Pub Date : 2025-12-01Epub Date: 2025-10-25DOI: 10.1016/j.molmet.2025.102276
Tongzhi Wu , Michael Horowitz , Karen L. Jones , Christopher K. Rayner
{"title":"Reframing metformin as a gut-targeted glucose-lowering therapy: Mechanistic insights and translational relevance","authors":"Tongzhi Wu , Michael Horowitz , Karen L. Jones , Christopher K. Rayner","doi":"10.1016/j.molmet.2025.102276","DOIUrl":"10.1016/j.molmet.2025.102276","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102276"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145458891","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 : 2025-12-01Epub Date: 2025-10-17DOI: 10.1016/j.molmet.2025.102272
Sara Alqudah , Beckey DeLucia , Lucas J. Osborn , Rachel L. Markley , Viharika Bobba , Sarah M. Preston , Tharika Thambidurai , Layan Hamidi Nia , Clifton G. Fulmer , Naseer Sangwan , Ina Nemet , Jan Claesen
Background/Purpose
Obesity-associated metabolic disorders, including type 2 diabetes and metabolic dysfunction associated fatty liver disease (MAFLD), are major global health burdens. While dietary polyphenols have shown promise in ameliorating these conditions, their efficacy is dependent on specialized gut microbial metabolism, and the underlying molecular mechanisms remain mostly elusive. Here, we demonstrate that dietary supplementation with polyphenol-rich elderberry (Eld) extract abrogates the effects of an obesogenic diet in a gut microbiota-dependent manner, preventing insulin resistance and reducing hepatic steatosis in mice.
Methods
We developed a targeted, quantitative liquid chromatography-tandem mass spectrometry method for detection of gut bacterial polyphenol catabolites and identified 3-phenylpropionic acid as a key microbial metabolite in the portal plasma of Eld supplemented animals.
Results
We showed that 3-phenylpropionic acid potently activates hepatic AMP-activated protein kinase α, explaining its role in improved liver lipid homeostasis. We further uncovered the metabolic pathway cumulating in 3-phenylpropionic acid for the common gut commensal Clostridium sporogenes.
Conclusion
Our findings establish 3-phenylpropionic acid as a diet-derived, microbiota-dependent metabolite with insulin-sensitizing and anti-steatotic activities and provide a molecular basis for prebiotic interventions to improve host metabolic health.
{"title":"The diet-derived gut microbial metabolite 3-phenylpropionic acid reverses insulin resistance and obesity-associated metabolic dysfunction","authors":"Sara Alqudah , Beckey DeLucia , Lucas J. Osborn , Rachel L. Markley , Viharika Bobba , Sarah M. Preston , Tharika Thambidurai , Layan Hamidi Nia , Clifton G. Fulmer , Naseer Sangwan , Ina Nemet , Jan Claesen","doi":"10.1016/j.molmet.2025.102272","DOIUrl":"10.1016/j.molmet.2025.102272","url":null,"abstract":"<div><h3>Background/Purpose</h3><div>Obesity-associated metabolic disorders, including type 2 diabetes and metabolic dysfunction associated fatty liver disease (MAFLD), are major global health burdens. While dietary polyphenols have shown promise in ameliorating these conditions, their efficacy is dependent on specialized gut microbial metabolism, and the underlying molecular mechanisms remain mostly elusive. Here, we demonstrate that dietary supplementation with polyphenol-rich elderberry (Eld) extract abrogates the effects of an obesogenic diet in a gut microbiota-dependent manner, preventing insulin resistance and reducing hepatic steatosis in mice.</div></div><div><h3>Methods</h3><div>We developed a targeted, quantitative liquid chromatography-tandem mass spectrometry method for detection of gut bacterial polyphenol catabolites and identified 3-phenylpropionic acid as a key microbial metabolite in the portal plasma of Eld supplemented animals.</div></div><div><h3>Results</h3><div>We showed that 3-phenylpropionic acid potently activates hepatic AMP-activated protein kinase α, explaining its role in improved liver lipid homeostasis. We further uncovered the metabolic pathway cumulating in 3-phenylpropionic acid for the common gut commensal <em>Clostridium sporogenes</em>.</div></div><div><h3>Conclusion</h3><div>Our findings establish 3-phenylpropionic acid as a diet-derived, microbiota-dependent metabolite with insulin-sensitizing and anti-steatotic activities and provide a molecular basis for prebiotic interventions to improve host metabolic health.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102272"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329570","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 : 2025-11-01Epub Date: 2025-08-25DOI: 10.1016/j.molmet.2025.102239
Mariko Aoyagi Keller , Andreas Ivessa , Tong Liu , Hong Li , Peter J. Romanienko , Michinari Nakamura
Diets influence metabolism and disease susceptibility, with lysine acetyltransferases (KATs) serving as key regulators through acetyl-CoA. We have previously demonstrated that a ketogenic diet alleviates cardiac pathology, though the underlying mechanisms remain largely unknown. Here we show that KAT6A acetylation is crucial for mitochondrial function and cell growth. Proteomic analysis revealed that KAT6A is acetylated at lysine (K)816 in the hearts of mice fed a ketogenic diet under hypertension, which enhances its interaction with AMPK regulatory subunits. RNA-sequencing analysis demonstrated that the KAT6A acetylation-mimetic mutant stimulates AMPK signaling in cardiomyocytes. Moreover, the acetylation-mimetic mutant mitigated phenylephrine-induced mitochondrial dysfunction and cardiomyocyte hypertrophy via AMPK activation. However, KAT6A-K816R acetylation-resistant knock-in mice unexpectedly exhibited smaller hearts with enhanced AMPK activity, conferring protection against neurohumoral stress-induced cardiac hypertrophy and remodeling. These findings indicate that KAT6A regulates metabolism and cellular growth by interacting with and modulating AMPK activity through K816-acetylation in a cell type-specific manner.
{"title":"KAT6A acetylation regulates AMPK function and hypertrophic remodeling in the heart","authors":"Mariko Aoyagi Keller , Andreas Ivessa , Tong Liu , Hong Li , Peter J. Romanienko , Michinari Nakamura","doi":"10.1016/j.molmet.2025.102239","DOIUrl":"10.1016/j.molmet.2025.102239","url":null,"abstract":"<div><div>Diets influence metabolism and disease susceptibility, with lysine acetyltransferases (KATs) serving as key regulators through acetyl-CoA. We have previously demonstrated that a ketogenic diet alleviates cardiac pathology, though the underlying mechanisms remain largely unknown. Here we show that KAT6A acetylation is crucial for mitochondrial function and cell growth. Proteomic analysis revealed that KAT6A is acetylated at lysine (K)816 in the hearts of mice fed a ketogenic diet under hypertension, which enhances its interaction with AMPK regulatory subunits. RNA-sequencing analysis demonstrated that the KAT6A acetylation-mimetic mutant stimulates AMPK signaling in cardiomyocytes. Moreover, the acetylation-mimetic mutant mitigated phenylephrine-induced mitochondrial dysfunction and cardiomyocyte hypertrophy via AMPK activation. However, KAT6A-K816R acetylation-resistant knock-in mice unexpectedly exhibited smaller hearts with enhanced AMPK activity, conferring protection against neurohumoral stress-induced cardiac hypertrophy and remodeling. These findings indicate that KAT6A regulates metabolism and cellular growth by interacting with and modulating AMPK activity through K816-acetylation in a cell type-specific manner.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102239"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961656","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 : 2025-11-01Epub Date: 2025-09-10DOI: 10.1016/j.molmet.2025.102248
Michaela E. Trautman , Cara L. Green , Michael R. MacArthur , Krittisak Chaiyakul , Yasmine H. Alam , Chung-Yang Yeh , Reji Babygirija , Isabella James , Michael Gilpin , Esther Zelenovskiy , Madelyn Green , Ryan N. Marshall , Alexander Raskin , Michelle M. Sonsalla , Victoria Flores , Judith A. Simcox , Irene M. Ong , Kristen C. Malecki , Cholsoon Jang , Dudley W. Lamming
The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, there are some reports that dietary supplementation with extra BCAAs has health benefits. Further, the interactions between sex, genetic background, and dietary isoleucine levels in response to a Western Diet (WD) remain incompletely understood. Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain-independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 – and we find that in humans, plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, an analysis of human NHANES data shows that isoleucine content varies widely across foods, and that individuals with higher Healthy Eating Index scores tend to consume lower amounts of isoleucine. Our results suggest that the dietary level of isoleucine is a potential mediator of the metabolic and molecular response to a WD, and imply that reducing dietary isoleucine may represent a theoretically translatable strategy to protect from the negative metabolic consequences of a WD.
{"title":"Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice","authors":"Michaela E. Trautman , Cara L. Green , Michael R. MacArthur , Krittisak Chaiyakul , Yasmine H. Alam , Chung-Yang Yeh , Reji Babygirija , Isabella James , Michael Gilpin , Esther Zelenovskiy , Madelyn Green , Ryan N. Marshall , Alexander Raskin , Michelle M. Sonsalla , Victoria Flores , Judith A. Simcox , Irene M. Ong , Kristen C. Malecki , Cholsoon Jang , Dudley W. Lamming","doi":"10.1016/j.molmet.2025.102248","DOIUrl":"10.1016/j.molmet.2025.102248","url":null,"abstract":"<div><div>The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, there are some reports that dietary supplementation with extra BCAAs has health benefits. Further, the interactions between sex, genetic background, and dietary isoleucine levels in response to a Western Diet (WD) remain incompletely understood. Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain-independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 – and we find that in humans, plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, an analysis of human NHANES data shows that isoleucine content varies widely across foods, and that individuals with higher Healthy Eating Index scores tend to consume lower amounts of isoleucine. Our results suggest that the dietary level of isoleucine is a potential mediator of the metabolic and molecular response to a WD, and imply that reducing dietary isoleucine may represent a theoretically translatable strategy to protect from the negative metabolic consequences of a WD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102248"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054381","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 : 2025-11-01Epub Date: 2025-09-03DOI: 10.1016/j.molmet.2025.102243
Federica Campolo , Ottavia Giampaoli , Federica Barbagallo , Biagio Palmisano , Anna Di Maio , Francesca Sciarra , Flavio Rizzo , Serena Monti , Sandra Albanese , Silvia Cardarelli , Maria Rita Assenza , Eleonora Poggiogalle , Adriano Patriarca , Fabio Sciubba , Antonio Filippini , Andrea Lenzi , Daniele Gianfrilli , Mauro Giorgi , Susanna Dolci , Fabio Naro , Andrea M. Isidori
Objective
Cyclic nucleotides are central regulators of adipogenesis and adaptive thermogenesis, with their intracellular concentrations tightly controlled by phosphodiesterases (PDEs). Among them, phosphodiesterase type 5 (PDE5A) regulates cyclic guanosine monophosphate (cGMP) turnover in adipocytes. Although PDE5A inhibition has been explored in diabetes, its role in systemic metabolism remains poorly defined.
Methods
We employed different Pde5a knockout mouse models to investigate the impact of PDE5A deficiency on adipose tissue biology and whole-body energy homeostasis. Phenotypic, histological, and metabolic assessments were performed under chow and high-fat diet conditions, with a focus on thermogenic activation, hepatic lipid accumulation, and glucose metabolism.
Results
Loss of Pde5a resulted in robust activation of brown adipose tissue and moderate browning of white adipose depots, accompanied by a reduction in hepatic lipid content. Upon high-fat diet challenge, Pde5a-deficient mice exhibited resistance to obesity, improved glucose handling, and enhanced thermogenic capacity. Mechanistically, these protective effects originated from early developmental knockdown of Pde5a, which induced metabolic reprogramming via activation of the cAMP–protein kinase A (PKA) signaling pathway. The convergence of cGMP and cAMP signaling cascades orchestrated systemic metabolic adaptations.
Conclusions
Our study identifies PDE5A as a previously unrecognized regulator of thermogenesis and energy balance. Targeting PDE5A may therefore represent a promising adjuvant therapeutic approach for the treatment of metabolic disorders.
{"title":"Pde5a deficiency prevents diet-induced obesity via adipose cAMP-PKA activation enhancing fat browning","authors":"Federica Campolo , Ottavia Giampaoli , Federica Barbagallo , Biagio Palmisano , Anna Di Maio , Francesca Sciarra , Flavio Rizzo , Serena Monti , Sandra Albanese , Silvia Cardarelli , Maria Rita Assenza , Eleonora Poggiogalle , Adriano Patriarca , Fabio Sciubba , Antonio Filippini , Andrea Lenzi , Daniele Gianfrilli , Mauro Giorgi , Susanna Dolci , Fabio Naro , Andrea M. Isidori","doi":"10.1016/j.molmet.2025.102243","DOIUrl":"10.1016/j.molmet.2025.102243","url":null,"abstract":"<div><h3>Objective</h3><div>Cyclic nucleotides are central regulators of adipogenesis and adaptive thermogenesis, with their intracellular concentrations tightly controlled by phosphodiesterases (PDEs). Among them, phosphodiesterase type 5 (PDE5A) regulates cyclic guanosine monophosphate (cGMP) turnover in adipocytes. Although PDE5A inhibition has been explored in diabetes, its role in systemic metabolism remains poorly defined.</div></div><div><h3>Methods</h3><div>We employed different <em>Pde5a</em> knockout mouse models to investigate the impact of PDE5A deficiency on adipose tissue biology and whole-body energy homeostasis. Phenotypic, histological, and metabolic assessments were performed under chow and high-fat diet conditions, with a focus on thermogenic activation, hepatic lipid accumulation, and glucose metabolism.</div></div><div><h3>Results</h3><div>Loss of <em>Pde5a</em> resulted in robust activation of brown adipose tissue and moderate browning of white adipose depots, accompanied by a reduction in hepatic lipid content. Upon high-fat diet challenge, <em>Pde5a</em>-deficient mice exhibited resistance to obesity, improved glucose handling, and enhanced thermogenic capacity. Mechanistically, these protective effects originated from early developmental knockdown of <em>Pde5a</em>, which induced metabolic reprogramming via activation of the cAMP–protein kinase A (PKA) signaling pathway. The convergence of cGMP and cAMP signaling cascades orchestrated systemic metabolic adaptations.</div></div><div><h3>Conclusions</h3><div>Our study identifies PDE5A as a previously unrecognized regulator of thermogenesis and energy balance. Targeting PDE5A may therefore represent a promising adjuvant therapeutic approach for the treatment of metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102243"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006372","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 : 2025-11-01Epub Date: 2025-09-01DOI: 10.1016/j.molmet.2025.102244
Hetty N. Wong , Nathan Qi , Edward B. Arias , Kae Won Cho , Deepak Nihalani , Gregory D. Cartee , Lawrence B. Holzman
Metabolic syndrome and insulin resistance are driven in part by dysregulated signaling through the c-Jun N-terminal kinase (JNK) pathway. The scaffold protein JIP1 and its upstream kinase DLK (dual leucine zipper kinase) form a dynamic signaling complex that modulates JNK activity, yet the physiological role of DLK in glucose metabolism remains undefined. Here, we identify DLK as a critical regulator of insulin sensitivity using three genetically modified mouse models: a hypomorphic DLK allele, a tamoxifen-inducible whole-body DLK knockout, and a high-fat diet–induced obese model with DLK ablation. All models exhibited enhanced insulin sensitivity independent of adiposity, characterized by increased glucose uptake in muscle and adipose tissue, and improved suppression of hepatic glucose production during hyperinsulinemic-euglycemic clamp studies. Mechanistically, we demonstrate that DLK functions in a cell-autonomous manner, limiting insulin signaling through modulation of AKT and IRS1 phosphorylation downstream of insulin stimulation. In cultured myoblasts and fibroblasts, DLK was required for JNK activation and subsequent dampening of insulin signaling. These findings establish DLK as a regulator of whole-body insulin sensitivity, independent of obesity through a JIP-JNK signaling module. The results suggest that targeting DLK could represent a therapeutic strategy for improving insulin sensitivity in metabolic disease.
代谢综合征和胰岛素抵抗在一定程度上是由通过c-Jun n -末端激酶（JNK）途径的信号失调驱动的。支架蛋白JIP1及其上游激酶DLK（双亮氨酸拉链激酶）形成一个动态信号复合物，调节JNK的活性，但DLK在葡萄糖代谢中的生理作用尚不清楚。在这里，我们通过三种转基因小鼠模型确定DLK是胰岛素敏感性的关键调节因子：一种是半形DLK等位基因，一种是他莫昔芬诱导的全身DLK敲除，一种是高脂肪饮食诱导的DLK消融肥胖模型。所有模型均表现出与肥胖无关的胰岛素敏感性增强，其特征是肌肉和脂肪组织中葡萄糖摄取增加，并且在高胰岛素-正血糖钳夹研究中改善了对肝脏葡萄糖产生的抑制。在机制上，我们证明DLK以细胞自主的方式发挥作用，通过调节胰岛素刺激下游的AKT和IRS1磷酸化来限制胰岛素信号传导。在培养的成肌细胞和成纤维细胞中，JNK激活和随后的胰岛素信号抑制需要DLK。这些发现表明DLK是全身胰岛素敏感性的调节因子，通过JIP-JNK信号模块独立于肥胖。结果表明，靶向DLK可能是一种改善代谢性疾病胰岛素敏感性的治疗策略。
{"title":"Dual leucine zipper-bearing kinase DLK is necessary for cell autonomous regulation of insulin sensitivity","authors":"Hetty N. Wong , Nathan Qi , Edward B. Arias , Kae Won Cho , Deepak Nihalani , Gregory D. Cartee , Lawrence B. Holzman","doi":"10.1016/j.molmet.2025.102244","DOIUrl":"10.1016/j.molmet.2025.102244","url":null,"abstract":"<div><div>Metabolic syndrome and insulin resistance are driven in part by dysregulated signaling through the c-Jun N-terminal kinase (JNK) pathway. The scaffold protein JIP1 and its upstream kinase DLK (dual leucine zipper kinase) form a dynamic signaling complex that modulates JNK activity, yet the physiological role of DLK in glucose metabolism remains undefined. Here, we identify DLK as a critical regulator of insulin sensitivity using three genetically modified mouse models: a hypomorphic DLK allele, a tamoxifen-inducible whole-body DLK knockout, and a high-fat diet–induced obese model with DLK ablation. All models exhibited enhanced insulin sensitivity independent of adiposity, characterized by increased glucose uptake in muscle and adipose tissue, and improved suppression of hepatic glucose production during hyperinsulinemic-euglycemic clamp studies. Mechanistically, we demonstrate that DLK functions in a cell-autonomous manner, limiting insulin signaling through modulation of AKT and IRS1 phosphorylation downstream of insulin stimulation. In cultured myoblasts and fibroblasts, DLK was required for JNK activation and subsequent dampening of insulin signaling. These findings establish DLK as a regulator of whole-body insulin sensitivity, independent of obesity through a JIP-JNK signaling module. The results suggest that targeting DLK could represent a therapeutic strategy for improving insulin sensitivity in metabolic disease.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102244"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993012","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 : 2025-11-01Epub Date: 2025-09-11DOI: 10.1016/j.molmet.2025.102250
Andrea R. Ortiz , Kevin Nay , Brittany A. Stork , Adam M. Dean , Sean M. Hartig , Cristian Coarfa , Surafel Tegegne , Christopher RM. Asquith , Daniel E. Frigo , Brian York , Anthony R. Means , Mark A. Febbraio , John W. Scott
Objective
Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca2+-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic energy metabolism, and a coordinator of macrophage-mediated inflammatory responses. However, its role in obesity-associated metabolic dysfunction is not fully defined. The aim of this study was to determine the contribution of CAMKK2 to the regulation of inflammation and systemic metabolism during diet-induced obesity.
Methods
Mice with myeloid-specific deletion of Camkk2 were generated and challenged with a high-fat diet. Metabolic phenotyping, histological analyses, and transcriptomic profiling were used to assess whole-body metabolism, liver lipid accumulation, and gene expression in macrophages and adipose tissue.
Results
Myeloid-specific Camkk2 deficiency protected mice from high fat diet-induced obesity, insulin resistance and liver steatosis. These protective effects were associated with rewiring of metabolic and inflammatory gene expression in both macrophages and adipose tissue, along with enhanced whole-body energy expenditure.
Conclusions
Our data establish CAMKK2 as an important regulator of macrophage function and putative therapeutic target for treating obesity and related metabolic disorders.
{"title":"Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure","authors":"Andrea R. Ortiz , Kevin Nay , Brittany A. Stork , Adam M. Dean , Sean M. Hartig , Cristian Coarfa , Surafel Tegegne , Christopher RM. Asquith , Daniel E. Frigo , Brian York , Anthony R. Means , Mark A. Febbraio , John W. Scott","doi":"10.1016/j.molmet.2025.102250","DOIUrl":"10.1016/j.molmet.2025.102250","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca<sup>2+</sup>-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic energy metabolism, and a coordinator of macrophage-mediated inflammatory responses. However, its role in obesity-associated metabolic dysfunction is not fully defined. The aim of this study was to determine the contribution of CAMKK2 to the regulation of inflammation and systemic metabolism during diet-induced obesity.</div></div><div><h3>Methods</h3><div>Mice with myeloid-specific deletion of <em>Camkk2</em> were generated and challenged with a high-fat diet. Metabolic phenotyping, histological analyses, and transcriptomic profiling were used to assess whole-body metabolism, liver lipid accumulation, and gene expression in macrophages and adipose tissue.</div></div><div><h3>Results</h3><div>Myeloid-specific <em>Camkk2</em> deficiency protected mice from high fat diet-induced obesity, insulin resistance and liver steatosis. These protective effects were associated with rewiring of metabolic and inflammatory gene expression in both macrophages and adipose tissue, along with enhanced whole-body energy expenditure.</div></div><div><h3>Conclusions</h3><div>Our data establish CAMKK2 as an important regulator of macrophage function and putative therapeutic target for treating obesity and related metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102250"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058505","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}
Insulin deficiency caused by the loss of β cells and/or impaired insulin secretion is a key factor in the pathogenesis of type 2 diabetes (T2D). The restoration of β cell number and function is thus a promising strategy to combat diabetes. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) has been shown to regulate human β cell proliferation. DYRK1A inhibitors are potential therapeutic tools, due to their ability to induce β cell proliferation. However, their anti-diabetic effects in the complex setting of type 2 diabetes remains unexplored. The aim of this study was to determine the impact of chronic DYRK1A inhibition on the remission of diabetes in pre-diabetic and overtly diabetic Goto-Kakizaki (GK) rats.
Methods
We assessed the impact of in vivo treatment with a DYRK1A inhibitor, Leucettinib-92, on β cell proliferation and insulin secretion in GK rats. Further, we evaluated the effects of long-term Leucettinib-92 treatment on the whole-body glucose metabolism in overtly diabetic GK rats through the assessment of fasting and post-absorptive glycemia, glucose tolerance and insulin sensitivity.
Results
Short-term in vivo treatment of prediabetic GK rats with Leucettinb-92 stimulated β cell proliferation in vivo, and sustainably prevented the development of overt hyperglycemia. Long-term treatment of adult GK rats with established diabetes increased the β cell mass and reduced basal hyperglycemia. Leucettinib-92 treatment also improved glucose tolerance, and glucose-induced insulin secretion in vivo.
Conclusions
We show that DYRK1A inhibition restores the β cell mass and function in a preclinical model of T2D, leading to the improvement of body's global glucose homeostasis.
{"title":"DYRK1A inhibition restores pancreatic functions and improves glucose metabolism in a preclinical model of type 2 diabetes","authors":"Romane Bertrand , Stefania Tolu , Delphine Picot , Cécile Tourrel-Cuzin , Ayoub Ouahab , Julien Dairou , Emmanuel Deau , Mattias F. Lindberg , Laurent Meijer , Jamileh Movassat , Benjamin Uzan","doi":"10.1016/j.molmet.2025.102242","DOIUrl":"10.1016/j.molmet.2025.102242","url":null,"abstract":"<div><h3>Objectives</h3><div>Insulin deficiency caused by the loss of β cells and/or impaired insulin secretion is a key factor in the pathogenesis of type 2 diabetes (T2D). The restoration of β cell number and function is thus a promising strategy to combat diabetes. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) has been shown to regulate human β cell proliferation. DYRK1A inhibitors are potential therapeutic tools, due to their ability to induce β cell proliferation. However, their anti-diabetic effects in the complex setting of type 2 diabetes remains unexplored. The aim of this study was to determine the impact of chronic DYRK1A inhibition on the remission of diabetes in pre-diabetic and overtly diabetic Goto-Kakizaki (GK) rats.</div></div><div><h3>Methods</h3><div>We assessed the impact of <em>in vivo</em> treatment with a DYRK1A inhibitor, Leucettinib-92, on β cell proliferation and insulin secretion in GK rats. Further, we evaluated the effects of long-term Leucettinib-92 treatment on the whole-body glucose metabolism in overtly diabetic GK rats through the assessment of fasting and post-absorptive glycemia, glucose tolerance and insulin sensitivity.</div></div><div><h3>Results</h3><div>Short-term <em>in vivo</em> treatment of prediabetic GK rats with Leucettinb-92 stimulated β cell proliferation <em>in vivo</em>, and sustainably prevented the development of overt hyperglycemia. Long-term treatment of adult GK rats with established diabetes increased the β cell mass and reduced basal hyperglycemia. Leucettinib-92 treatment also improved glucose tolerance, and glucose-induced insulin secretion <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>We show that DYRK1A inhibition restores the β cell mass and function in a preclinical model of T2D, leading to the improvement of body's global glucose homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102242"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961608","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}
This study aimed to evaluate the role of alpha- and delta-cell signals on beta-cells within pancreatic mouse islets. Specifically, we investigated how these signals regulate glucose sensitivity, gene expression and function in beta-cells.
Methods
We first implemented our previous protocol to FACS purify alpha-, beta-, and delta-cells by adding CD81 as a positive marker for alpha-cells. We next developed an approach to reaggregate these sorted cell populations, creating chimeric islets with different proportions of each endocrine cell type. We used these chimeric islets to study the effect of alpha- and delta-cells on glucose sensitivity, gene expression and function in beta-cells.
Results
We generated chimeric islets containing either all three endocrine cell types, alpha- + beta-cells or only beta-cells. We demonstrate that beta-cell glucose sensitivity and identity are independent of signals from alpha- and delta-cells. We identified a subset of genes including Pro-dynorphin, Fumarate hydratase and Txnip whose expression in beta-cells depends on alpha-cells signals acting through the glucagon- and glucagon-like peptide receptors. Finally, we demonstrated that in mouse beta-cell, KCl-mediated insulin secretion relies on an activation of the glucagon-receptor, while glucose-stimulated insulin secretion depends on glucagon-like peptide receptor activation.
Conclusions
We developed an innovative and easy-to-use model to reconstruct chimeric islets containing different frequencies of alpha-, beta- and delta-cells. Through this approach, we provide new insights into the complex regulatory mechanisms governing the role of alpha and delta cells on beta-cell features within islets.
{"title":"Constructing chimeric mouse islets to study alpha- and delta-cell influence on beta-cell feature","authors":"Alexis Fouque , Masaya Oshima , Nina Mode , Romain Ducellier , Delphine Thibaut , Florence Gbahou , Latif Rachdi , Over Cabrera , Raphaël Scharfmann","doi":"10.1016/j.molmet.2025.102245","DOIUrl":"10.1016/j.molmet.2025.102245","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to evaluate the role of alpha- and delta-cell signals on beta-cells within pancreatic mouse islets. Specifically, we investigated how these signals regulate glucose sensitivity, gene expression and function in beta-cells.</div></div><div><h3>Methods</h3><div>We first implemented our previous protocol to FACS purify alpha-, beta-, and delta-cells by adding CD81 as a positive marker for alpha-cells. We next developed an approach to reaggregate these sorted cell populations, creating chimeric islets with different proportions of each endocrine cell type. We used these chimeric islets to study the effect of alpha- and delta-cells on glucose sensitivity, gene expression and function in beta-cells.</div></div><div><h3>Results</h3><div>We generated chimeric islets containing either all three endocrine cell types, alpha- + beta-cells or only beta-cells. We demonstrate that beta-cell glucose sensitivity and identity are independent of signals from alpha- and delta-cells. We identified a subset of genes including Pro-dynorphin, Fumarate hydratase and Txnip whose expression in beta-cells depends on alpha-cells signals acting through the glucagon- and glucagon-like peptide receptors. Finally, we demonstrated that in mouse beta-cell, KCl-mediated insulin secretion relies on an activation of the glucagon-receptor, while glucose-stimulated insulin secretion depends on glucagon-like peptide receptor activation.</div></div><div><h3>Conclusions</h3><div>We developed an innovative and easy-to-use model to reconstruct chimeric islets containing different frequencies of alpha-, beta- and delta-cells. Through this approach, we provide new insights into the complex regulatory mechanisms governing the role of alpha and delta cells on beta-cell features within islets.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102245"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993046","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 : 2025-11-01Epub Date: 2025-09-03DOI: 10.1016/j.molmet.2025.102246
Karina Cunha e Rocha , Breanna Tan , Julia Kempf , Cristina Medina , Varsha Beldona , Chengjia Qian , Ying Duan , Qian Xiang , Ahjin Yoo , Xiaomi Du , Amit R. Majithia , Wei Ying
Obesity is intricately linked to various metabolic diseases; however, some individuals maintain metabolic health despite being classified as obese. A critical factor underlying this paradox is the expansion of white adipose tissue (WAT), which can occur through two mechanisms: hypertrophy (the enlargement of existing fat cells) and hyperplasia (the formation of new fat cells from adipocyte precursor cells, or APCs). Hyperplasia is regarded as a healthier mode of WAT expansion, as it tends to reduce inflammation and protect against insulin resistance. Thus, interventions that promote hyperplasia over hypertrophy could improve metabolic health in obese individuals. In this study, we investigate the role of microRNA-690 (miR-690), an anti-inflammatory and insulin-sensitizing molecule, in maintaining the APC population and facilitating the healthy expansion of epididymal WAT (eWAT). Our findings indicate that in lean mice, macrophages support the APC population by transferring miR-690 to APCs. However, during obesity, the recruitment of pro-inflammatory lipid-associated macrophages (LAMs) to eWAT diminishes miR-690 delivery to APCs, impairing adipogenesis and leading to unhealthy WAT expansion. We demonstrate that strategies aimed at increasing the availability of miR-690 to APCs or mimicking its effects can restore APC functionality. Additionally, mutations in Nadk, the target of miR-690, were shown to mitigate the adverse effects of obesity on APC maintenance in eWAT. These findings suggest that targeting the miR-690-Nadk axis in APCs may provide novel therapeutic strategies to promote healthy adipose tissue expansion and protect against obesity-related metabolic diseases.
{"title":"Adipose tissue macrophage-derived miR-690 modulates adipocyte precursor cell maintenance and adipogenesis","authors":"Karina Cunha e Rocha , Breanna Tan , Julia Kempf , Cristina Medina , Varsha Beldona , Chengjia Qian , Ying Duan , Qian Xiang , Ahjin Yoo , Xiaomi Du , Amit R. Majithia , Wei Ying","doi":"10.1016/j.molmet.2025.102246","DOIUrl":"10.1016/j.molmet.2025.102246","url":null,"abstract":"<div><div>Obesity is intricately linked to various metabolic diseases; however, some individuals maintain metabolic health despite being classified as obese. A critical factor underlying this paradox is the expansion of white adipose tissue (WAT), which can occur through two mechanisms: hypertrophy (the enlargement of existing fat cells) and hyperplasia (the formation of new fat cells from adipocyte precursor cells, or APCs). Hyperplasia is regarded as a healthier mode of WAT expansion, as it tends to reduce inflammation and protect against insulin resistance. Thus, interventions that promote hyperplasia over hypertrophy could improve metabolic health in obese individuals. In this study, we investigate the role of microRNA-690 (miR-690), an anti-inflammatory and insulin-sensitizing molecule, in maintaining the APC population and facilitating the healthy expansion of epididymal WAT (eWAT). Our findings indicate that in lean mice, macrophages support the APC population by transferring miR-690 to APCs. However, during obesity, the recruitment of pro-inflammatory lipid-associated macrophages (LAMs) to eWAT diminishes miR-690 delivery to APCs, impairing adipogenesis and leading to unhealthy WAT expansion. We demonstrate that strategies aimed at increasing the availability of miR-690 to APCs or mimicking its effects can restore APC functionality. Additionally, mutations in Nadk, the target of miR-690, were shown to mitigate the adverse effects of obesity on APC maintenance in eWAT. These findings suggest that targeting the miR-690-Nadk axis in APCs may provide novel therapeutic strategies to promote healthy adipose tissue expansion and protect against obesity-related metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102246"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006335","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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