced in thermogenic adipocytes by cold exposure, and mimicking this event through overexpression in mice is fully sufficient to increase energy expenditure and counteract metabolic disease. Yet the factors mediating physiological <em>Gpr3</em> expression remain unknown.</div></div><div><h3>Methods</h3><div>Here, we apply ATAC-Seq to identify cold-induced promoter elements of <em>Gpr3</em>. We uncover a role for the estrogen-related receptors, ERRα and ERRγ, in the physiological transcriptional control of <em>Gpr3</em> using adipose-specific double knock-out mice with and without adeno-associated virus (AAV)-mediated rescue.</div></div><div><h3>Results</h3><div>We show that ERRα directly binds the cold-induced promoter element of <em>Gpr3</em> and that ERRα, ERRβ, and ERRγ each activate the <em>Gpr3</em> promoter <em>in vitro</em> when co-transfected with PGC-1α. Adipocyte ERRα and ERRγ are required for the <em>in vivo</em> transcriptional induction of <em>Gpr3</em> during cold exposure. Importantly, deficient <em>Gpr3</em> cold-inducibility in adipose-specific ERRα and ERRγ KO mice is fully rescued by delivery of AAVs re-expressing either ERRα or ERRγ directly into brown adipose tissue.</div></div><div><h3>Conclusions</h3><div>ERRα and ERRγ are critical regulators of cold-induced transcription of <em>Gpr3</em> and represent a targetable strategy for pharmacologically unlocking GPR3-induced energy expenditure.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102277"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145422226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of gut-liver-derived mediators on the organ crosstalk with brain, heart, and kidney: A systematic review","authors":"Shruti Bhargava ,&nbsp;Zhuangting Rao ,&nbsp;Raymond Vanholder ,&nbsp;Frank Tacke ,&nbsp;Heidi Noels ,&nbsp;Vera Jankowski ,&nbsp;Juliane Hermann ,&nbsp;Joachim Jankowski","doi":"10.1016/j.molmet.2025.102295","DOIUrl":"10.1016/j.molmet.2025.102295","url":null,"abstract":"<div><h3>Introduction</h3><div>The current understanding of interactions and crosstalk among essential organs remains incomplete, mainly due to the limitations of studies on the systemic mechanisms at play. The gut and the liver are essential for the functioning of the entire body, and their derived mediators circulate through blood or lymph, impacting other organs like the brain, heart, and kidneys.</div></div><div><h3>Aim</h3><div>This publication reviews gut-liver-derived mediators, which were tested and validated <em>in vivo</em> in humans and rodents, together with the current knowledge of their systemic effects on key vital organs.</div></div><div><h3>Method</h3><div>Original articles published up to February 2025, based on clinical trials or in vivo experimental models, were retrieved from PubMed and Web of Science.</div></div><div><h3>Results</h3><div>During this systematic analysis, 28 gut-liver-derived mediators were identified from 52 publications and classified into five distinct groups based on their molecular characteristics: (a) low molecular weight metabolites, (b) endotoxins, (c) hormones, (d) lipids and (e) proteins. Additionally, the mechanism of action for each of these molecules was specified, aimed at providing a mechanistic overview of their effects on the brain, heart, and kidneys.</div></div><div><h3>Discussion</h3><div>The diverse and occasionally conflicting impact of the identified mediators on comorbidities necessitates further investigations pinpointing key mechanisms influencing disease genesis and progression.</div></div><div><h3>Conclusion</h3><div>Our research shows the necessity of a thorough examination of these mediators, exploring their diagnostic and therapeutic potential in a holistic multi-organ setting, to elucidate inter-organ crosstalk.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102295"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beta-cell-specific C3 deficiency exacerbates metabolic dysregulation and insulin resistance in obesity","authors":"Ben C. King ,&nbsp;Lucie Colineau ,&nbsp;Julia Slaby ,&nbsp;Olga Kolodziej ,&nbsp;Vaishnavi Dandavate ,&nbsp;Robin Olsson ,&nbsp;Malin Fex ,&nbsp;Anna M. Blom","doi":"10.1016/j.molmet.2025.102302","DOIUrl":"10.1016/j.molmet.2025.102302","url":null,"abstract":"<div><h3>Background</h3><div>C3 is highly expressed in human and rodent pancreatic islets, which secrete insulin to regulate blood glucose homeostasis. We have previously shown that cytosolic C3 protects pancreatic beta-cells from stress, by allowing cytoprotective autophagy, and that the same intracellular pool of C3 also protects beta-cells from cytokine-induced apoptosis.</div></div><div><h3>Methods</h3><div>We now generated a beta-cell specific C3 knockout mouse (beta-C3-KO) to test whether cell-intrinsic C3 is required for beta-cell function in a whole animal model. These mice were placed on high-fat diet (HFD), blood glucose and insulin measurements taken over time, and tissues examined at endpoint by qPCR and immunofluorescence.</div></div><div><h3>Results</h3><div>While no differences were found between in baseline metabolic performance when comparing floxed controls and beta-C3KO mice, significant differences were found when mice were put on high-fat diet (HFD). Beta-C3-KO mice gained more weight, exhibited higher fasting blood glucose and insulin levels, and showed signs of adipose tissue inflammation and insulin resistance. Consistent with previous results showing that C3 alleviates beta-cell stress, increased amounts of unprocessed pro-insulin were found in the circulation of HFD-fed beta-C3-KO mice, as well as in islets from these mice. Beta-C3-KO HFD mouse islets also had a higher proportion of insulin staining, and isolated islets released more insulin <em>in vitro</em>.</div></div><div><h3>Conclusion</h3><div>The interaction of increased insulin secretion and HFD leads to enhanced weight gain. Cell-intrinsic expression of C3 is important for optimal function of mouse pancreatic beta-cells under metabolic pressure <em>in vivo</em>.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102302"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NLRP3 inhibition by VTX3232 tempers inflammation resulting in reduced body weight, hyperglycemia, and hepatic steatosis in obese male mice","authors":"Jennyfer Bultinck ,&nbsp;Shendong Yuan ,&nbsp;Ludovico Cantuti-Castelvetri ,&nbsp;Lander Brosens ,&nbsp;Debby Bracke ,&nbsp;James Collins ,&nbsp;Jens Goethals ,&nbsp;Christina Christianson ,&nbsp;John Nuss ,&nbsp;Kathleen Ogilvie","doi":"10.1016/j.molmet.2025.102282","DOIUrl":"10.1016/j.molmet.2025.102282","url":null,"abstract":"<div><div>The NLRP3 inflammasome is a key innate immune sensor that orchestrates inflammatory responses to diverse stress signals, including metabolic danger cues. Dysregulated NLRP3 activation has been implicated in chronic diseases such as type 2 diabetes, atherosclerosis, and neurodegeneration, underscoring the broad pathophysiological role of the NLRP3 pathway. In the context of obesity and its associated conditions, NLRP3 inhibition by VTX3232, an oral, selective, and brain-penetrant NLRP3 inhibitor, potently suppressed the release of proinflammatory cytokines (IL-1β, IL-18, IL-1α, IL-6, and TNF) from macrophages and microglia stimulated with metabolic stressors including palmitic acid and cholesterol crystals. Moreover, NLRP3 inhibition by VTX3232 also blocked NLRP3-driven insulin resistance in primary human hepatocytes and adipocytes while normalizing the acute phase response and FGF-21 secretion in hepatocytes under palmitic acid-induced inflammation. In vivo, NLRP3 inhibition by VTX3232 reduced systemic and tissue-specific inflammation in a mouse model of diet-induced obesity, reflected by decreased circulating inflammatory mediators, reduced hepatic inflammation, fewer crown-like structures in adipose tissue, and diminished hypothalamic gliosis. These anti-inflammatory effects were accompanied by improvements in body weight, food intake, and obesity-associated comorbidities such as hyperglycemia, hepatic steatosis, and markers of cardiovascular and renal disease. Notably, these effects were confined to the context of obesity, as no impact was observed in lean mice. When combined with glucagon-like peptide-1 receptor agonism by semaglutide, NLRP3 inhibition by VTX3232 yielded additive metabolic benefits, highlighting complementary mechanisms of action. Together, these findings reinforce the biological rationale for targeting NLRP3 in inflammatory conditions such as obesity, expand on the role of NLRP3 in metabolic inflammation, and underscore the importance of continued investigation into the NLRP3 pathway as a central node in cardiometabolic disease.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102282"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}