Pub Date : 2026-01-01Epub Date: 2025-12-02DOI: 10.1016/j.molmet.2025.102292
Giulia Milan , Olga A. Mareninova , Marco Fantuz , Martina Spacci , Carlotta Paoli , Jerik A. Pineda , Roberta Noè , Beatrice Calciolari , Roberto Zoncu , Anna S. Gukovskaya , Alessandro Carrer
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.
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 Acly ameliorates cerulein-induced pancreatitis, while pharmacological targeting of NPC1 exacerbates tissue damage.
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 ex vivo and in vivo, in an mTORC1-dependent manner.
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.
{"title":"Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation","authors":"Giulia Milan , Olga A. Mareninova , Marco Fantuz , Martina Spacci , Carlotta Paoli , Jerik A. Pineda , Roberta Noè , Beatrice Calciolari , Roberto Zoncu , Anna S. Gukovskaya , 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}
Pub Date : 2026-01-01Epub Date: 2025-11-29DOI: 10.1016/j.molmet.2025.102293
Zheng Ge , Zitian Liu , Shuohui Dong , Xiang Zhao , Guangwei Yang , Ao Yu , Wei Guo , Xiang Zhang , Qunzheng Wu , Kexin Wang
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.
{"title":"High-fat diet induces senescence in ADSCs via CDK4 ubiquitination-mediated cell cycle disruption, contributing to impaired glucose tolerance","authors":"Zheng Ge , Zitian Liu , Shuohui Dong , Xiang Zhao , Guangwei Yang , Ao Yu , Wei Guo , Xiang Zhang , Qunzheng Wu , 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}
Pub Date : 2026-01-01Epub Date: 2025-12-19DOI: 10.1016/j.molmet.2025.102312
Olga Kubrak , Alina Malita , Nadja Ahrentløv, Stanislav Nagy, Michael J. Texada, Kim Rewitz
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 Drosophila. 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.
男性和女性有不同的生理和生殖需求，因此在新陈代谢和行为上表现出广泛的差异。动物之间最一致的差异之一是雌性比雄性储存更多的体脂，这是一种从苍蝇到人类都保存下来的代谢特征。鉴于肠道激素在能量平衡中的核心作用，我们想知道肠道内分泌信号是否导致了这些性别差异。因此，我们对肠内分泌细胞（EEC）衍生的信号进行了多维筛选，涉及雄性和雌性果蝇的广泛代谢和行为特征。在这里，我们揭示了脑电图衍生信号广泛的性别偏见作用，其中许多在哺乳动物中是保守的，包括能量储存、应激抵抗、喂养和睡眠。我们发现eec衍生的酰胺肽激素维持了女性的典型状态，包括增加的脂肪储备，增强的应激恢复能力和蛋白质偏向的食物选择。相比之下，非酰胺肽Allatostatin C （AstC）通过刺激能量动员来促进雄性样性状，从而拮抗酰胺肽功能。女性肠道中含有更多的astc阳性eec。通过消除肽酰甘氨酸α-羟化单加氧酶（大多数肠道肽激素成熟所需的酶）来破坏肽酰胺化，破坏了雌性典型的生理和行为，将雌性转变为雄性状态。在单个修饰肽中，利尿激素31 （DH31）和神经肽F （NPF）被认为是女性生理的关键介质。这些发现确定了肠道激素信号是性别特异性代谢和行为状态的决定因素。
{"title":"Gut hormone signaling drives sex differences in metabolism and behavior","authors":"Olga Kubrak , Alina Malita , Nadja Ahrentløv, Stanislav Nagy, Michael J. Texada, 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}
Pub Date : 2026-01-01Epub Date: 2025-12-03DOI: 10.1016/j.molmet.2025.102297
Wolfgang S. Lieb , Carlos O. Oueslati Morales , Kornelia Ellwanger , Claudia Koch , Sylke Lutz , Stephan A. Eisler , Annika M. Möller , Veronika Leiss , Angelika Hausser
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.
{"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 , Carlos O. Oueslati Morales , Kornelia Ellwanger , Claudia Koch , Sylke Lutz , Stephan A. Eisler , Annika M. Möller , Veronika Leiss , 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}
Pub Date : 2026-01-01Epub Date: 2025-11-29DOI: 10.1016/j.molmet.2025.102295
Shruti Bhargava , Zhuangting Rao , Raymond Vanholder , Frank Tacke , Heidi Noels , Vera Jankowski , Juliane Hermann , Joachim Jankowski
Introduction
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.
Aim
This publication reviews gut-liver-derived mediators, which were tested and validated in vivo in humans and rodents, together with the current knowledge of their systemic effects on key vital organs.
Method
Original articles published up to February 2025, based on clinical trials or in vivo experimental models, were retrieved from PubMed and Web of Science.
Results
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.
Discussion
The diverse and occasionally conflicting impact of the identified mediators on comorbidities necessitates further investigations pinpointing key mechanisms influencing disease genesis and progression.
Conclusion
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.
目前对重要器官之间的相互作用和串扰的理解仍然不完整，主要是由于对系统机制的研究有限。肠道和肝脏对整个身体的功能至关重要，它们衍生的介质通过血液或淋巴循环，影响其他器官，如大脑、心脏和肾脏。本出版物回顾了在人类和啮齿类动物体内进行测试和验证的肠道-肝脏来源的介质，以及它们对关键重要器官的系统性影响的最新知识。截至2025年2月发表的基于临床试验或体内实验模型的原创文章，从PubMed和Web of Science检索。在这项系统分析中，从52份出版物中鉴定出28种肠-肝源性介质，并根据其分子特征将其分为五组：(a)低分子量代谢物，(b)内毒素，(c)激素，(d)脂质和(e)蛋白质。此外，每种分子的作用机制都被指定，旨在提供它们对大脑、心脏和肾脏影响的机制概述。已确定的介质对合并症的影响多种多样，有时相互冲突，因此需要进一步研究确定影响疾病发生和进展的关键机制。我们的研究表明，有必要对这些介质进行彻底的检查，探索它们在整体多器官环境中的诊断和治疗潜力，以阐明器官间的串扰。
{"title":"The impact of gut-liver-derived mediators on the organ crosstalk with brain, heart, and kidney: A systematic review","authors":"Shruti Bhargava , Zhuangting Rao , Raymond Vanholder , Frank Tacke , Heidi Noels , Vera Jankowski , Juliane Hermann , 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}
Pub Date : 2026-01-01Epub Date: 2025-10-30DOI: 10.1016/j.molmet.2025.102277
Olivia Sveidahl Johansen , Rebecca L. McIntyre , Janane F. Rahbani , Qiaoqiao Zhang , Charlotte Scholtes , Damien Marc Lagarde , Cyrielle Billon , Isabelle Côté , Maria Delgado-Martin , David Tandio , Astrid Linde Basse , Elodie Eury , Anastasia Kralli , Thomas P. Burris , Vincent Giguère , Lawrence Kazak , Zachary Gerhart-Hines
Objectives
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. Gpr3 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 Gpr3 expression remain unknown.
Methods
Here, we apply ATAC-Seq to identify cold-induced promoter elements of Gpr3. We uncover a role for the estrogen-related receptors, ERRα and ERRγ, in the physiological transcriptional control of Gpr3 using adipose-specific double knock-out mice with and without adeno-associated virus (AAV)-mediated rescue.
Results
We show that ERRα directly binds the cold-induced promoter element of Gpr3 and that ERRα, ERRβ, and ERRγ each activate the Gpr3 promoter in vitro when co-transfected with PGC-1α. Adipocyte ERRα and ERRγ are required for the in vivo transcriptional induction of Gpr3 during cold exposure. Importantly, deficient Gpr3 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.
Conclusions
ERRα and ERRγ are critical regulators of cold-induced transcription of Gpr3 and represent a targetable strategy for pharmacologically unlocking GPR3-induced energy expenditure.
{"title":"Cold exposure induces the constitutively active thermogenic receptor, GPR3, via ERRα and ERRγ","authors":"Olivia Sveidahl Johansen , Rebecca L. McIntyre , Janane F. Rahbani , Qiaoqiao Zhang , Charlotte Scholtes , Damien Marc Lagarde , Cyrielle Billon , Isabelle Côté , Maria Delgado-Martin , David Tandio , Astrid Linde Basse , Elodie Eury , Anastasia Kralli , Thomas P. Burris , Vincent Giguère , Lawrence Kazak , 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}
Pub Date : 2026-01-01Epub Date: 2025-12-11DOI: 10.1016/j.molmet.2025.102302
Ben C. King , Lucie Colineau , Julia Slaby , Olga Kolodziej , Vaishnavi Dandavate , Robin Olsson , Malin Fex , Anna M. Blom
Background
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.
Methods
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.
Results
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 in vitro.
Conclusion
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 in vivo.
{"title":"Beta-cell-specific C3 deficiency exacerbates metabolic dysregulation and insulin resistance in obesity","authors":"Ben C. King , Lucie Colineau , Julia Slaby , Olga Kolodziej , Vaishnavi Dandavate , Robin Olsson , Malin Fex , 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}
Pub Date : 2026-01-01Epub Date: 2025-11-14DOI: 10.1016/j.molmet.2025.102282
Jennyfer Bultinck , Shendong Yuan , Ludovico Cantuti-Castelvetri , Lander Brosens , Debby Bracke , James Collins , Jens Goethals , Christina Christianson , John Nuss , Kathleen Ogilvie
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.
{"title":"NLRP3 inhibition by VTX3232 tempers inflammation resulting in reduced body weight, hyperglycemia, and hepatic steatosis in obese male mice","authors":"Jennyfer Bultinck , Shendong Yuan , Ludovico Cantuti-Castelvetri , Lander Brosens , Debby Bracke , James Collins , Jens Goethals , Christina Christianson , John Nuss , 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}
Pub Date : 2026-01-01Epub Date: 2025-12-09DOI: 10.1016/j.molmet.2025.102300
Nadia N. Aalling , Petar V. Todorov , Shad Hassan , Dylan M. Belmont-Rausch , Oliver Pugerup Christensen , Claes Ottzen Laurentiussen , Anja M. Jørgensen , Kimberly M. Alonge , Jarrad M. Scarlett , Zaman Mirzadeh , Jenny M. Brown , Michael W. Schwartz , Tune H. Pers
In rodent models of type 2 diabetes, a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces sustained remission of hyperglycemia. Overactive agouti-related peptide (AgRP) neurons, located in the hypothalamic arcuate nucleus, are a hallmark of diabetic states, and their long-term inhibition has been linked to FGF1's antidiabetic effects. To investigate the underlying mechanism(s), we performed single-nucleus RNA sequencing of the mediobasal hypothalamus at Days 5 and 14 post-injection in wild-type and diabetic (Lepob/ob) mice treated with FGF1 or vehicle. We found that AgRP neurons from Lepob/ob mice form a transcriptionally distinct, hyperactive subpopulation. By Day 5, icv FGF1 induced a subset of these neurons to shift toward a less active, wild-type-like state, characterized by reduced activity-linked gene expression that persisted through Day 14. Spatial transcriptomics revealed that this FGF1-responsive AgRP subset is positioned dorsally within the arcuate nucleus. The transcriptional shift was accompanied by transcriptional processes indicative of increased GABAergic signaling, axonogenesis, and astrocyte–AgRP and oligodendrocyte–AgRP interactions. These glial inputs involve astrocytic neurexins and the perineuronal net (PNN) component phosphacan, suggesting both intrinsic and extrinsic mechanisms underlie FGF1-induced AgRP silencing. Combined with evidence that FGF1 increases PNN assembly in the arcuate nucleus, our findings reveal a cell-type–specific model for how FGF1 elicits long-term reprogramming of hypothalamic circuits to achieve diabetes remission.
{"title":"Sustained diabetes remission induced by FGF1 involves a shift in transcriptionally distinct AgRP neuron subpopulations","authors":"Nadia N. Aalling , Petar V. Todorov , Shad Hassan , Dylan M. Belmont-Rausch , Oliver Pugerup Christensen , Claes Ottzen Laurentiussen , Anja M. Jørgensen , Kimberly M. Alonge , Jarrad M. Scarlett , Zaman Mirzadeh , Jenny M. Brown , Michael W. Schwartz , Tune H. Pers","doi":"10.1016/j.molmet.2025.102300","DOIUrl":"10.1016/j.molmet.2025.102300","url":null,"abstract":"<div><div>In rodent models of type 2 diabetes, a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces sustained remission of hyperglycemia. Overactive agouti-related peptide (AgRP) neurons, located in the hypothalamic arcuate nucleus, are a hallmark of diabetic states, and their long-term inhibition has been linked to FGF1's antidiabetic effects. To investigate the underlying mechanism(s), we performed single-nucleus RNA sequencing of the mediobasal hypothalamus at Days 5 and 14 post-injection in wild-type and diabetic (Lep<sup><em>ob/ob</em></sup>) mice treated with FGF1 or vehicle. We found that AgRP neurons from Lep<sup><em>ob/ob</em></sup> mice form a transcriptionally distinct, hyperactive subpopulation. By Day 5, icv FGF1 induced a subset of these neurons to shift toward a less active, wild-type-like state, characterized by reduced activity-linked gene expression that persisted through Day 14. Spatial transcriptomics revealed that this FGF1-responsive AgRP subset is positioned dorsally within the arcuate nucleus. The transcriptional shift was accompanied by transcriptional processes indicative of increased GABAergic signaling, axonogenesis, and astrocyte–AgRP and oligodendrocyte–AgRP interactions. These glial inputs involve astrocytic neurexins and the perineuronal net (PNN) component phosphacan, suggesting both intrinsic and extrinsic mechanisms underlie FGF1-induced AgRP silencing. Combined with evidence that FGF1 increases PNN assembly in the arcuate nucleus, our findings reveal a cell-type–specific model for how FGF1 elicits long-term reprogramming of hypothalamic circuits to achieve diabetes remission.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102300"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724524","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}
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