Pub Date : 2026-01-09DOI: 10.1016/j.molmet.2026.102317
Severin Boulassel , Pascale C.F. Schreier , Andreas Beck , Hyeri Choi , Anna M. Melyshi , Peter S. Reinach , Megan Duraj , Mikhail Vinogradov , Bibiazhar Suleimen , Johanna Berger , Katharina Jacob , Andreas Breit , Susanna Zierler , Ingrid Boekhoff , Thomas Gudermann , Noushafarin Khajavi
Objectives
Glucagon is essential for maintaining glucose homeostasis, yet the molecular mechanisms governing α-cell function remain incompletely understood. Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed ion channel with an intrinsic kinase domain, which regulates the mammalian target of rapamycin (mTOR) signaling in various cell types. Given the central role of mTOR in α-cell regulation, this study investigates how TRPM7 influences α-cell biology and examines whether its function is modulated through interaction with the mTOR signaling pathway.
Methods
Islets were isolated from wild-type (WT) mice and mice lacking TRPM7 kinase activity (Trpm7R/R). Functional analyses included Bio-Plex assays, RNA sequencing, glucagon ELISA, qRT-PCR, Western blotting, immunocytochemistry, and patch-clamp recordings. αTC1c9 cells were used as a murine α-cell model. NS8593, a small synthetic compound, was used as a potent TRPM7 inhibitor.
Results
Ex vivo analysis revealed impaired mTOR signaling in Trpm7R/R islets. Trpm7R/R islets secreted less glucagon in response to various secretagogues compared to WT controls. This reduction was partially caused by diminished glucagon content due to downregulation of key transcriptional regulators of glucagon biosynthesis, including Gcg and Mafb. Morphological analysis identified reduced proliferation and enhanced apoptosis of Trpm7R/R α-cells. Similarly, pharmacological inhibition of TRPM7 impaired mTOR signaling, suppressed α -cell identity, and α-cell proliferation in both WT islets and αTC1c9 cells.
Conclusions
Loss of TRPM7 kinase function impairs mTOR signaling, leading to reduced α-cell proliferation and glucagon secretion. Our findings show that the TRPM7 kinase/mTOR signaling pathway axis is a critical regulator of α-cell function in mice.
{"title":"TRPM7 kinase regulates α-cell proliferation and glucagon production in mice","authors":"Severin Boulassel , Pascale C.F. Schreier , Andreas Beck , Hyeri Choi , Anna M. Melyshi , Peter S. Reinach , Megan Duraj , Mikhail Vinogradov , Bibiazhar Suleimen , Johanna Berger , Katharina Jacob , Andreas Breit , Susanna Zierler , Ingrid Boekhoff , Thomas Gudermann , Noushafarin Khajavi","doi":"10.1016/j.molmet.2026.102317","DOIUrl":"10.1016/j.molmet.2026.102317","url":null,"abstract":"<div><h3>Objectives</h3><div>Glucagon is essential for maintaining glucose homeostasis, yet the molecular mechanisms governing α-cell function remain incompletely understood. Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed ion channel with an intrinsic kinase domain, which regulates the mammalian target of rapamycin (mTOR) signaling in various cell types. Given the central role of mTOR in α-cell regulation, this study investigates how TRPM7 influences α-cell biology and examines whether its function is modulated through interaction with the mTOR signaling pathway.</div></div><div><h3>Methods</h3><div>Islets were isolated from wild-type (WT) mice and mice lacking TRPM7 kinase activity (<em>Trpm7</em><sup><em>R/R</em></sup>). Functional analyses included Bio-Plex assays, RNA sequencing, glucagon ELISA, qRT-PCR, Western blotting, immunocytochemistry, and patch-clamp recordings. αTC1c9 cells were used as a murine α-cell model. NS8593, a small synthetic compound, was used as a potent TRPM7 inhibitor.</div></div><div><h3>Results</h3><div><em>Ex vivo</em> analysis revealed impaired mTOR signaling in <em>Trpm7</em><sup><em>R/R</em></sup> islets. <em>Trpm7</em><sup><em>R/R</em></sup> islets secreted less glucagon in response to various secretagogues compared to WT controls. This reduction was partially caused by diminished glucagon content due to downregulation of key transcriptional regulators of glucagon biosynthesis, including <em>Gcg</em> and <em>Mafb</em>. Morphological analysis identified reduced proliferation and enhanced apoptosis of <em>Trpm7</em><sup><em>R/R</em></sup> α-cells. Similarly, pharmacological inhibition of TRPM7 impaired mTOR signaling, suppressed α -cell identity, and α-cell proliferation in both WT islets and αTC1c9 cells.</div></div><div><h3>Conclusions</h3><div>Loss of TRPM7 kinase function impairs mTOR signaling, leading to reduced α-cell proliferation and glucagon secretion. Our findings show that the TRPM7 kinase/mTOR signaling pathway axis is a critical regulator of α-cell function in mice.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102317"},"PeriodicalIF":6.6,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952517","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 : 2026-01-06DOI: 10.1016/j.molmet.2025.102316
Maxime Labroy , Marc-Oliver Paré , Line Berthiaume , Mélissa Thomas , Cynthia Jobin , Alain Veilleux , Martin Pelletier , Frédéric Pouliot , Jean-Yves Masson , Étienne Audet-Walsh
Following recurrence, the cornerstone clinical therapy to treat prostate cancer (PCa) is to inhibit the androgen receptor (AR) signaling. While AR inhibition is initially successful, tumors will eventually develop treatment resistance and evolve into lethal castration-resistant PCa. To discover new anti-metabolic treatments for PCa, a high-throughput anti-metabolic drug screening was performed in PC3 cells, an AR-negative PCa cell line. This screening identified the dihydroorotate dehydrogenase (DHODH) enzyme as a metabolic vulnerability, using both AR-positive and AR-negative models, including the neuroendocrine cell line LASCPC-01 and patient-derived organoids. DHODH is required for de novo pyrimidine synthesis and is the sole mitochondrial enzyme of this pathway. Using extracellular flux assays and targeted metabolomics, DHODH inhibition was shown to impair the pyrimidine synthesis pathway, as expected, along with a significant reprogramming of mitochondrial metabolism, with a massive increase in fumarate (>10-fold). Using 13C6-glucose, it was shown that following DHODH inhibition, PCa cells redirect carbons from glucose toward biosynthetic pathways rather than the TCA cycle. In parallel, using 13C5-glutamine, it was shown that PCa cells use this amino acid to fuel a reverse TCA cycle. Finally, 13C1-aspartate and 15N1-glutamine highlighted the connection between pyrimidine synthesis and the urea cycle, redirecting pyrimidine synthesis intermediates toward the urea cycle as a stress response mechanism upon DHODH inhibition. Consequently, combination therapies targeting DHODH and glutamine metabolism were synergistic in impairing PCa cell proliferation. Altogether, these results highlight DHODH as a metabolic vulnerability of AR-positive and AR-negative PCa cells by regulating central carbon and nitrogen metabolism.
{"title":"Targeting DHODH reveals a metabolic vulnerability in AR-positive and AR-negative prostate cancer cells via pyrimidine synthesis and metabolic crosstalk with the TCA and urea cycles","authors":"Maxime Labroy , Marc-Oliver Paré , Line Berthiaume , Mélissa Thomas , Cynthia Jobin , Alain Veilleux , Martin Pelletier , Frédéric Pouliot , Jean-Yves Masson , Étienne Audet-Walsh","doi":"10.1016/j.molmet.2025.102316","DOIUrl":"10.1016/j.molmet.2025.102316","url":null,"abstract":"<div><div>Following recurrence, the cornerstone clinical therapy to treat prostate cancer (PCa) is to inhibit the androgen receptor (AR) signaling. While AR inhibition is initially successful, tumors will eventually develop treatment resistance and evolve into lethal castration-resistant PCa. To discover new anti-metabolic treatments for PCa, a high-throughput anti-metabolic drug screening was performed in PC3 cells, an AR-negative PCa cell line. This screening identified the dihydroorotate dehydrogenase (DHODH) enzyme as a metabolic vulnerability, using both AR-positive and AR-negative models, including the neuroendocrine cell line LASCPC-01 and patient-derived organoids. DHODH is required for <em>de novo</em> pyrimidine synthesis and is the sole mitochondrial enzyme of this pathway. Using extracellular flux assays and targeted metabolomics, DHODH inhibition was shown to impair the pyrimidine synthesis pathway, as expected, along with a significant reprogramming of mitochondrial metabolism, with a massive increase in fumarate (>10-fold). Using <sup>13</sup>C<sub>6</sub>-glucose, it was shown that following DHODH inhibition, PCa cells redirect carbons from glucose toward biosynthetic pathways rather than the TCA cycle. In parallel, using <sup>13</sup>C<sub>5</sub>-glutamine, it was shown that PCa cells use this amino acid to fuel a reverse TCA cycle. Finally, <sup>13</sup>C<sub>1</sub>-aspartate and <sup>15</sup>N<sub>1</sub>-glutamine highlighted the connection between pyrimidine synthesis and the urea cycle, redirecting pyrimidine synthesis intermediates toward the urea cycle as a stress response mechanism upon DHODH inhibition. Consequently, combination therapies targeting DHODH and glutamine metabolism were synergistic in impairing PCa cell proliferation. Altogether, these results highlight DHODH as a metabolic vulnerability of AR-positive and AR-negative PCa cells by regulating central carbon and nitrogen metabolism.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102316"},"PeriodicalIF":6.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934061","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.2025.102312
Olga Kubrak , Alina Malita , Nadja Ahrentløv, Stanislav Nagy, Michael J. Texada, Kim Rewitz
Males and females have different physiological and reproductive demands and consequently exhibit widespread differences in metabolism and behavior. One of the most consistent differences across animals is that females store more body fat than males, a metabolic trait conserved from flies to humans. Given the central role of gut hormones in energy balance, we asked whether gut endocrine signaling underlies these sex differences. We therefore performed a multidimensional screen of enteroendocrine cell (EEC)-derived signaling across a broad panel of metabolic and behavioral traits in male and female Drosophila. Here, we uncover extensive sex-biased roles for EEC-derived signals – many of which are conserved in mammals – in energy storage, stress resistance, feeding, and sleep. We find that EEC-derived amidated peptide hormones sustain female-typical states, including elevated fat reserves, enhanced stress resilience, and protein-biased food choice. In contrast, the non-amidated peptide Allatostatin C (AstC) promotes male-like traits by stimulating energy mobilization, thereby antagonizing amidated-peptide function. Female guts contain more AstC-positive EECs. Disruption of peptide amidation by eliminating peptidylglycine α-hydroxylating monooxygenase – the enzyme required for maturation of most gut peptide hormones – abolished female-typical physiology and behavior, shifting females toward a male-like state. Among individual amidated peptides, Diuretic hormone 31 (Dh31) and Neuropeptide F (NPF) emerged as key mediators of female physiology. These findings establish gut hormone signaling as a determinant of sex-specific metabolic and behavioral states.
男性和女性有不同的生理和生殖需求，因此在新陈代谢和行为上表现出广泛的差异。动物之间最一致的差异之一是雌性比雄性储存更多的体脂，这是一种从苍蝇到人类都保存下来的代谢特征。鉴于肠道激素在能量平衡中的核心作用，我们想知道肠道内分泌信号是否导致了这些性别差异。因此，我们对肠内分泌细胞（EEC）衍生的信号进行了多维筛选，涉及雄性和雌性果蝇的广泛代谢和行为特征。在这里，我们揭示了脑电图衍生信号广泛的性别偏见作用，其中许多在哺乳动物中是保守的，包括能量储存、应激抵抗、喂养和睡眠。我们发现eec衍生的酰胺肽激素维持了女性的典型状态，包括增加的脂肪储备，增强的应激恢复能力和蛋白质偏向的食物选择。相比之下，非酰胺肽Allatostatin C （AstC）通过刺激能量动员来促进雄性样性状，从而拮抗酰胺肽功能。女性肠道中含有更多的astc阳性eec。通过消除肽酰甘氨酸α-羟化单加氧酶（大多数肠道肽激素成熟所需的酶）来破坏肽酰胺化，破坏了雌性典型的生理和行为，将雌性转变为雄性状态。在单个修饰肽中，利尿激素31 （DH31）和神经肽F （NPF）被认为是女性生理的关键介质。这些发现确定了肠道激素信号是性别特异性代谢和行为状态的决定因素。
{"title":"Gut hormone signaling drives sex differences in metabolism and behavior","authors":"Olga Kubrak , Alina Malita , Nadja Ahrentløv, Stanislav Nagy, Michael J. Texada, Kim Rewitz","doi":"10.1016/j.molmet.2025.102312","DOIUrl":"10.1016/j.molmet.2025.102312","url":null,"abstract":"<div><div>Males and females have different physiological and reproductive demands and consequently exhibit widespread differences in metabolism and behavior. One of the most consistent differences across animals is that females store more body fat than males, a metabolic trait conserved from flies to humans. Given the central role of gut hormones in energy balance, we asked whether gut endocrine signaling underlies these sex differences. We therefore performed a multidimensional screen of enteroendocrine cell (EEC)-derived signaling across a broad panel of metabolic and behavioral traits in male and female <em>Drosophila</em>. Here, we uncover extensive sex-biased roles for EEC-derived signals – many of which are conserved in mammals – in energy storage, stress resistance, feeding, and sleep. We find that EEC-derived amidated peptide hormones sustain female-typical states, including elevated fat reserves, enhanced stress resilience, and protein-biased food choice. In contrast, the non-amidated peptide Allatostatin C (AstC) promotes male-like traits by stimulating energy mobilization, thereby antagonizing amidated-peptide function. Female guts contain more AstC-positive EECs. Disruption of peptide amidation by eliminating peptidylglycine α-hydroxylating monooxygenase – the enzyme required for maturation of most gut peptide hormones – abolished female-typical physiology and behavior, shifting females toward a male-like state. Among individual amidated peptides, Diuretic hormone 31 (Dh31) and Neuropeptide F (NPF) emerged as key mediators of female physiology. These findings establish gut hormone signaling as a determinant of sex-specific metabolic and behavioral states.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102312"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.molmet.2025.102302
Ben C. King , Lucie Colineau , Julia Slaby , Olga Kolodziej , Vaishnavi Dandavate , Robin Olsson , Malin Fex , Anna M. Blom
Background
C3 is highly expressed in human and rodent pancreatic islets, which secrete insulin to regulate blood glucose homeostasis. We have previously shown that cytosolic C3 protects pancreatic beta-cells from stress, by allowing cytoprotective autophagy, and that the same intracellular pool of C3 also protects beta-cells from cytokine-induced apoptosis.
Methods
We now generated a beta-cell specific C3 knockout mouse (beta-C3-KO) to test whether cell-intrinsic C3 is required for beta-cell function in a whole animal model. These mice were placed on high-fat diet (HFD), blood glucose and insulin measurements taken over time, and tissues examined at endpoint by qPCR and immunofluorescence.
Results
While no differences were found between in baseline metabolic performance when comparing floxed controls and beta-C3KO mice, significant differences were found when mice were put on high-fat diet (HFD). Beta-C3-KO mice gained more weight, exhibited higher fasting blood glucose and insulin levels, and showed signs of adipose tissue inflammation and insulin resistance. Consistent with previous results showing that C3 alleviates beta-cell stress, increased amounts of unprocessed pro-insulin were found in the circulation of HFD-fed beta-C3-KO mice, as well as in islets from these mice. Beta-C3-KO HFD mouse islets also had a higher proportion of insulin staining, and isolated islets released more insulin in vitro.
Conclusion
The interaction of increased insulin secretion and HFD leads to enhanced weight gain. Cell-intrinsic expression of C3 is important for optimal function of mouse pancreatic beta-cells under metabolic pressure in vivo.
{"title":"Beta-cell-specific C3 deficiency exacerbates metabolic dysregulation and insulin resistance in obesity","authors":"Ben C. King , Lucie Colineau , Julia Slaby , Olga Kolodziej , Vaishnavi Dandavate , Robin Olsson , Malin Fex , Anna M. Blom","doi":"10.1016/j.molmet.2025.102302","DOIUrl":"10.1016/j.molmet.2025.102302","url":null,"abstract":"<div><h3>Background</h3><div>C3 is highly expressed in human and rodent pancreatic islets, which secrete insulin to regulate blood glucose homeostasis. We have previously shown that cytosolic C3 protects pancreatic beta-cells from stress, by allowing cytoprotective autophagy, and that the same intracellular pool of C3 also protects beta-cells from cytokine-induced apoptosis.</div></div><div><h3>Methods</h3><div>We now generated a beta-cell specific C3 knockout mouse (beta-C3-KO) to test whether cell-intrinsic C3 is required for beta-cell function in a whole animal model. These mice were placed on high-fat diet (HFD), blood glucose and insulin measurements taken over time, and tissues examined at endpoint by qPCR and immunofluorescence.</div></div><div><h3>Results</h3><div>While no differences were found between in baseline metabolic performance when comparing floxed controls and beta-C3KO mice, significant differences were found when mice were put on high-fat diet (HFD). Beta-C3-KO mice gained more weight, exhibited higher fasting blood glucose and insulin levels, and showed signs of adipose tissue inflammation and insulin resistance. Consistent with previous results showing that C3 alleviates beta-cell stress, increased amounts of unprocessed pro-insulin were found in the circulation of HFD-fed beta-C3-KO mice, as well as in islets from these mice. Beta-C3-KO HFD mouse islets also had a higher proportion of insulin staining, and isolated islets released more insulin <em>in vitro</em>.</div></div><div><h3>Conclusion</h3><div>The interaction of increased insulin secretion and HFD leads to enhanced weight gain. Cell-intrinsic expression of C3 is important for optimal function of mouse pancreatic beta-cells under metabolic pressure <em>in vivo</em>.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102302"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.molmet.2025.102300
Nadia N. Aalling , Petar V. Todorov , Shad Hassan , Dylan M. Belmont-Rausch , Oliver Pugerup Christensen , Claes Ottzen Laurentiussen , Anja M. Jørgensen , Kimberly M. Alonge , Jarrad M. Scarlett , Zaman Mirzadeh , Jenny M. Brown , Michael W. Schwartz , Tune H. Pers
In rodent models of type 2 diabetes, a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces sustained remission of hyperglycemia. Overactive agouti-related peptide (AgRP) neurons, located in the hypothalamic arcuate nucleus, are a hallmark of diabetic states, and their long-term inhibition has been linked to FGF1's antidiabetic effects. To investigate the underlying mechanism(s), we performed single-nucleus RNA sequencing of the mediobasal hypothalamus at Days 5 and 14 post-injection in wild-type and diabetic (Lepob/ob) mice treated with FGF1 or vehicle. We found that AgRP neurons from Lepob/ob mice form a transcriptionally distinct, hyperactive subpopulation. By Day 5, icv FGF1 induced a subset of these neurons to shift toward a less active, wild-type-like state, characterized by reduced activity-linked gene expression that persisted through Day 14. Spatial transcriptomics revealed that this FGF1-responsive AgRP subset is positioned dorsally within the arcuate nucleus. The transcriptional shift was accompanied by transcriptional processes indicative of increased GABAergic signaling, axonogenesis, and astrocyte–AgRP and oligodendrocyte–AgRP interactions. These glial inputs involve astrocytic neurexins and the perineuronal net (PNN) component phosphacan, suggesting both intrinsic and extrinsic mechanisms underlie FGF1-induced AgRP silencing. Combined with evidence that FGF1 increases PNN assembly in the arcuate nucleus, our findings reveal a cell-type–specific model for how FGF1 elicits long-term reprogramming of hypothalamic circuits to achieve diabetes remission.
{"title":"Sustained diabetes remission induced by FGF1 involves a shift in transcriptionally distinct AgRP neuron subpopulations","authors":"Nadia N. Aalling , Petar V. Todorov , Shad Hassan , Dylan M. Belmont-Rausch , Oliver Pugerup Christensen , Claes Ottzen Laurentiussen , Anja M. Jørgensen , Kimberly M. Alonge , Jarrad M. Scarlett , Zaman Mirzadeh , Jenny M. Brown , Michael W. Schwartz , Tune H. Pers","doi":"10.1016/j.molmet.2025.102300","DOIUrl":"10.1016/j.molmet.2025.102300","url":null,"abstract":"<div><div>In rodent models of type 2 diabetes, a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces sustained remission of hyperglycemia. Overactive agouti-related peptide (AgRP) neurons, located in the hypothalamic arcuate nucleus, are a hallmark of diabetic states, and their long-term inhibition has been linked to FGF1's antidiabetic effects. To investigate the underlying mechanism(s), we performed single-nucleus RNA sequencing of the mediobasal hypothalamus at Days 5 and 14 post-injection in wild-type and diabetic (Lep<sup><em>ob/ob</em></sup>) mice treated with FGF1 or vehicle. We found that AgRP neurons from Lep<sup><em>ob/ob</em></sup> mice form a transcriptionally distinct, hyperactive subpopulation. By Day 5, icv FGF1 induced a subset of these neurons to shift toward a less active, wild-type-like state, characterized by reduced activity-linked gene expression that persisted through Day 14. Spatial transcriptomics revealed that this FGF1-responsive AgRP subset is positioned dorsally within the arcuate nucleus. The transcriptional shift was accompanied by transcriptional processes indicative of increased GABAergic signaling, axonogenesis, and astrocyte–AgRP and oligodendrocyte–AgRP interactions. These glial inputs involve astrocytic neurexins and the perineuronal net (PNN) component phosphacan, suggesting both intrinsic and extrinsic mechanisms underlie FGF1-induced AgRP silencing. Combined with evidence that FGF1 increases PNN assembly in the arcuate nucleus, our findings reveal a cell-type–specific model for how FGF1 elicits long-term reprogramming of hypothalamic circuits to achieve diabetes remission.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102300"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diabetes is associated with compromised reproductive health; however, the cellular and molecular mechanisms underlying its impact on ovarian function remain largely unclear. In this study, we integrated single-cell RNA sequencing, DNA methylation profiling, and metabolomic analyses to comprehensively characterize the ovarian cellular landscape, epigenetic alterations, and metabolic reprogramming in diabetic female mice, with a focus on identifying diabetes-induced changes in ovarian cells. Our cell type-specific transcriptomic analysis revealed that dysregulated steroid hormone biosynthesis and impaired fatty acid metabolism are prominent features of diabetic ovarian dysfunction. Notably, key genes including Cyp11a1, Fshr, and Lhcgr exhibited reduced expression accompanied by increased DNA methylation levels in their gene regions within granulosa cells under diabetic conditions. Furthermore, disrupted granulosa cell differentiation was evident, leading to aberrant luteal cell formation and compromised luteal function. In parallel, metabolomic profiling revealed profound metabolic reprogramming in diabetic ovaries, with significant alterations in lipid metabolism pathways, including elevated unsaturated fatty acid and reduced glycerophospholipid metabolism. Taken together, these findings provide novel insights into the molecular pathways underlying ovarian dysfunction in the context of diabetes, thereby enhancing our understanding of folliculogenesis in metabolic disorders.
{"title":"Multi-omics atlas of ovarian cellular and molecular responses to diabetes","authors":"Zheng-Hui Zhao , Xue-Ying Chen , Cheng-Yan Zhuo, Xiang-Hong Ou, Qing-Yuan Sun","doi":"10.1016/j.molmet.2025.102307","DOIUrl":"10.1016/j.molmet.2025.102307","url":null,"abstract":"<div><div>Diabetes is associated with compromised reproductive health; however, the cellular and molecular mechanisms underlying its impact on ovarian function remain largely unclear. In this study, we integrated single-cell RNA sequencing, DNA methylation profiling, and metabolomic analyses to comprehensively characterize the ovarian cellular landscape, epigenetic alterations, and metabolic reprogramming in diabetic female mice, with a focus on identifying diabetes-induced changes in ovarian cells. Our cell type-specific transcriptomic analysis revealed that dysregulated steroid hormone biosynthesis and impaired fatty acid metabolism are prominent features of diabetic ovarian dysfunction. Notably, key genes including <em>Cyp11a1</em>, <em>Fshr</em>, and <em>Lhcgr</em> exhibited reduced expression accompanied by increased DNA methylation levels in their gene regions within granulosa cells under diabetic conditions. Furthermore, disrupted granulosa cell differentiation was evident, leading to aberrant luteal cell formation and compromised luteal function. In parallel, metabolomic profiling revealed profound metabolic reprogramming in diabetic ovaries, with significant alterations in lipid metabolism pathways, including elevated unsaturated fatty acid and reduced glycerophospholipid metabolism. Taken together, these findings provide novel insights into the molecular pathways underlying ovarian dysfunction in the context of diabetes, thereby enhancing our understanding of folliculogenesis in metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102307"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763324","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.2025.102301
Katie Duckett , Alyce McClellan , Laura J. Corbin , Irene Cimino , Ahmed Elhakeem , Ana Goncalves Soares , Alice Williamson , Eloise Cross , Zammy Fairhurst-Hunter , Slavé Petrovski , Debra Rimmington , Jesús Alegre-Díaz , Jaime Berumen , Pablo Kuri-Morales , Roberto Tapia-Conyer , BELIEVE study,, Jacek Mokrosinski , I. Sadaf Farooqi , Asif Rasheed , Danish Saleheen , Stephen O’Rahilly
Hypothalamic neurons expressing either POMC or AGRP sense nutritional state directly and indirectly and transmit these neuropeptide signals to other brain centres through the melanocortin 3 and 4 receptors. MC4R is primarily concerned with the control of appetite and energy expenditure while MC3R is more closely related to the control of linear growth and the timing of puberty. The role of MC3R in the long-term control of energy balance and body composition is less clear, particularly in humans. We have undertaken studies in humans, domestic dogs and mice with the goal of clarifying the relative impact of MC3R deficiency on energy balance, growth and sexual development. By studying three large consanguineously enriched cohorts, totalling approximately 300K people, we identified nine individuals who are homozygous for functionally null MC3R variants. The body mass index (BMI) of the homozygous MC3R variant carriers was not significantly different from that of age, sex and demographically matched controls, with six of the nine homozygotes having a BMI <30 kg/m2.
We detected a canine MC3R missense variant (p.M320I) which is common in labrador retrievers and showed that this significantly impairs receptor signalling. Dogs homozygous for p.M320I were lighter and showed delayed pubertal development but were not significantly more obese than wild-type or heterozygous dogs. We also established that the lack of Mc3r delayed pubertal development in both male and female mice.
Finally, we studied growth and pubertal trajectories of individuals carrying rare loss-of-function MC3R variants and found that male carriers had delayed peak weight velocity and genital development but had no evidence for excess body fat compared to non-carriers.
Our results support MC3R having a conserved role across mammals in controlling growth and pubertal timing. While MC3R deficiency may influence linear growth and body composition, complete loss of MC3R does not result in a penetrant human obesity syndrome.
{"title":"Cross-species studies implicate the melanocortin 3 receptor more strongly in the control of pubertal development than energy balance","authors":"Katie Duckett , Alyce McClellan , Laura J. Corbin , Irene Cimino , Ahmed Elhakeem , Ana Goncalves Soares , Alice Williamson , Eloise Cross , Zammy Fairhurst-Hunter , Slavé Petrovski , Debra Rimmington , Jesús Alegre-Díaz , Jaime Berumen , Pablo Kuri-Morales , Roberto Tapia-Conyer , BELIEVE study,, Jacek Mokrosinski , I. Sadaf Farooqi , Asif Rasheed , Danish Saleheen , Stephen O’Rahilly","doi":"10.1016/j.molmet.2025.102301","DOIUrl":"10.1016/j.molmet.2025.102301","url":null,"abstract":"<div><div>Hypothalamic neurons expressing either POMC or AGRP sense nutritional state directly and indirectly and transmit these neuropeptide signals to other brain centres through the melanocortin 3 and 4 receptors. MC4R is primarily concerned with the control of appetite and energy expenditure while MC3R is more closely related to the control of linear growth and the timing of puberty. The role of MC3R in the long-term control of energy balance and body composition is less clear, particularly in humans. We have undertaken studies in humans, domestic dogs and mice with the goal of clarifying the relative impact of MC3R deficiency on energy balance, growth and sexual development. By studying three large consanguineously enriched cohorts, totalling approximately 300K people, we identified nine individuals who are homozygous for functionally null <em>MC3R</em> variants. The body mass index (BMI) of the homozygous <em>MC3R</em> variant carriers was not significantly different from that of age, sex and demographically matched controls, with six of the nine homozygotes having a BMI <30 kg/m<sup>2</sup>.</div><div>We detected a canine <em>MC3R</em> missense variant (p.M320I) which is common in labrador retrievers and showed that this significantly impairs receptor signalling. Dogs homozygous for p.M320I were lighter and showed delayed pubertal development but were not significantly more obese than wild-type or heterozygous dogs. We also established that the lack of <em>Mc3r</em> delayed pubertal development in both male and female mice.</div><div>Finally, we studied growth and pubertal trajectories of individuals carrying rare loss-of-function <em>MC3R</em> variants and found that male carriers had delayed peak weight velocity and genital development but had no evidence for excess body fat compared to non-carriers.</div><div>Our results support MC3R having a conserved role across mammals in controlling growth and pubertal timing. While MC3R deficiency may influence linear growth and body composition, complete loss of MC3R does not result in a penetrant human obesity syndrome.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102301"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743434","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.2025.102298
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}
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