Pub Date : 2026-01-23DOI: 10.1016/j.molmet.2026.102323
Tanya Pattnaik, Benjamin Wang, Patrick Sweeney
The pregnancy period is accompanied by increased feeding behavior to accommodate the elevated energy demands associated with fetal growth and development. However, the underlying neural circuitry and molecular mechanisms mediating increased feeding during pregnancy are largely unknown. Here, we utilized a combination of fiber photometry, chemogenetics, and mouse behavioral assays to characterize altered feeding behavior during pregnancy in mice. We uncover that pregnancy increases the average activity of the mesolimbic dopamine system during feeding behavior in mice. VTA dopamine neurons promote increased high fat diet feeding during pregnancy as inhibition of these cells selectively reduces acute high fat diet intake in pregnant mice. Further, pregnant mice exhibit increased sensitivity to food deprivation, an effect which requires activity of the mesolimbic dopamine system. Together, these findings provide a circuit basis mediating altered palatable food intake and sensitivity to negative energy balance during pregnancy in mice.
{"title":"Elevated activity of the mesolimbic dopamine system promotes feeding during pregnancy in mice.","authors":"Tanya Pattnaik, Benjamin Wang, Patrick Sweeney","doi":"10.1016/j.molmet.2026.102323","DOIUrl":"10.1016/j.molmet.2026.102323","url":null,"abstract":"<p><p>The pregnancy period is accompanied by increased feeding behavior to accommodate the elevated energy demands associated with fetal growth and development. However, the underlying neural circuitry and molecular mechanisms mediating increased feeding during pregnancy are largely unknown. Here, we utilized a combination of fiber photometry, chemogenetics, and mouse behavioral assays to characterize altered feeding behavior during pregnancy in mice. We uncover that pregnancy increases the average activity of the mesolimbic dopamine system during feeding behavior in mice. VTA dopamine neurons promote increased high fat diet feeding during pregnancy as inhibition of these cells selectively reduces acute high fat diet intake in pregnant mice. Further, pregnant mice exhibit increased sensitivity to food deprivation, an effect which requires activity of the mesolimbic dopamine system. Together, these findings provide a circuit basis mediating altered palatable food intake and sensitivity to negative energy balance during pregnancy in mice.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102323"},"PeriodicalIF":6.6,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046826","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 : 2026-01-21DOI: 10.1016/j.molmet.2026.102322
Fabian Bock , Xinyu Dong , Kakali Ghoshal , David A. Cappel , John W. Deaver , Dan S. Lark , Luciano Cozzani , Deanna P. Bracy , Louise Lantier , Allison Do , Richard L. Printz , Santosh Thapa , Owen P. McGuinness , David H. Wasserman , Ambra Pozzi , Roy Zent , Nathan C. Winn
Skeletal muscle and liver insulin resistance are early features in the sequelae of type 2 diabetes. Integrins are extracellular matrix receptors expressed on skeletal muscle cells and hepatocytes, which have been implicated in modulating obesity-associated insulin resistance. Integrins regulate cell function through intracellular proteins including the ILK-PINCH-Parvin (IPP) complex. ILK signaling amplifies skeletal muscle and liver insulin resistance in diet-induced obesity in mice but the role of α-Parvin is unexplored. The hyperinsulinemic-euglycemic clamp was used to assess hepatic and muscle insulin action. We demonstrate that deletion of hepatocyte-specific α-Parvin had only minimal influence on obesity-induced liver or whole-body insulin resistance. In contrast, deletion of α-Parvin in skeletal muscle caused a striking reduction in muscle glucose uptake during an insulin clamp in lean mice which was not exacerbated by diet-induced obesity. The decrease in muscle glucose uptake in lean mice was due to a decrease in insulin-mediated GLUT4 membrane recruitment, which was associated with significant morphological abnormalities including actin cytoskeleton dysfunction. In addition, severe muscular dysfunction, blunted mitochondrial oxidative capacity and reduced aerobic exercise capacity were manifest in muscle α-Parvin KO mice. Thus, α-Parvin has a minor role in liver insulin action but is required for insulin-stimulated glucose uptake in skeletal muscle in lean mice due to its role in actin cytoskeleton regulation. These data suggest that individual IPP complex proteins link cell structure to metabolism via distinct mechanisms in a tissue-specific fashion.
{"title":"α-Parvin promotes glucose uptake and metabolism in skeletal muscle with minimal influence on hepatic insulin sensitivity","authors":"Fabian Bock , Xinyu Dong , Kakali Ghoshal , David A. Cappel , John W. Deaver , Dan S. Lark , Luciano Cozzani , Deanna P. Bracy , Louise Lantier , Allison Do , Richard L. Printz , Santosh Thapa , Owen P. McGuinness , David H. Wasserman , Ambra Pozzi , Roy Zent , Nathan C. Winn","doi":"10.1016/j.molmet.2026.102322","DOIUrl":"10.1016/j.molmet.2026.102322","url":null,"abstract":"<div><div>Skeletal muscle and liver insulin resistance are early features in the sequelae of type 2 diabetes. Integrins are extracellular matrix receptors expressed on skeletal muscle cells and hepatocytes, which have been implicated in modulating obesity-associated insulin resistance. Integrins regulate cell function through intracellular proteins including the ILK-PINCH-Parvin (IPP) complex. ILK signaling amplifies skeletal muscle and liver insulin resistance in diet-induced obesity in mice but the role of α-Parvin is unexplored. The hyperinsulinemic-euglycemic clamp was used to assess hepatic and muscle insulin action. We demonstrate that deletion of hepatocyte-specific α-Parvin had only minimal influence on obesity-induced liver or whole-body insulin resistance. In contrast, deletion of α-Parvin in skeletal muscle caused a striking reduction in muscle glucose uptake during an insulin clamp in lean mice which was not exacerbated by diet-induced obesity. The decrease in muscle glucose uptake in lean mice was due to a decrease in insulin-mediated GLUT4 membrane recruitment, which was associated with significant morphological abnormalities including actin cytoskeleton dysfunction. In addition, severe muscular dysfunction, blunted mitochondrial oxidative capacity and reduced aerobic exercise capacity were manifest in muscle α-Parvin KO mice. Thus, α-Parvin has a minor role in liver insulin action but is required for insulin-stimulated glucose uptake in skeletal muscle in lean mice due to its role in actin cytoskeleton regulation. These data suggest that individual IPP complex proteins link cell structure to metabolism via distinct mechanisms in a tissue-specific fashion.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"105 ","pages":"Article 102322"},"PeriodicalIF":6.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041281","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 : 2026-01-20DOI: 10.1016/j.molmet.2026.102321
Hanh Duyen Tran, Yiming Zuo, Carissa Wong, Alice Pollard, Steve Bloom, Ben Jones
Background and aim: The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target for type 2 diabetes and obesity. Agonists showing bias in favour of G protein signalling over β-arrestin recruitment and GLP-1R internalisation, e.g. tirzepatide and orforglipron, have favourable clinical efficacy profiles. However, understanding of the effects of biased agonism has been hampered by differences in ligand properties such as affinity, efficacy, stability and pharmacokinetics. Here we used GLP-1R C-tail mutations that inhibit phosphorylation to mimic G protein-biased GLP-1R agonism without the need for ligand modifications.
Methods: Serine doublet phosphorylation sites in the human and mouse GLP-1R C-tails were mutated to alanine. Wild-type and mutant GLP-1Rs were examined for β-arrestin recruitment, internalisation, Gαs activation, and signalling readouts in HEK293 cells and pancreatic β-cell models. Native GLP-1 plus oppositely biased ligands exendin-phe1 (ExF1; G protein-biased) and exendin-asp3 (ExD3; β-arrestin-biased) were used to compare ligand- and receptor-mediated biased agonism.
Results: Loss of three C-terminal phosphorylation sites reduced GLP-1- and ExD3-mediated GLP-1R internalisation and β-arrestin recruitment to that seen with ExF1. The phosphodeficient GLP-1R showed preferential plasma membrane Gαs activation over longer stimulations, with associated increases in whole cell cAMP generation and kinomic signalling. The distal GLP-1R phosphorylation site played a larger role in β-arrestin recruitment, and the proximal sites were more important for GLP-1R internalisation and regulating cAMP production.
Conclusions: Genetic changes that reduce in β-arrestin recruitment and slow GLP-1R internalisation can enhance GLP-1R signalling, providing conceptual support for the use of G protein bias to improve GLP-1R agonist efficacy.
背景与目的：胰高血糖素样肽-1受体（GLP-1R）是2型糖尿病和肥胖的主要治疗靶点。与β-阻滞蛋白募集和GLP-1R内化相比，偏向于G蛋白信号传导的激动剂，如替西肽和奥福glipron，具有良好的临床疗效。然而，由于配体性质的差异，如亲和力、有效性、稳定性和药代动力学，对偏倚激动作用的理解受到了阻碍。在这里，我们使用抑制磷酸化的GLP-1R c尾突变来模拟G蛋白偏向的GLP-1R激动作用，而不需要配体修饰。方法：将人和小鼠GLP-1R c -尾丝氨酸双链磷酸化位点突变为丙氨酸。在HEK293细胞和胰腺β细胞模型中检测野生型和突变型GLP-1Rs的β-阻滞蛋白募集、内化、g - αs激活和信号输出。使用天然GLP-1加上相反偏倚的配体exendin-phe1 （ExF1； G蛋白偏倚）和exendin-asp3 （ExD3； β-阻滞蛋白偏倚）来比较配体和受体介导的偏倚激动作用。结果：三个c端磷酸化位点的缺失减少了GLP-1和exd3介导的GLP-1R内化和β-抑制蛋白募集，与ExF1相比。相比于长时间的刺激，缺磷GLP-1R表现出更优先的质膜Gαs激活，并伴有全细胞cAMP生成和运动组信号传导的增加。远端GLP-1R磷酸化位点在β-阻滞蛋白募集中发挥更大作用，而近端GLP-1R磷酸化位点在GLP-1R内化和cAMP产生调节中更为重要。结论：减少β-阻滞蛋白募集和减缓GLP-1R内化的基因变化可以增强GLP-1R信号传导，这为使用G蛋白偏倚来提高GLP-1R激动剂的功效提供了概念支持。
{"title":"Modelling G protein-biased agonism using GLP-1 receptor C-terminal mutations.","authors":"Hanh Duyen Tran, Yiming Zuo, Carissa Wong, Alice Pollard, Steve Bloom, Ben Jones","doi":"10.1016/j.molmet.2026.102321","DOIUrl":"10.1016/j.molmet.2026.102321","url":null,"abstract":"<p><strong>Background and aim: </strong>The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target for type 2 diabetes and obesity. Agonists showing bias in favour of G protein signalling over β-arrestin recruitment and GLP-1R internalisation, e.g. tirzepatide and orforglipron, have favourable clinical efficacy profiles. However, understanding of the effects of biased agonism has been hampered by differences in ligand properties such as affinity, efficacy, stability and pharmacokinetics. Here we used GLP-1R C-tail mutations that inhibit phosphorylation to mimic G protein-biased GLP-1R agonism without the need for ligand modifications.</p><p><strong>Methods: </strong>Serine doublet phosphorylation sites in the human and mouse GLP-1R C-tails were mutated to alanine. Wild-type and mutant GLP-1Rs were examined for β-arrestin recruitment, internalisation, Gα<sub>s</sub> activation, and signalling readouts in HEK293 cells and pancreatic β-cell models. Native GLP-1 plus oppositely biased ligands exendin-phe1 (ExF1; G protein-biased) and exendin-asp3 (ExD3; β-arrestin-biased) were used to compare ligand- and receptor-mediated biased agonism.</p><p><strong>Results: </strong>Loss of three C-terminal phosphorylation sites reduced GLP-1- and ExD3-mediated GLP-1R internalisation and β-arrestin recruitment to that seen with ExF1. The phosphodeficient GLP-1R showed preferential plasma membrane Gα<sub>s</sub> activation over longer stimulations, with associated increases in whole cell cAMP generation and kinomic signalling. The distal GLP-1R phosphorylation site played a larger role in β-arrestin recruitment, and the proximal sites were more important for GLP-1R internalisation and regulating cAMP production.</p><p><strong>Conclusions: </strong>Genetic changes that reduce in β-arrestin recruitment and slow GLP-1R internalisation can enhance GLP-1R signalling, providing conceptual support for the use of G protein bias to improve GLP-1R agonist efficacy.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102321"},"PeriodicalIF":6.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030056","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 : 2026-01-13DOI: 10.1016/j.molmet.2026.102320
Amanda E. Brandon , Chenxu Yan , Xuan Zhang , Chi Kin Ip , Zhongmin Gao , Nicola J. Lee , Oana C. Marian , Alex Perez , Anthony S. Don , Herbert Herzog , Lewin Small , Yan-Chuan Shi , Carsten Schmitz-Peiffer
Objectives
Global but not liver-specific deletion of protein kinase C epsilon (PKCε) improves glucose tolerance in fat-fed mice, suggesting that extra-hepatic tissues are involved. AgRP neurons within the arcuate nucleus (ARC) of the hypothalamus can affect glucose homeostasis acutely, in addition to their role in energy homeostasis. We therefore deleted PKCε specifically in AgRP neurons to examine its effects at this site.
Methods
Fat-fed AgRP-PKCε−/− mice were subjected to glucose tolerance tests and euglycaemic-hyperinsulinaemic clamps. c-Fos and tyrosine hydroxylase were used as markers to map neuronal activity in serial brain sections. Transcriptional changes in liver and adipose tissue were examined by qRT-PCR while alterations in protein levels and phosphorylation were determined by immunoblotting and mass spectrometry.
Results
Fat-fed AgRP-PKCε−/− mice exhibited improved glucose tolerance but not insulin sensitivity determined by clamp. c-Fos mapping demonstrated that glucose challenge resulted in greater activation of neurons in the paraventricular nucleus (PVN) in AgRP-PKCε−/− mice, but reduced expression of tyrosine hydroxylase in the PVN, suggestive of reduced sympathetic outflow. This was associated with a reduction in hormone sensitive lipase phosphorylation and plasma fatty acid levels. Proteomic analysis indicated overlapping alterations in proteins and protein phosphorylation in adipose tissue and liver, consistent with changes in a common, potentially neuronal, cell type.
Conclusions
Ablation of PKCε in AgRP neurons improves glucose homeostasis in fat-fed mice. This appears to be mediated through glucose sensing mechanisms, potentially reducing sympathetic outflow from the hypothalamus to tissues such as adipose, reducing lipolysis to indirectly lower hepatic glucose production.
{"title":"Protein kinase C epsilon deletion in AgRP neurons modulates hypothalamic glucose sensing and improves glucose tolerance in mice","authors":"Amanda E. Brandon , Chenxu Yan , Xuan Zhang , Chi Kin Ip , Zhongmin Gao , Nicola J. Lee , Oana C. Marian , Alex Perez , Anthony S. Don , Herbert Herzog , Lewin Small , Yan-Chuan Shi , Carsten Schmitz-Peiffer","doi":"10.1016/j.molmet.2026.102320","DOIUrl":"10.1016/j.molmet.2026.102320","url":null,"abstract":"<div><h3>Objectives</h3><div>Global but not liver-specific deletion of protein kinase C epsilon (PKCε) improves glucose tolerance in fat-fed mice, suggesting that extra-hepatic tissues are involved. AgRP neurons within the arcuate nucleus (ARC) of the hypothalamus can affect glucose homeostasis acutely, in addition to their role in energy homeostasis. We therefore deleted PKCε specifically in AgRP neurons to examine its effects at this site.</div></div><div><h3>Methods</h3><div>Fat-fed AgRP-PKCε<sup>−/−</sup> mice were subjected to glucose tolerance tests and euglycaemic-hyperinsulinaemic clamps. c-Fos and tyrosine hydroxylase were used as markers to map neuronal activity in serial brain sections. Transcriptional changes in liver and adipose tissue were examined by qRT-PCR while alterations in protein levels and phosphorylation were determined by immunoblotting and mass spectrometry.</div></div><div><h3>Results</h3><div>Fat-fed AgRP-PKCε<sup>−/−</sup> mice exhibited improved glucose tolerance but not insulin sensitivity determined by clamp. c-Fos mapping demonstrated that glucose challenge resulted in greater activation of neurons in the paraventricular nucleus (PVN) in AgRP-PKCε<sup>−/−</sup> mice, but reduced expression of tyrosine hydroxylase in the PVN, suggestive of reduced sympathetic outflow. This was associated with a reduction in hormone sensitive lipase phosphorylation and plasma fatty acid levels. Proteomic analysis indicated overlapping alterations in proteins and protein phosphorylation in adipose tissue and liver, consistent with changes in a common, potentially neuronal, cell type.</div></div><div><h3>Conclusions</h3><div>Ablation of PKCε in AgRP neurons improves glucose homeostasis in fat-fed mice. This appears to be mediated through glucose sensing mechanisms, potentially reducing sympathetic outflow from the hypothalamus to tissues such as adipose, reducing lipolysis to indirectly lower hepatic glucose production.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102320"},"PeriodicalIF":6.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990056","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 : 2026-01-09DOI: 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}
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