Pub Date : 2025-12-16DOI: 10.1016/j.molmet.2025.102303
M. Yang , A. de Araujo , J. Shakir , I. Braga , R. Mendez-Hernandez , G.S.S. Tofani , A. Bali , J. de Lartigue , H. Song , J.E. McCutcheon , C.D. Morrison , G. de Lartigue
Animals adaptively adjust nutrient intake based on internal physiological need. Although protein deficiency elicits robust behavioral and endocrine responses, the sensory mechanisms that detect dietary protein and guide selective feeding remain incompletely understood. Here, we identify a population of vagal sensory neurons that respond selectively to intragastric protein and are required for adaptive regulation of protein intake. Using activity-dependent genetic labeling and in vivo calcium imaging, we show that these neurons are activated by dietary protein, exhibit enhanced responses in protein-restricted states, and are distinct from previously characterized calorie-sensing populations. Selective ablation of protein-responsive vagal sensory neurons disrupts the ability to adapt eating behavior to internal protein need, blunts motivation to work for protein rewards, and prevents behavioral updating following protein repletion. These neurons also mediate protein-specific satiety, limiting further protein intake without affecting carbohydrate consumption. Notably, protein preference is suppressed under mild caloric restriction, indicating that caloric and amino acid needs are hierarchically organized and likely monitored by separate interoceptive systems. Our findings reveal a novel vagal circuit that integrates internal protein status with nutrient-specific cues to guide adaptive protein appetite and maintain amino acid homeostasis.
{"title":"Vagal sensory neurons encode internal protein status to guide eating","authors":"M. Yang , A. de Araujo , J. Shakir , I. Braga , R. Mendez-Hernandez , G.S.S. Tofani , A. Bali , J. de Lartigue , H. Song , J.E. McCutcheon , C.D. Morrison , G. de Lartigue","doi":"10.1016/j.molmet.2025.102303","DOIUrl":"10.1016/j.molmet.2025.102303","url":null,"abstract":"<div><div>Animals adaptively adjust nutrient intake based on internal physiological need. Although protein deficiency elicits robust behavioral and endocrine responses, the sensory mechanisms that detect dietary protein and guide selective feeding remain incompletely understood. Here, we identify a population of vagal sensory neurons that respond selectively to intragastric protein and are required for adaptive regulation of protein intake. Using activity-dependent genetic labeling and in vivo calcium imaging, we show that these neurons are activated by dietary protein, exhibit enhanced responses in protein-restricted states, and are distinct from previously characterized calorie-sensing populations. Selective ablation of protein-responsive vagal sensory neurons disrupts the ability to adapt eating behavior to internal protein need, blunts motivation to work for protein rewards, and prevents behavioral updating following protein repletion. These neurons also mediate protein-specific satiety, limiting further protein intake without affecting carbohydrate consumption. Notably, protein preference is suppressed under mild caloric restriction, indicating that caloric and amino acid needs are hierarchically organized and likely monitored by separate interoceptive systems. Our findings reveal a novel vagal circuit that integrates internal protein status with nutrient-specific cues to guide adaptive protein appetite and maintain amino acid homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102303"},"PeriodicalIF":6.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781567","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 : 2025-12-16DOI: 10.1016/j.molmet.2025.102305
Julius E R Grothen, Jaime M Martinez, Nikos Sidiropoulos, Lucas Massier, Danae Zareifi, Jiawei Zhong, Ida Davidsen, Jette W Platou, Jette Mandelbaum, Pia Rothe, Henning Hvid, Mads Grønborg, Christian Toft Madsen, Jens M Bruun, Mikael Rydén, Niklas Mejhert, Jørn W Helge, Zachary Gerhart-Hines, Thomas Å Pedersen
Background: Combination of increased physical exercise and hypocaloric diet has long been recognized to improve cardiometabolic health and adipose tissue function, including lipid turnover. How such lifestyle interventions mediate benefits at the cellular level remains unknown. Given the critical role of subcutaneous white adipose tissue (scWAT) to systemic metabolic homeostasis, we set out to interrogate how exercise and diet lifestyle intervention impacted scWAT in individuals living with obesity, with a particular focus on lipolytic capacity and cell-specific gene profiling.
Methods: Single nuclei RNA sequencing (snRNAseq) was performed on cryopreserved scWAT biopsies originally collected before and after lifestyle intervention, involving regular exercise and hypocaloric diet in obese individuals. Findings on regulation of lipolysis in adipocytes were followed up with meta-analysis of clinical studies and pharmacological experiments in mature human adipocytes.
Results: snRNAseq analysis revealed intervention-induced changes in all scWAT cell-types. In adipocytes genes linked to protein and organelle turnover, branch chain amino acid catabolism, and lipolytic control were most significantly regulated. We identified a cell autonomous brake on adipocyte lipolysis via the neuropeptide Y receptor 1 (NPY1R). Expression of adipocyte NPY1R was reduced after weight loss and correlated positively with body fat percentage and body mass index. Findings were confirmed in meta-analysis across 23 studies. Finally, we found a negative correlation between NPY1R and beta-adrenergic-induced lipolysis and that NPY dose-dependently attenuated lipolysis and cAMP-signaling in primary human subcutaneous adipocytes.
Conclusions: Our work suggests that decreases in adipocyte NPY1R during weight loss boost lipolytic capacity and contribute to improved systemic cardiometabolic health.
{"title":"Single cell transcriptomics of human weight loss links adipocyte NPY1R to control of lipolysis.","authors":"Julius E R Grothen, Jaime M Martinez, Nikos Sidiropoulos, Lucas Massier, Danae Zareifi, Jiawei Zhong, Ida Davidsen, Jette W Platou, Jette Mandelbaum, Pia Rothe, Henning Hvid, Mads Grønborg, Christian Toft Madsen, Jens M Bruun, Mikael Rydén, Niklas Mejhert, Jørn W Helge, Zachary Gerhart-Hines, Thomas Å Pedersen","doi":"10.1016/j.molmet.2025.102305","DOIUrl":"10.1016/j.molmet.2025.102305","url":null,"abstract":"<p><strong>Background: </strong>Combination of increased physical exercise and hypocaloric diet has long been recognized to improve cardiometabolic health and adipose tissue function, including lipid turnover. How such lifestyle interventions mediate benefits at the cellular level remains unknown. Given the critical role of subcutaneous white adipose tissue (scWAT) to systemic metabolic homeostasis, we set out to interrogate how exercise and diet lifestyle intervention impacted scWAT in individuals living with obesity, with a particular focus on lipolytic capacity and cell-specific gene profiling.</p><p><strong>Methods: </strong>Single nuclei RNA sequencing (snRNAseq) was performed on cryopreserved scWAT biopsies originally collected before and after lifestyle intervention, involving regular exercise and hypocaloric diet in obese individuals. Findings on regulation of lipolysis in adipocytes were followed up with meta-analysis of clinical studies and pharmacological experiments in mature human adipocytes.</p><p><strong>Results: </strong>snRNAseq analysis revealed intervention-induced changes in all scWAT cell-types. In adipocytes genes linked to protein and organelle turnover, branch chain amino acid catabolism, and lipolytic control were most significantly regulated. We identified a cell autonomous brake on adipocyte lipolysis via the neuropeptide Y receptor 1 (NPY1R). Expression of adipocyte NPY1R was reduced after weight loss and correlated positively with body fat percentage and body mass index. Findings were confirmed in meta-analysis across 23 studies. Finally, we found a negative correlation between NPY1R and beta-adrenergic-induced lipolysis and that NPY dose-dependently attenuated lipolysis and cAMP-signaling in primary human subcutaneous adipocytes.</p><p><strong>Conclusions: </strong>Our work suggests that decreases in adipocyte NPY1R during weight loss boost lipolytic capacity and contribute to improved systemic cardiometabolic health.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102305"},"PeriodicalIF":6.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781569","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 : 2025-12-15DOI: 10.1016/j.molmet.2025.102308
Nandini K. Doshi , Tristan Pesaresi , Trishya Pagadala , William Dion , Yang Zhang , Natalie L. David , Tânia Amorim , Wenjia Wang , G.V. Naveen Kumar , Bokai Zhu , Silvia Liu , Parth Patwari , Pouneh K. Fazeli , Matthew L. Steinhauser
Sterile inflammation is associated with a broad range of metabolic stressors including both dietary excess and prolonged fasting. In a 10-day human fasting study, we previously identified a surge in the circulating inflammatory biomarker, C-reactive protein (CRP), which we leveraged in the current study to identify novel metabolic inflammatory correlates. With a variety of longitudinal metabolic variables as input, including metabolomics, we identified branched chain amino acids (BCAA) as the top candidate inflammatory correlate. We then used in vitro myeloid/macrophage culture and in vivo murine models to test BCAA as a determinant of inflammatory signaling. Short-term exposure to BCAA alone had modest effects on a variety of immune readouts; however, when coupled with a second stimulus, such as exposure to endotoxin or when administered to diet-induced obese mice, members of the JAK/STAT/cytokine signaling pathways were augmented on the transcriptional level by concurrent BCAA administration in multiple tissues, including visceral adipose and liver. The modifying effect of BCAA on inflammatory stressors translated into increased levels of circulating inflammatory cytokines. Collectively, these data position BCAA as an immune priming factor, a potential mechanism underlying the well-established association between circulating BCAA and diverse diseases of aging.
{"title":"Branched chain amino acids prime metabolic inflammation","authors":"Nandini K. Doshi , Tristan Pesaresi , Trishya Pagadala , William Dion , Yang Zhang , Natalie L. David , Tânia Amorim , Wenjia Wang , G.V. Naveen Kumar , Bokai Zhu , Silvia Liu , Parth Patwari , Pouneh K. Fazeli , Matthew L. Steinhauser","doi":"10.1016/j.molmet.2025.102308","DOIUrl":"10.1016/j.molmet.2025.102308","url":null,"abstract":"<div><div>Sterile inflammation is associated with a broad range of metabolic stressors including both dietary excess and prolonged fasting. In a 10-day human fasting study, we previously identified a surge in the circulating inflammatory biomarker, C-reactive protein (CRP), which we leveraged in the current study to identify novel metabolic inflammatory correlates. With a variety of longitudinal metabolic variables as input, including metabolomics, we identified branched chain amino acids (BCAA) as the top candidate inflammatory correlate. We then used <em>in vitro</em> myeloid/macrophage culture and <em>in vivo</em> murine models to test BCAA as a determinant of inflammatory signaling. Short-term exposure to BCAA alone had modest effects on a variety of immune readouts; however, when coupled with a second stimulus, such as exposure to endotoxin or when administered to diet-induced obese mice, members of the JAK/STAT/cytokine signaling pathways were augmented on the transcriptional level by concurrent BCAA administration in multiple tissues, including visceral adipose and liver. The modifying effect of BCAA on inflammatory stressors translated into increased levels of circulating inflammatory cytokines. Collectively, these data position BCAA as an immune priming factor, a potential mechanism underlying the well-established association between circulating BCAA and diverse diseases of aging.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102308"},"PeriodicalIF":6.6,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775023","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 : 2025-12-09DOI: 10.1016/j.molmet.2025.102299
Ethan C. Fein , Sarmistha Mukherjee , Joseph A. Baur , Patrick Seale
Brown adipose tissue (BAT) dissipates energy as heat in response to β-adrenergic signaling induced by the sympathetic nervous system (SNS). While this pathway is essential for the cold-induced remodeling and metabolic activity of BAT, its role in developmental programming is unclear. Here, we show that brown adipocytes acquire thermogenic identity during embryogenesis independently of sympathetic innervation and β-adrenergic signaling. Genetic sympathectomy or disrupted β-adrenergic signaling had minimal effects on thermogenic gene expression or tissue morphology during either embryonic or postnatal BAT development in the absence of cold stress. Functional analyses revealed that the SNS is likely required for circulatory support of BAT activity during β-adrenergic stimulation but not for the development of the thermogenic capacity of BAT itself. These findings demonstrate that developmental and cold-responsive BAT remodeling are mechanistically distinct processes. Defining the molecular programs that drive BAT development may reveal new strategies to enhance BAT formation and function without relying on β-adrenergic stimulation.
{"title":"The innate thermogenic capacity of brown adipose tissue develops independently of sympathetic signaling","authors":"Ethan C. Fein , Sarmistha Mukherjee , Joseph A. Baur , Patrick Seale","doi":"10.1016/j.molmet.2025.102299","DOIUrl":"10.1016/j.molmet.2025.102299","url":null,"abstract":"<div><div>Brown adipose tissue (BAT) dissipates energy as heat in response to β-adrenergic signaling induced by the sympathetic nervous system (SNS). While this pathway is essential for the cold-induced remodeling and metabolic activity of BAT, its role in developmental programming is unclear. Here, we show that brown adipocytes acquire thermogenic identity during embryogenesis independently of sympathetic innervation and β-adrenergic signaling. Genetic sympathectomy or disrupted β-adrenergic signaling had minimal effects on thermogenic gene expression or tissue morphology during either embryonic or postnatal BAT development in the absence of cold stress. Functional analyses revealed that the SNS is likely required for circulatory support of BAT activity during β-adrenergic stimulation but not for the development of the thermogenic capacity of BAT itself. These findings demonstrate that developmental and cold-responsive BAT remodeling are mechanistically distinct processes. Defining the molecular programs that drive BAT development may reveal new strategies to enhance BAT formation and function without relying on β-adrenergic stimulation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102299"},"PeriodicalIF":6.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743408","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 : 2025-12-04DOI: 10.1016/j.molmet.2025.102296
Matthew T. Dickerson , Prasanna K. Dadi , Reagan P. McDevitt , Jordyn R. Dobson , Soma Behera , Spencer J. Peachee , Shannon E. Gibson , Tenzin Wangmo , David A. Jacobson
Electrogenic Na+/K+ ATPases (NKAs) control β-cell Ca2+ influx and insulin secretion by integrating the signal strength of stimulatory G protein (Gs)-coupled ligands (e.g., GLP-1, glucagon) and inhibitory G protein (Gi)-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 Gi-GPCR effects and augmenting Gs-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.
{"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 , Prasanna K. Dadi , Reagan P. McDevitt , Jordyn R. Dobson , Soma Behera , Spencer J. Peachee , Shannon E. Gibson , Tenzin Wangmo , David A. Jacobson","doi":"10.1016/j.molmet.2025.102296","DOIUrl":"10.1016/j.molmet.2025.102296","url":null,"abstract":"<div><div>Electrogenic Na<sup>+</sup>/K<sup>+</sup> ATPases (NKAs) control β-cell Ca<sup>2+</sup> influx and insulin secretion by integrating the signal strength of stimulatory G protein (G<sub>s</sub>)-coupled ligands (e.g., GLP-1, glucagon) and inhibitory G protein (G<sub>i</sub>)-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 Ca<sup>2+</sup> entry by impairing glycolysis-dependent NKA activation and reduces Na<sup>+</sup> clearance efficiency during Ca<sup>2+</sup> oscillations, resulting in prolonged silent phases. Thus, glycolytic stimulation of Na<sup>+</sup> influx dictates silent phase duration via the kinetics of Na<sup>+</sup> 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<sub>i</sub>-GPCR effects and augmenting G<sub>s</sub>-coupled GLP-1 receptor-mediated cAMP production and Ca<sup>2+</sup> entry. β-cell NKAβ1 knockdown in human pseudoislets led to tonically elevated intracellular Ca<sup>2+</sup> and increased insulin secretion. These findings establish NKAβ1-containing NKA complexes as critical regulators of β-cell electrical activity, Ca<sup>2+</sup> 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":"2025-12-04","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}
Pub 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":"2025-12-03","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 : 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":"2025-12-02","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 : 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":"2025-11-29","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 : 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。
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Pub Date : 2025-11-29DOI: 10.1016/j.molmet.2025.102294
Dipsikha Biswas , Ever Espino-Gonzalez , Danial Ahwazi , Jordana B. Freemantle , Amy M. Ehrlich , Charline Jomard , Jonas Brorson , Agnete N. Schou , Jean Farup , Julien Gondin , Jesper Just , Marc Foretz , Jonas T. Treebak , Marianne Agerholm , Kei Sakamoto
Objectives
Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle.
Methods
Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1−/−/γ3−/−) and single knockout (imγ1−/− and imγ3−/−) mice were generated. Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed.
Results
snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. Ex vivo, glucose uptake stimulated by either AICAR or MK-8722 was severely blunted in imγ1−/−/γ3−/− muscle, and MK-8722-induced blood glucose lowering was significantly blunted in vivo. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3−/−, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1−/− mice.
Conclusions
While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.
{"title":"Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle","authors":"Dipsikha Biswas , Ever Espino-Gonzalez , Danial Ahwazi , Jordana B. Freemantle , Amy M. Ehrlich , Charline Jomard , Jonas Brorson , Agnete N. Schou , Jean Farup , Julien Gondin , Jesper Just , Marc Foretz , Jonas T. Treebak , Marianne Agerholm , Kei Sakamoto","doi":"10.1016/j.molmet.2025.102294","DOIUrl":"10.1016/j.molmet.2025.102294","url":null,"abstract":"<div><h3>Objectives</h3><div>Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle.</div></div><div><h3>Methods</h3><div>Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1<sup>−/−</sup>/γ3<sup>−/−</sup>) and single knockout (imγ1<sup>−/−</sup> and imγ3<sup>−/−</sup>) mice were generated<em>. Ex vivo</em> glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and <em>in vivo</em> MK-8722-induced blood glucose lowering was assessed.</div></div><div><h3>Results</h3><div>snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. <em>Ex vivo</em>, glucose uptake stimulated by either AICAR or MK-8722 was severely blunted in imγ1<sup>−/−</sup>/γ3<sup>−/−</sup> muscle, and MK-8722-induced blood glucose lowering was significantly blunted <em>in vivo</em>. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3<sup>−/−</sup>, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1<sup>−/−</sup> mice.</div></div><div><h3>Conclusions</h3><div>While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102294"},"PeriodicalIF":6.6,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654769","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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