Pub Date : 2026-01-01DOI: 10.1016/j.molmet.2025.102298
William Roell, Jorge Alsina-Fernandez, Hongchang Qu, Tamer Coskun, Charles Benson, Axel Haupt, Ronan P. Kelly, Libbey O'Farrell, Kyle W. Sloop, James P. Steele, James Ficorilli, Ajit Regmi, Mallikarjuna Rettiganti, Shweta Urva, Kieren J. Mather, Edward Pratt
<div><h3>Background</h3><div>Tirzepatide, a single-molecule dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor (R) agonist, has shown superiority in the reduction of blood glucose and body weight, above selective GLP-1R agonists, but the contribution of GIP to these effects remains incompletely understood.</div></div><div><h3>Objectives</h3><div>To characterize the preclinical and in-human effects of a long-acting GIPR agonist monotherapy in healthy participants and patients with type 2 diabetes (T2D).</div></div><div><h3>Methods</h3><div>A long-acting GIPR agonist (LY3537021) was characterized <em>in vitro</em> and in Long-Evans diet-induced obese rats and Wistar rats. Next, a phase 1, randomized, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) study explored the safety, tolerability, pharmacokinetics, and pharmacodynamics of LY3537021 in healthy participants and participants with T2D in Singapore.</div></div><div><h3>Results</h3><div><em>In vitro</em>, LY3537021 demonstrated potency greater than native GIP and selectivity for the GIPR. <em>In vivo</em> in rats, chronic treatment with LY3537021 resulted in weight loss and improved glycemic control during a glucose tolerance test. The phase 1 clinical study enrolled 85 healthy participants and patients with T2D (SAD, n = 47 [aged 25–64 years]; MAD, n = 38 [aged 25–69 years]; average baseline BMI was 25.9–27.0 kg/m<sup>2</sup> across the arms). During the MAD part, dose-dependent decreases in mean body weight were observed in all LY3537021 dose groups, regardless of T2D status, and persisted at 35 days after the last dose. For example, participants with T2D treated with 25 mg of LY3537021 lost a mean of 3.14 kg of body weight compared with 0.36 kg in the placebo group (p < 0.05) at day 57. Transient reductions in fasting glucose were observed in these participants, but the reductions were not sustained and not significantly different from placebo at day 29. The time to maximum observed drug concentrations varied across cohorts (8–96 h), and the half-life was estimated at approximately 12 days for non-T2D and T2D cohorts with the 25-mg dose, supporting once-weekly administration. There was no delay in gastric emptying following a single subcutaneous dose of 0.3–25 mg LY3537021. LY3537021 was well tolerated with infrequent gastrointestinal adverse events.</div></div><div><h3>Conclusions</h3><div><em>In vivo</em> studies demonstrated that LY3537021 reduced body weight and improved glycemia during a glucose challenge in rats. The phase 1 study demonstrated that the long-acting GIPR agonist LY3537021 was well tolerated, induced weight loss, and improved glucose control in humans. These observations better define the therapeutic benefit of long-acting GIPR agonists and support a distinct contribution of GIP agonism to the benefits observed with multi-agonist peptides that act via the GIPR. Future studies are needed in more di
{"title":"Long-acting GIPR agonist LY3537021 reduces body weight and fasting blood glucose in patients with T2D: Preclinical development and phase 1 randomized ascending dose studies","authors":"William Roell, Jorge Alsina-Fernandez, Hongchang Qu, Tamer Coskun, Charles Benson, Axel Haupt, Ronan P. Kelly, Libbey O'Farrell, Kyle W. Sloop, James P. Steele, James Ficorilli, Ajit Regmi, Mallikarjuna Rettiganti, Shweta Urva, Kieren J. Mather, Edward Pratt","doi":"10.1016/j.molmet.2025.102298","DOIUrl":"10.1016/j.molmet.2025.102298","url":null,"abstract":"<div><h3>Background</h3><div>Tirzepatide, a single-molecule dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor (R) agonist, has shown superiority in the reduction of blood glucose and body weight, above selective GLP-1R agonists, but the contribution of GIP to these effects remains incompletely understood.</div></div><div><h3>Objectives</h3><div>To characterize the preclinical and in-human effects of a long-acting GIPR agonist monotherapy in healthy participants and patients with type 2 diabetes (T2D).</div></div><div><h3>Methods</h3><div>A long-acting GIPR agonist (LY3537021) was characterized <em>in vitro</em> and in Long-Evans diet-induced obese rats and Wistar rats. Next, a phase 1, randomized, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) study explored the safety, tolerability, pharmacokinetics, and pharmacodynamics of LY3537021 in healthy participants and participants with T2D in Singapore.</div></div><div><h3>Results</h3><div><em>In vitro</em>, LY3537021 demonstrated potency greater than native GIP and selectivity for the GIPR. <em>In vivo</em> in rats, chronic treatment with LY3537021 resulted in weight loss and improved glycemic control during a glucose tolerance test. The phase 1 clinical study enrolled 85 healthy participants and patients with T2D (SAD, n = 47 [aged 25–64 years]; MAD, n = 38 [aged 25–69 years]; average baseline BMI was 25.9–27.0 kg/m<sup>2</sup> across the arms). During the MAD part, dose-dependent decreases in mean body weight were observed in all LY3537021 dose groups, regardless of T2D status, and persisted at 35 days after the last dose. For example, participants with T2D treated with 25 mg of LY3537021 lost a mean of 3.14 kg of body weight compared with 0.36 kg in the placebo group (p < 0.05) at day 57. Transient reductions in fasting glucose were observed in these participants, but the reductions were not sustained and not significantly different from placebo at day 29. The time to maximum observed drug concentrations varied across cohorts (8–96 h), and the half-life was estimated at approximately 12 days for non-T2D and T2D cohorts with the 25-mg dose, supporting once-weekly administration. There was no delay in gastric emptying following a single subcutaneous dose of 0.3–25 mg LY3537021. LY3537021 was well tolerated with infrequent gastrointestinal adverse events.</div></div><div><h3>Conclusions</h3><div><em>In vivo</em> studies demonstrated that LY3537021 reduced body weight and improved glycemia during a glucose challenge in rats. The phase 1 study demonstrated that the long-acting GIPR agonist LY3537021 was well tolerated, induced weight loss, and improved glucose control in humans. These observations better define the therapeutic benefit of long-acting GIPR agonists and support a distinct contribution of GIP agonism to the benefits observed with multi-agonist peptides that act via the GIPR. Future studies are needed in more di","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102298"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757074","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 : 2026-01-01DOI: 10.1016/j.molmet.2025.102306
Xiaohan Yang , Lun Hua , Dengfeng Gao , Yanni Wu , Yi Yang , Xianyang Jin , Xuemei Jiang , Chao Jin , Bin Feng , Lianqiang Che , Shengyu Xu , Yan Lin , Long Jin , Yong Zhuo , Mingzhou Li , De Wu
High-protein (HP) diets are widely adopted in Western societies for body-weight management; yet, they exacerbate senescence-associated metabolic deterioration, posing an unresolved pathophysiological conundrum. Here, we demonstrate that long-term HP intake mediates adipocyte-specific NAD+ depletion and mitochondrial dysfunction in white adipose tissue (WAT). Single-nucleus transcriptomic analyses revealed adipocyte-restricted senescence signatures in HP-fed mice. Mechanistically, HP intake triggers macrophage-specific upregulation of CD38 (a key NAD+ hydrolase), which depletes adipocyte NAD+ pools and thereby accelerates cellular senescence. Restoration of NAD+ levels, either via supplementation with NAD+ precursor or pharmacological inhibition of CD38 activity, alleviated the senescence-associated metabolic sequelae induced by HP diets. Our findings establish macrophage-adipocyte NAD+ crosstalk as a central axis linking dietary protein excess to WAT aging, providing actionable targets for the prevention and treatment of age-related metabolic disorders.
{"title":"Long-term high-protein diet intake accelerates adipocyte senescence through macrophage CD38-mediated NAD+ depletion","authors":"Xiaohan Yang , Lun Hua , Dengfeng Gao , Yanni Wu , Yi Yang , Xianyang Jin , Xuemei Jiang , Chao Jin , Bin Feng , Lianqiang Che , Shengyu Xu , Yan Lin , Long Jin , Yong Zhuo , Mingzhou Li , De Wu","doi":"10.1016/j.molmet.2025.102306","DOIUrl":"10.1016/j.molmet.2025.102306","url":null,"abstract":"<div><div>High-protein (HP) diets are widely adopted in Western societies for body-weight management; yet, they exacerbate senescence-associated metabolic deterioration, posing an unresolved pathophysiological conundrum. Here, we demonstrate that long-term HP intake mediates adipocyte-specific NAD<sup>+</sup> depletion and mitochondrial dysfunction in white adipose tissue (WAT). Single-nucleus transcriptomic analyses revealed adipocyte-restricted senescence signatures in HP-fed mice. Mechanistically, HP intake triggers macrophage-specific upregulation of CD38 (a key NAD<sup>+</sup> hydrolase), which depletes adipocyte NAD<sup>+</sup> pools and thereby accelerates cellular senescence. Restoration of NAD<sup>+</sup> levels, either via supplementation with NAD<sup>+</sup> precursor or pharmacological inhibition of CD38 activity, alleviated the senescence-associated metabolic sequelae induced by HP diets. Our findings establish macrophage-adipocyte NAD<sup>+</sup> crosstalk as a central axis linking dietary protein excess to WAT aging, providing actionable targets for the prevention and treatment of age-related metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102306"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763253","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 : 2026-01-01DOI: 10.1016/j.molmet.2025.102311
Bernardo Yusta, Chi Kin Wong, Dianne Matthews, Jacqueline A. Koehler, Laurie L. Baggio, Daniel J. Drucker
Background
Glucagon-like peptide-2 (GLP-2) reduces systemic and gut inflammation while preserving mucosal integrity. Preclinical and clinical reports implicate GLP-2 receptor (GLP-2R) agonism as a potential therapy for graft vs. host disease (GvHD).
Methods
Here we assessed whether enhanced vs. loss of GLP-2R signaling modifies gut injury and inflammation in experimental murine acute GvHD (aGvHD). Allogeneic hematopoietic cell transplantation (HCT) was performed using bone marrow and splenocytes from BALB/cJ donor mice to induce aGvHD in C57BL/6J recipients. Chimerism was determined by flow cytometry of immune cell compartments. Inflammation was assessed by measuring circulating cytokines and histological scoring of gut mucosal damage. GLP-2 responsivity was assessed using histology and gene expression analyses. The gut microbiome was assessed by 16S rRNA sequencing.
Results
Allogeneic chimerism was >90% in peripheral blood and in the gut epithelial compartment. Gut GLP-2R signaling was preserved following allogeneic bone marrow transplantation. Surprisingly, GLP-2R agonism using teduglutide did not reduce circulating cytokines, gut injury, immune cell infiltration or the severity of aGvHD. In contrast, transplant recipient Glp2r−/− mice exhibited reduced survival, associated with increased bacteremia. Shifts in microbial species abundance with gain or loss of GLP-2R signaling were not correlated with aGvHD clinical outcomes.
Conclusions
Activation of GLP-2R signaling did not reduce the severity of experimental aGvHD, failing to replicate a previous study using an identical aGvHD protocol. Nevertheless, loss of GLP-2R signaling in transplant recipients decreased survival and increased bacteremia, implicating an essential role for endogenous GLP-2R signaling in maintaining barrier function in the context of immune-mediated gut epithelial injury.
{"title":"Loss of GLP-2R signaling in Glp2r−/− mice increases the long-term severity of graft versus host disease","authors":"Bernardo Yusta, Chi Kin Wong, Dianne Matthews, Jacqueline A. Koehler, Laurie L. Baggio, Daniel J. Drucker","doi":"10.1016/j.molmet.2025.102311","DOIUrl":"10.1016/j.molmet.2025.102311","url":null,"abstract":"<div><h3>Background</h3><div>Glucagon-like peptide-2 (GLP-2) reduces systemic and gut inflammation while preserving mucosal integrity. Preclinical and clinical reports implicate GLP-2 receptor (GLP-2R) agonism as a potential therapy for graft vs. host disease (GvHD).</div></div><div><h3>Methods</h3><div>Here we assessed whether enhanced vs. loss of GLP-2R signaling modifies gut injury and inflammation in experimental murine acute GvHD (aGvHD). Allogeneic hematopoietic cell transplantation (HCT) was performed using bone marrow and splenocytes from BALB/cJ donor mice to induce aGvHD in C57BL/6J recipients. Chimerism was determined by flow cytometry of immune cell compartments. Inflammation was assessed by measuring circulating cytokines and histological scoring of gut mucosal damage. GLP-2 responsivity was assessed using histology and gene expression analyses. The gut microbiome was assessed by 16S rRNA sequencing.</div></div><div><h3>Results</h3><div>Allogeneic chimerism was >90% in peripheral blood and in the gut epithelial compartment. Gut GLP-2R signaling was preserved following allogeneic bone marrow transplantation. Surprisingly, GLP-2R agonism using teduglutide did not reduce circulating cytokines, gut injury, immune cell infiltration or the severity of aGvHD. In contrast, transplant recipient <em>Glp2r</em><sup>−/−</sup> mice exhibited reduced survival, associated with increased bacteremia. Shifts in microbial species abundance with gain or loss of GLP-2R signaling were not correlated with aGvHD clinical outcomes.</div></div><div><h3>Conclusions</h3><div>Activation of GLP-2R signaling did not reduce the severity of experimental aGvHD, failing to replicate a previous study using an identical aGvHD protocol. Nevertheless, loss of GLP-2R signaling in transplant recipients decreased survival and increased bacteremia, implicating an essential role for endogenous GLP-2R signaling in maintaining barrier function in the context of immune-mediated gut epithelial injury.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102311"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794410","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 : 2026-01-01DOI: 10.1016/j.molmet.2025.102315
Tobias Hagemann , Anne Hoffmann , Kerstin Rohde-Zimmermann , Helen Broghammer , Lucas Massier , Peter Kovacs , Michael Stumvoll , Matthias Blüher , John T. Heiker , Juliane Weiner
Background
Controlling brown adipose tissue (BAT) plasticity offers potential for novel obesity therapies. DNA methylation is closely linked to thermogenic and metabolic pathways and thereby influences BAT function. How metabolic state and cold exposure interact to shape methylation-dependent BAT gene regulation was investigated.
Methods
Five-week-old mice were fed either chow for 11 weeks (lean) or high-fat diet for 22 weeks to induce obesity (DIO), after which cold exposure was applied for seven days. BAT transcriptomes (RNAseq) and methylomes (RRBS) were generated, and differentially methylated and expressed genes (DMEGs) showing metabolic state–dependent cold responses were identified. Pathway enrichment, epigenetic regulator screening, and transcription factor (TF) motif analyses were performed. DNA methylation was experimentally modulated in vitro to validate selected gene expression responses.
Results
A total of 1,364 differentially expressed genes (DEGs) were uniquely affected by the interaction of metabolic state and cold, with most downregulated in DIO mice. Sixty-five DMEGs (4 % of DEGs) showed metabolic state–specific responses to cold. In DIO mice, DMEGs were enriched in pathways associated with mitochondrial dysfunction, altered lipid metabolism, neuroendocrine signaling, and stress responses. Several epigenetic regulators, including Tet2, Dnmt3a, and Apobec1, exhibited metabolic state- and cold-dependent expression, and TF-motif analyses highlighted roles for AhrArnt and Foxn1. In vitro assays confirmed that DNA methylation influences expression of thermogenic genes.
Conclusion
These findings provide the first evidence that the epigenetic cold response of BAT differs by metabolic condition. BAT remodeling is shaped by coordinated transcriptional and epigenetic mechanisms integrating environmental and metabolic cues.
{"title":"Diet and temperature interactively impact brown adipose tissue gene regulation controlled by DNA methylation","authors":"Tobias Hagemann , Anne Hoffmann , Kerstin Rohde-Zimmermann , Helen Broghammer , Lucas Massier , Peter Kovacs , Michael Stumvoll , Matthias Blüher , John T. Heiker , Juliane Weiner","doi":"10.1016/j.molmet.2025.102315","DOIUrl":"10.1016/j.molmet.2025.102315","url":null,"abstract":"<div><h3>Background</h3><div>Controlling brown adipose tissue (BAT) plasticity offers potential for novel obesity therapies. DNA methylation is closely linked to thermogenic and metabolic pathways and thereby influences BAT function. How metabolic state and cold exposure interact to shape methylation-dependent BAT gene regulation was investigated.</div></div><div><h3>Methods</h3><div>Five-week-old mice were fed either chow for 11 weeks (lean) or high-fat diet for 22 weeks to induce obesity (DIO), after which cold exposure was applied for seven days. BAT transcriptomes (RNAseq) and methylomes (RRBS) were generated, and differentially methylated and expressed genes (DMEGs) showing metabolic state–dependent cold responses were identified. Pathway enrichment, epigenetic regulator screening, and transcription factor (TF) motif analyses were performed. DNA methylation was experimentally modulated <em>in vitro</em> to validate selected gene expression responses.</div></div><div><h3>Results</h3><div>A total of 1,364 differentially expressed genes (DEGs) were uniquely affected by the interaction of metabolic state and cold, with most downregulated in DIO mice. Sixty-five DMEGs (4 % of DEGs) showed metabolic state–specific responses to cold. In DIO mice, DMEGs were enriched in pathways associated with mitochondrial dysfunction, altered lipid metabolism, neuroendocrine signaling, and stress responses. Several epigenetic regulators, including <em>Tet2, Dnmt3a,</em> and <em>Apobec1</em>, exhibited metabolic state- and cold-dependent expression, and TF-motif analyses highlighted roles for AhrArnt and Foxn1. In vitro assays confirmed that DNA methylation influences expression of thermogenic genes.</div></div><div><h3>Conclusion</h3><div>These findings provide the first evidence that the epigenetic cold response of BAT differs by metabolic condition. BAT remodeling is shaped by coordinated transcriptional and epigenetic mechanisms integrating environmental and metabolic cues.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102315"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896141","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 : 2026-01-01DOI: 10.1016/j.molmet.2025.102304
Shiqian Chen , Carolina B. Lobato , Carissa Wong , Yusman Manchanda , Katrina Viloria , Iona Davies , Daniel B. Andersen , Julia Ast , Kyle W. Sloop , David J. Hodson , Johannes Broichhagen , Steve Bloom , Jens J. Holst , Tricia Tan , Alejandra Tomas , Ben Jones
Internalisation of G protein-coupled receptors (GPCRs) can contribute to altered cellular responses by directing signalling from non-canonical locations, such as endosomes. If signalling processes are locally constrained, active receptors in different subcellular locations could produce different downstream effects. This phenomenon may be relevant to the optimal targeting of the glucagon-like peptide-1 receptor (GLP-1R), a type 2 diabetes and obesity target GPCR for which several ligands with varying internalisation tendency have been discovered. To investigate, we compared the signalling localisation effects of two prototypical GLP-1RAs with opposite signal bias and effects on GLP-1R trafficking: exendin-asp3 (ExD3), a full agonist that drives rapid internalisation, and exendin-phe1 (ExF1), which shows much slower internalisation. After using bioorthogonal labelling and fluorescent agonist conjugates to verify the divergent trafficking patterns of ExF1 and ExD3 in β-cell lines and primary pancreatic islets, we used live cell biosensors to monitor signalling at different subcellular locations. This revealed that cAMP/PKA/ERK signalling in β-cells is in fact distributed widely across the cell over short- (<5 min) and medium-term (up to 60 min) stimulation at pharmacological (>10 pM) concentrations, with no major differences in signal localisation that could be linked to internalised versus cell surface-bound GLP-1R. Moreover, washout experiments highlighted that, whilst fast-internalising ExD3 shows much greater accumulation and binding to GLP-1R in endosomes than slow-internalising ExF1, it is a rather inefficient driver of both cAMP production in β-cells and insulin secretion from perfused rat pancreata. These data provide a greater understanding of the cellular effects of biased GLP-1R agonism.
{"title":"Spatially diffuse cAMP signalling with oppositely biased GLP-1 receptor agonists in β-cells despite differences in receptor localisation","authors":"Shiqian Chen , Carolina B. Lobato , Carissa Wong , Yusman Manchanda , Katrina Viloria , Iona Davies , Daniel B. Andersen , Julia Ast , Kyle W. Sloop , David J. Hodson , Johannes Broichhagen , Steve Bloom , Jens J. Holst , Tricia Tan , Alejandra Tomas , Ben Jones","doi":"10.1016/j.molmet.2025.102304","DOIUrl":"10.1016/j.molmet.2025.102304","url":null,"abstract":"<div><div>Internalisation of G protein-coupled receptors (GPCRs) can contribute to altered cellular responses by directing signalling from non-canonical locations, such as endosomes. If signalling processes are locally constrained, active receptors in different subcellular locations could produce different downstream effects. This phenomenon may be relevant to the optimal targeting of the glucagon-like peptide-1 receptor (GLP-1R), a type 2 diabetes and obesity target GPCR for which several ligands with varying internalisation tendency have been discovered. To investigate, we compared the signalling localisation effects of two prototypical GLP-1RAs with opposite signal bias and effects on GLP-1R trafficking: exendin-asp3 (ExD3), a full agonist that drives rapid internalisation, and exendin-phe1 (ExF1), which shows much slower internalisation. After using bioorthogonal labelling and fluorescent agonist conjugates to verify the divergent trafficking patterns of ExF1 and ExD3 in β-cell lines and primary pancreatic islets, we used live cell biosensors to monitor signalling at different subcellular locations. This revealed that cAMP/PKA/ERK signalling in β-cells is in fact distributed widely across the cell over short- (<5 min) and medium-term (up to 60 min) stimulation at pharmacological (>10 pM) concentrations, with no major differences in signal localisation that could be linked to internalised <em>versus</em> cell surface-bound GLP-1R. Moreover, washout experiments highlighted that, whilst fast-internalising ExD3 shows much greater accumulation and binding to GLP-1R in endosomes than slow-internalising ExF1, it is a rather inefficient driver of both cAMP production in β-cells and insulin secretion from perfused rat pancreata. These data provide a greater understanding of the cellular effects of biased GLP-1R agonism.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102304"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757158","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 : 2026-01-01DOI: 10.1016/j.molmet.2025.102313
Irmak Gezginer , Giulia Mazzini , Christelle Le Foll , Diana Kindler , Thomas A. Lutz , Daniel Razansky
Obesity remains a major global health challenge, yet the brain-wide effects of hormones regulating appetite remain incompletely understood. Amylin, co-secreted with insulin by pancreatic β-cells, promotes satiation and is a promising therapeutic target for metabolic disorders. While its receptor distribution is well-characterized, its influence on large-scale neural dynamics is unknown. Here, resting-state fMRI was used to map time-resolved connectivity changes following peripheral amylin administration in wild-type (WT) and receptor activity-modifying protein 1/3 knockout (RAMP1/3 KO) mice. In WT animals, amylin triggered rapid and transient network reconfigurations, engaging canonical satiation hubs such as the area postrema and parabrachial nucleus, and extending to sensory-integrative areas including the inferior colliculus and insular cortex. Early hindbrain responses propagated to hypothalamic, thalamic, and mesolimbic circuits implicated in appetite and reward. These effects, along with amylin-driven modulation of large-scale networks and low-frequency oscillations, were absent in KO mice. The findings position amylin as a potent modulator of distributed brain circuits, offering a framework for targeted obesity treatments.
{"title":"Pancreatic amylin dynamically reconfigures distributed brain networks governing appetite regulation in mice","authors":"Irmak Gezginer , Giulia Mazzini , Christelle Le Foll , Diana Kindler , Thomas A. Lutz , Daniel Razansky","doi":"10.1016/j.molmet.2025.102313","DOIUrl":"10.1016/j.molmet.2025.102313","url":null,"abstract":"<div><div>Obesity remains a major global health challenge, yet the brain-wide effects of hormones regulating appetite remain incompletely understood. Amylin, co-secreted with insulin by pancreatic β-cells, promotes satiation and is a promising therapeutic target for metabolic disorders. While its receptor distribution is well-characterized, its influence on large-scale neural dynamics is unknown. Here, resting-state fMRI was used to map time-resolved connectivity changes following peripheral amylin administration in wild-type (WT) and receptor activity-modifying protein 1/3 knockout (RAMP1/3 KO) mice. In WT animals, amylin triggered rapid and transient network reconfigurations, engaging canonical satiation hubs such as the area postrema and parabrachial nucleus, and extending to sensory-integrative areas including the inferior colliculus and insular cortex. Early hindbrain responses propagated to hypothalamic, thalamic, and mesolimbic circuits implicated in appetite and reward. These effects, along with amylin-driven modulation of large-scale networks and low-frequency oscillations, were absent in KO mice. The findings position amylin as a potent modulator of distributed brain circuits, offering a framework for targeted obesity treatments.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102313"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827245","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 : 2025-12-26DOI: 10.1016/j.molmet.2025.102314
April E. Hartley , Katyayani Sukhavasi , Sile Hu , Matthew Traylor , Mar Gonzalez-Ramirez , Kristian Ebbesen Hanghøj , Husain Talukdar , Arno Ruusalepp , Ellen Björkegren , Johan LM. Björkegren , Joanna MM. Howson , Yalda Jamshidi
Understanding tissue-specific mechanisms of protein regulation gives crucial insights into cardiometabolic disease and informs drug discovery. Most proteomic studies have primarily concentrated on plasma, overlooking tissue-specific effects. Utilizing Olink technology, we assessed relative protein levels across plasma and tissue (aortic wall, mammary artery, liver, and skeletal muscle) from the STARNET cohort: 284 individuals with a high prevalence of coronary artery disease (CAD). We identified 608 cis protein quantitative trait loci (pQTLs), primarily in plasma, reflecting greater protein variability. Of 190 proteins with cis-pQTLs in non-plasma tissues, 50% also had plasma pQTLs, validating Olink technology in these tissues while reinforcing the relevance of plasma data for understanding protein regulation. To identify potential mechanistic pathways linking genetic variants to clinical traits, we performed Bayesian colocalization and Mendelian randomization. These analyses revealed shared genetic regulation between tissues at the gene expression and protein level, and key cardiometabolic traits including low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. Notably, analyses provide further support to SORT1 and PSRC1 gene and protein expression having liver-specific influences on CAD risk and lipid profiles. We also observed distinct genetic regulation of gene expression and protein within the same tissues, underscoring the value of tissue proteomics for therapeutic insights.
{"title":"Deciphering tissue-specific protein regulation for insights into cardiometabolic disease","authors":"April E. Hartley , Katyayani Sukhavasi , Sile Hu , Matthew Traylor , Mar Gonzalez-Ramirez , Kristian Ebbesen Hanghøj , Husain Talukdar , Arno Ruusalepp , Ellen Björkegren , Johan LM. Björkegren , Joanna MM. Howson , Yalda Jamshidi","doi":"10.1016/j.molmet.2025.102314","DOIUrl":"10.1016/j.molmet.2025.102314","url":null,"abstract":"<div><div>Understanding tissue-specific mechanisms of protein regulation gives crucial insights into cardiometabolic disease and informs drug discovery. Most proteomic studies have primarily concentrated on plasma, overlooking tissue-specific effects. Utilizing Olink technology, we assessed relative protein levels across plasma and tissue (aortic wall, mammary artery, liver, and skeletal muscle) from the STARNET cohort: 284 individuals with a high prevalence of coronary artery disease (CAD). We identified 608 <em>cis</em> protein quantitative trait loci (pQTLs), primarily in plasma, reflecting greater protein variability. Of 190 proteins with <em>cis</em>-pQTLs in non-plasma tissues, 50% also had plasma pQTLs, validating Olink technology in these tissues while reinforcing the relevance of plasma data for understanding protein regulation. To identify potential mechanistic pathways linking genetic variants to clinical traits, we performed Bayesian colocalization and Mendelian randomization. These analyses revealed shared genetic regulation between tissues at the gene expression and protein level, and key cardiometabolic traits including low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. Notably, analyses provide further support to SORT1 and PSRC1 gene and protein expression having liver-specific influences on CAD risk and lipid profiles. We also observed distinct genetic regulation of gene expression and protein within the same tissues, underscoring the value of tissue proteomics for therapeutic insights.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102314"},"PeriodicalIF":6.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850202","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 : 2025-12-19DOI: 10.1016/j.molmet.2025.102310
Melissa A Fulham, John D Griffin, Sylvie Perez, Zhongyuan Sun, Natalie A Daurio, Gang Xing, Michelle F Clasquin, Melissa R Miller, Craig L Hyde, Scott P Kelly, Magalie Boucher, Rachel Poskanzer, Ramya Gamini, Evanthia Pashos, Ying Zhang, Elaine Kuang, Josh Fienman, Kendra K Bence, Gregory J Tesz
Objectives: Hereditary fructose intolerance (HFI), caused by Aldolase B deficiency, is a rare genetic disorder where fructose exposure leads to severe metabolic pathologies including Type-2 diabetes and liver steatosis. Despite adhering to fructose-free diets, some individuals still present with disease. Using a rat model of HFI we demonstrate that fructose independent pathologies exist and identify the molecular pathways driving disease.
Methods: Aldob was deleted in Sprague Dawley rats using CRIPSR/Cas9 (AldoB-KO). Phenotypic, metabolomic and transcriptomic studies were conducted to identify mechanisms promoting fructose-independent pathologies. Potential molecular causes were tested using pharmacologic inhibitors and ASOs.
Results: Deletion of Aldob caused hepatic steatosis, fibrosis and stunted growth in rats weaned on low fructose chow recapitulating human HFI. On fructose-free chow, AldoB-KO rats were phenotypically normal. However, upon fasting, male and female AldoB-KO rats developed hepatic steatosis and hyperlipidemia due to impaired fatty acid oxidation (FAOx) and elevated de novo lipogenesis (DNL). Transcriptional and metabolomic profiling revealed increased hepatic Carbohydrate Response Element Binding Protein (ChREBP) activation in AldoB-KO rats due to glycolytic metabolite accumulation caused by impaired gluconeogenesis. Treatment with Acetyl-CoA Carboxylase (ACC) and Diacylglycerol Acyl Transferase 2 (DGAT2) inhibitors reduced hepatic lipids and plasma triglycerides in AldoB-KO rats. Finally, using electronic health records we observed increased metabolic dysfunction-associated steatohepatitis (MASH) diagnosis in individuals with HFI.
Conclusions: Aldob deletion caused fructose-independent hyperlipidemia and steatosis upon fasting in rats. Individuals with HFI may have risk for hepatic disease and hyperlipidemia even upon fructose abstinence suggesting additional therapies may be needed to mitigate disease.
{"title":"Impaired hepatic metabolism in Hereditary Fructose Intolerance confers fructose-independent risk for steatosis and hypertriglyceridemia.","authors":"Melissa A Fulham, John D Griffin, Sylvie Perez, Zhongyuan Sun, Natalie A Daurio, Gang Xing, Michelle F Clasquin, Melissa R Miller, Craig L Hyde, Scott P Kelly, Magalie Boucher, Rachel Poskanzer, Ramya Gamini, Evanthia Pashos, Ying Zhang, Elaine Kuang, Josh Fienman, Kendra K Bence, Gregory J Tesz","doi":"10.1016/j.molmet.2025.102310","DOIUrl":"10.1016/j.molmet.2025.102310","url":null,"abstract":"<p><strong>Objectives: </strong>Hereditary fructose intolerance (HFI), caused by Aldolase B deficiency, is a rare genetic disorder where fructose exposure leads to severe metabolic pathologies including Type-2 diabetes and liver steatosis. Despite adhering to fructose-free diets, some individuals still present with disease. Using a rat model of HFI we demonstrate that fructose independent pathologies exist and identify the molecular pathways driving disease.</p><p><strong>Methods: </strong>Aldob was deleted in Sprague Dawley rats using CRIPSR/Cas9 (AldoB-KO). Phenotypic, metabolomic and transcriptomic studies were conducted to identify mechanisms promoting fructose-independent pathologies. Potential molecular causes were tested using pharmacologic inhibitors and ASOs.</p><p><strong>Results: </strong>Deletion of Aldob caused hepatic steatosis, fibrosis and stunted growth in rats weaned on low fructose chow recapitulating human HFI. On fructose-free chow, AldoB-KO rats were phenotypically normal. However, upon fasting, male and female AldoB-KO rats developed hepatic steatosis and hyperlipidemia due to impaired fatty acid oxidation (FAOx) and elevated de novo lipogenesis (DNL). Transcriptional and metabolomic profiling revealed increased hepatic Carbohydrate Response Element Binding Protein (ChREBP) activation in AldoB-KO rats due to glycolytic metabolite accumulation caused by impaired gluconeogenesis. Treatment with Acetyl-CoA Carboxylase (ACC) and Diacylglycerol Acyl Transferase 2 (DGAT2) inhibitors reduced hepatic lipids and plasma triglycerides in AldoB-KO rats. Finally, using electronic health records we observed increased metabolic dysfunction-associated steatohepatitis (MASH) diagnosis in individuals with HFI.</p><p><strong>Conclusions: </strong>Aldob deletion caused fructose-independent hyperlipidemia and steatosis upon fasting in rats. Individuals with HFI may have risk for hepatic disease and hyperlipidemia even upon fructose abstinence suggesting additional therapies may be needed to mitigate disease.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102310"},"PeriodicalIF":6.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805074","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 : 2025-12-17DOI: 10.1016/j.molmet.2025.102309
William De Nardo , Jacqueline Bayliss , Sheik Nadeem Elahee Doomun , Olivia Lee , Paula M. Miotto , Natasha D. Suriani , Shuai Nie , Michael Leeming , Diego A. Miranda , David P. De Souza , Matthew J. Watt
Abstract/objective
Metabolic associated steatotic liver disease (MASLD) is the most prevalent liver disorder and a major risk factor for hepatic fibrosis. Activated hepatic stellate cells (HSCs) are the primary source of collagen production in the liver, contributing to fibrosis. However, the mechanisms by which HSCs reprogram their metabolism to support sustained collagen production, particularly in a lipid-rich environment such as MASLD, remain inadequately understood. In this study, we investigated the effect of extracellular fatty acids on HSC substrate metabolism, HSC activation, and collagen synthesis.
Methods
Immortalized human HSCs (LX-2 cells) were cultured with or without transforming growth factor-beta 1 (TGF-β1) and varying concentrations of palmitate or oleate. Cellular lipid composition was assessed by mass spectrometry lipidomics. Fatty acid metabolism was assessed using radiometric techniques and isotopic labelling experiments using 13C-glucose or 13C-palmitate. HSC activation was assessed by measuring ACTA2, TGFB1, and COL1A1 mRNA levels and collagen secretion by ELISA.
Results
TGF-β1 reduced the abundance of many lipid types in LX-2 cells. Exogenous palmitate did not increase HSC activation, as determined by ACTA2, TGFB1, COL1A1 mRNA levels. Palmitate potentiated TGF-β1 induced collagen secretion but not in the presence of oleate. Palmitate reduced glucose incorporation into glycine in activated HSCs and induced a reciprocal increase in palmitate incorporation into glycine, most likely via carbons derived from TCA cycle intermediates. Pharmacological inhibition of fatty acid uptake reduced TGF-β1-mediated collagen secretion.
Conclusions
These results suggest that in activated HSCs, palmitate oxidation is reduced and that TCA cycle intermediates derived from palmitate are used as carbon sources for amino acid production that supports collagen synthesis and secretion.
{"title":"Effect of free fatty acids on TGF-β1 mediated fibrogenesis in hepatic stellate cells","authors":"William De Nardo , Jacqueline Bayliss , Sheik Nadeem Elahee Doomun , Olivia Lee , Paula M. Miotto , Natasha D. Suriani , Shuai Nie , Michael Leeming , Diego A. Miranda , David P. De Souza , Matthew J. Watt","doi":"10.1016/j.molmet.2025.102309","DOIUrl":"10.1016/j.molmet.2025.102309","url":null,"abstract":"<div><h3>Abstract/objective</h3><div>Metabolic associated steatotic liver disease (MASLD) is the most prevalent liver disorder and a major risk factor for hepatic fibrosis. Activated hepatic stellate cells (HSCs) are the primary source of collagen production in the liver, contributing to fibrosis. However, the mechanisms by which HSCs reprogram their metabolism to support sustained collagen production, particularly in a lipid-rich environment such as MASLD, remain inadequately understood. In this study, we investigated the effect of extracellular fatty acids on HSC substrate metabolism, HSC activation, and collagen synthesis.</div></div><div><h3>Methods</h3><div>Immortalized human HSCs (LX-2 cells) were cultured with or without transforming growth factor-beta 1 (TGF-β1) and varying concentrations of palmitate or oleate. Cellular lipid composition was assessed by mass spectrometry lipidomics. Fatty acid metabolism was assessed using radiometric techniques and isotopic labelling experiments using <sup>13</sup>C-glucose or <sup>13</sup>C-palmitate. HSC activation was assessed by measuring <em>ACTA2, TGFB1, and COL1A1</em> mRNA levels and collagen secretion by ELISA.</div></div><div><h3>Results</h3><div>TGF-β1 reduced the abundance of many lipid types in LX-2 cells. Exogenous palmitate did not increase HSC activation, as determined by <em>ACTA2, TGFB1, COL1A1</em> mRNA levels. Palmitate potentiated TGF-β1 induced collagen secretion but not in the presence of oleate. Palmitate reduced glucose incorporation into glycine in activated HSCs and induced a reciprocal increase in palmitate incorporation into glycine, most likely via carbons derived from TCA cycle intermediates. Pharmacological inhibition of fatty acid uptake reduced TGF-β1-mediated collagen secretion.</div></div><div><h3>Conclusions</h3><div>These results suggest that in activated HSCs, palmitate oxidation is reduced and that TCA cycle intermediates derived from palmitate are used as carbon sources for amino acid production that supports collagen synthesis and secretion.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102309"},"PeriodicalIF":6.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794426","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.2025.102303
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}
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