Johannes Reiner , Nooshin Mohebali , Jens Kurth , Maria Witte , Cornelia Prehn , Tobias Lindner , Peggy Berlin , Nagi Elleisy , Robert H. Förster , Alexander Cecil , Robert Jaster , Jerzy Adamski , Sarah M. Schwarzenböck , Brigitte Vollmar , Bernd J. Krause , Georg Lamprecht
{"title":"Glucagon-like peptide-2 pharmacotherapy activates hepatic Farnesoid X receptor-signaling to attenuate resection-associated bile acid loss in mice","authors":"Johannes Reiner , Nooshin Mohebali , Jens Kurth , Maria Witte , Cornelia Prehn , Tobias Lindner , Peggy Berlin , Nagi Elleisy , Robert H. Förster , Alexander Cecil , Robert Jaster , Jerzy Adamski , Sarah M. Schwarzenböck , Brigitte Vollmar , Bernd J. Krause , Georg Lamprecht","doi":"10.1016/j.molmet.2025.102121","DOIUrl":"10.1016/j.molmet.2025.102121","url":null,"abstract":"<div><h3>Objective</h3><div>Villus growth in the small bowel by Glucagon-like peptide-2 (GLP-2) pharmacotherapy improves intestinal absorption capacity and is now used clinically for the treatment of short bowel syndrome and intestinal failure occurring after extensive intestinal resection. Another recently acknowledged effect of GLP-2 treatment is the inhibition of gallbladder motility and increased gallbladder refilling. However, the impact of these two GLP-2-characteristic effects on bile acid metabolism in health and after intestinal resection is not understood.</div></div><div><h3>Methods</h3><div>Mice were injected with the GLP-2-analogue teduglutide or vehicle. We combined the selenium-75-homocholic acid taurine (SeHCAT) assay with novel spatial imaging in healthy mice and after ileocecal resection (ICR mice) and associated the results with clinical stage targeted bile acid metabolomics as well as gene expression analyses.</div></div><div><h3>Results</h3><div>ICR mice had virtual complete intestinal loss of secondary bile acids, and an increased ratio of 12α-hydroxylated vs. non-12α-hydroxylated bile acids, which was attenuated by teduglutide. Teduglutide promoted SeHCAT retention in healthy and in ICR mice. Acute concentration of the SeHCAT-signal into the hepatobiliary system was observed. Teduglutide induced significant repression of hepatic cyp8b1 expression, likely by induction of MAF BZIP Transcription Factor G.</div></div><div><h3>Conclusions</h3><div>The data suggest that GLP-2-pharmacotherapy in mice significantly slows bile acid circulation primarily via <em>hepatic</em> Farnesoid X receptor-signaling.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102121"},"PeriodicalIF":7.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amanda K. Casey , Nathan M. Stewart , Naqi Zaidi , Hillery F. Gray , Hazel A. Fields , Masahiro Sakurai , Carlos A. Pinzon-Arteaga , Bret M. Evers , Jun Wu , Kim Orth
{"title":"Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis","authors":"Amanda K. Casey , Nathan M. Stewart , Naqi Zaidi , Hillery F. Gray , Hazel A. Fields , Masahiro Sakurai , Carlos A. Pinzon-Arteaga , Bret M. Evers , Jun Wu , Kim Orth","doi":"10.1016/j.molmet.2025.102120","DOIUrl":"10.1016/j.molmet.2025.102120","url":null,"abstract":"<div><div>The bi-functional enzyme FicD catalyzes AMPylation and deAMPylation of the endoplasmic reticulum chaperone BiP to modulate ER homeostasis and the unfolded protein response (UPR). Human hFicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated the m<em>FicD</em><sup><em>R371S</em></sup> mutation in mice to create a pre-clinical murine model for neonatal diabetes. We observed elevated BiP AMPylation levels across multiple tissues and signature markers for diabetes including glucose intolerance and reduced serum insulin levels. While the pancreas of m<em>FicD</em><sup><em>R371S</em></sup> mice appeared normal at birth, adult <em>mFicD</em><sup><em>R371S</em></sup> mice displayed disturbed pancreatic islet organization that progressed with age. <em>mFicD</em><sup><em>R371S</em></sup> mice provide a preclinical mouse model for the study of UPR associated diabetes and demonstrate the essentiality of FicD for tissue resilience.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102120"},"PeriodicalIF":7.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anne-Marie Lundsgaard , Rita Del Giudice , Josephine M. Kanta , Mark Larance , Sarah L. Armour , Amalie London , Michael M. Richter , Nicoline R. Andersen , Trine S. Nicolaisen , Christian S. Carl , Kim A. Sjøberg , Kirstine Nyvold Bojsen-Møller , Jakob G. Knudsen , Jens O. Lagerstedt , Andreas M. Fritzen , Bente Kiens
{"title":"Apolipoprotein A-IV is induced by high-fat diets and mediates positive effects on glucose and lipid metabolism","authors":"Anne-Marie Lundsgaard , Rita Del Giudice , Josephine M. Kanta , Mark Larance , Sarah L. Armour , Amalie London , Michael M. Richter , Nicoline R. Andersen , Trine S. Nicolaisen , Christian S. Carl , Kim A. Sjøberg , Kirstine Nyvold Bojsen-Møller , Jakob G. Knudsen , Jens O. Lagerstedt , Andreas M. Fritzen , Bente Kiens","doi":"10.1016/j.molmet.2025.102119","DOIUrl":"10.1016/j.molmet.2025.102119","url":null,"abstract":"<div><h3>Objective</h3><div>Low-carbohydrate, high-fat diets under eucaloric conditions are associated with several health-beneficial metabolic effects in humans, particularly in the liver. We recently observed that apolipoprotein A-IV (apoA-IV), a highly abundant apolipoprotein, was among the most upregulated proteins in circulation after six weeks of consuming a high-fat diet in humans. However, the impact of dietary changes in regulating apoA-IV, and the potential effects of apoA-IV on regulation of glucose- and lipid metabolism remain to be fully established.</div></div><div><h3>Methods</h3><div>We investigated the regulation of circulating fasting concentrations of apoA-IV in humans in response to diets enriched in either fat or carbohydrates. Moreover, to study the whole-body and tissue-specific glucose and lipid metabolic effects of apoA-IV, we administrered apoA-IV recombinant protein to mice and isolated pancreatic islets.</div></div><div><h3>Results</h3><div>We demonstrate that in healthy human individuals high-fat intake increased fasting plasma apoA-IV concentrations by up to 54%, while high-carbohydrate intake suppressed plasma apoA-IV concentrations. In mice, administration of apoA-IV acutely lowered blood glucose levels both in lean and obese mice. Interestingly, this was related to a dual mechanism, involving both inhibition of hepatic glucose production and increased glucose uptake into white and brown adipose tissues. In addition to an effect on hepatic glucose production, the apoA-IV-induced liver proteome revealed increased capacity for lipoprotein clearance. The effects of apoA-IV in the liver and adipose tissues were concomitant with increased whole-body fatty acid oxidation. Upon glucose stimulation, an improvement in glucose tolerance by apoA-IV administration was related to potentiation of glucose-induced insulin secretion, while apoA-IV inhibited glucagon secretion <em>ex vivo</em> in islets.</div></div><div><h3>Conclusions</h3><div>We find that apoA-IV is potently increased by intake of fat in humans, and that several beneficial metabolic effects, previously associated with high fat intake in humans, are mimicked by administration of apoA-IV protein to mice.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102119"},"PeriodicalIF":7.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Timo D. Müller , Alice Adriaenssens , Bo Ahrén , Matthias Blüher , Andreas L. Birkenfeld , Jonathan E. Campbell , Matthew P. Coghlan , David D'Alessio , Carolyn F. Deacon , Stefano DelPrato , Jonathan D. Douros , Daniel J. Drucker , Natalie S. Figueredo Burgos , Peter R. Flatt , Brian Finan , Ruth E. Gimeno , Fiona M. Gribble , Matthew R. Hayes , Christian Hölscher , Jens J. Holst , Matthias H. Tschöp
{"title":"Glucose-dependent insulinotropic polypeptide (GIP)","authors":"Timo D. Müller , Alice Adriaenssens , Bo Ahrén , Matthias Blüher , Andreas L. Birkenfeld , Jonathan E. Campbell , Matthew P. Coghlan , David D'Alessio , Carolyn F. Deacon , Stefano DelPrato , Jonathan D. Douros , Daniel J. Drucker , Natalie S. Figueredo Burgos , Peter R. Flatt , Brian Finan , Ruth E. Gimeno , Fiona M. Gribble , Matthew R. Hayes , Christian Hölscher , Jens J. Holst , Matthias H. Tschöp","doi":"10.1016/j.molmet.2025.102118","DOIUrl":"10.1016/j.molmet.2025.102118","url":null,"abstract":"<div><h3>Background</h3><div>Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP.</div></div><div><h3>Scope of Review</h3><div>In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases.</div></div><div><h3>Major Conclusions</h3><div>Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102118"},"PeriodicalIF":7.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The small GTPase Rap1 in POMC neurons regulates leptin actions and glucose metabolism","authors":"Kentaro Kaneko , Weisheng Lu , Yong Xu , Alexei Morozov , Makoto Fukuda","doi":"10.1016/j.molmet.2025.102117","DOIUrl":"10.1016/j.molmet.2025.102117","url":null,"abstract":"<div><div>The hypothalamic leptin-proopiomelanocortin (POMC) pathway is critical for regulating metabolism. POMC neurons in the arcuate nucleus respond to leptin and play a pivotal role in mediating energy and glucose balance. However, during diet-induced obesity (DIO), these neurons often develop resistance to exogenous leptin. Recently, the small GTPase Rap1 has been implicated as an inhibitor of neuronal leptin signaling; however, its specific role within POMC neurons remains unexplored. We generated tamoxifen-inducible, POMC neuron-specific Rap1 knockout mice to selectively delete both <em>Rap1a</em> and <em>Rap1b</em> isoforms in POMC neurons. By analyzing these mice through metabolic phenotyping, immunohistochemistry, and biochemical assays, we show that deleting Rap1a and Rap1b in POMC neurons prior to exposing the mice to a high-fat diet significantly prevented weight gain compared to control mice. Furthermore, while DIO mice with intact Rap1 failed to respond to exogenous leptin, genetically removing the Rap1 genes from DIO mice enhanced the ability of exogenous leptin to induce anorectic effects. Remarkably, acute deletion of Rap1 in POMC neurons of already obese mice improved hyperglycemia within one week, with minimal effect on body weight. This glycemic improvement was accompanied by improved glucose tolerance, enhanced insulin sensitivity, and improved cellular insulin signaling. Collectively, these findings suggest that loss of Rap1 in POMC neurons enhances leptin sensitivity, acutely improves glucose balance, and may offer a potential strategy to lower hyperglycemia in dietary obesity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102117"},"PeriodicalIF":7.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liran Xu , Chao Yang , Kaidan Pang , Ying Zhang , Yu He , Siyu Liu , Huijing Tian , Zehua Shao , Siyu Wang , Xingqian Liu , Ting Li , Yapeng Cao , Luqin Yan , Jinjin Liu , Yanan Wang , Yongxin Li , Wei Zhao , Youhua Wang , Yang Yan , Shengpeng Wang
{"title":"Adipocyte Septin-7 attenuates obesogenic adipogenesis and promotes lipolysis to prevent obesity","authors":"Liran Xu , Chao Yang , Kaidan Pang , Ying Zhang , Yu He , Siyu Liu , Huijing Tian , Zehua Shao , Siyu Wang , Xingqian Liu , Ting Li , Yapeng Cao , Luqin Yan , Jinjin Liu , Yanan Wang , Yongxin Li , Wei Zhao , Youhua Wang , Yang Yan , Shengpeng Wang","doi":"10.1016/j.molmet.2025.102114","DOIUrl":"10.1016/j.molmet.2025.102114","url":null,"abstract":"<div><h3>Objectives</h3><div>The white adipose tissue (WAT) expansion plays a significant role in the development of obesity. Cytoskeletal remodeling directly impacts adipogenic program, however, the precise mechanism remains poorly understood. Here, we identified a crucial role of Septin-7 (SEPT7), a cytoskeleton component, in the regulation of diet-induced processes of adipogenesis, lipogenesis, and lipolysis in WAT.</div></div><div><h3>Methods</h3><div>A high-fat diet (HFD)-induced obesity model was constructed using mice with inducible adipocyte-specific SEPT7 deficiency. The impact of SEPT7 on adipocyte morphology, cell number and metabolism capacity were evaluated with immunofluorescence, isoproterenol induced lipolysis assay, glucose tolerance test and insulin tolerance test. Adipocyte mTmG reporter line was established to trace <em>in vivo</em> adipogenesis. The preadipocyte 3T3-L1 cell was induced for exploring role of SEPT7 in adipocyte differentiation. qRT-PCR and Western-blot were used to investigate the expression of PPARγ, C/EBPα, and HSL in 3T3-L1 cell with siRNA-mediated SEPT7 knockdown.</div></div><div><h3>Results</h3><div>SEPT7 expression was greatly induced in obesogenic human and murine adipocytes. Mice lacking SEPT7 in mature white adipocytes demonstrated defective differentiation of preadipocyte into mature adipocytes when fed HFD resulting in larger adipocytes, increased WAT inflammation and reduced lipolysis, which leading to increased WAT mass, liver fat accumulation and impaired glucose tolerance. Mechanistically, we identified SEPT7 restrains store-operated Ca<sup>2+</sup> entry (SOCE) and regulates adipocyte adipogenesis and lipolysis by targeting PPARγ, C/EBPα and HSL.</div></div><div><h3>Conclusions</h3><div>We demonstrated that SEPT7 negatively regulates adipogenesis while promotes lipolysis and its repression drives WAT expansion and impaired metabolic health.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102114"},"PeriodicalIF":7.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephen P. Ashcroft , Amy M. Ehrlich , Krzysztof Burek , Logan A. Pendergrast , Caio Y. Yonamine , Jonas T. Treebak , Juleen R. Zierath
{"title":"Enhanced metabolic adaptations following late dark phase wheel running in high-fat diet-fed mice","authors":"Stephen P. Ashcroft , Amy M. Ehrlich , Krzysztof Burek , Logan A. Pendergrast , Caio Y. Yonamine , Jonas T. Treebak , Juleen R. Zierath","doi":"10.1016/j.molmet.2025.102116","DOIUrl":"10.1016/j.molmet.2025.102116","url":null,"abstract":"<div><div>Exercise interventions represent an effective strategy to prevent and treat metabolic diseases and the time-of-day-dependent effects of exercise on metabolic outcomes are becoming increasingly apparent. We aimed to study the influence of time-restricted wheel running on whole-body energy and glucose homeostasis. Male, 8-week-old, C57BL/6NTac mice were fed either a 60% high-fat diet (HFD) or a 10% low-fat diet (LFD) for 4 weeks. Following this, mice were given access to a running wheel between zeitgeber time (ZT) 12–16 (early dark phase) or ZT 20-0 (late dark phase). Sedentary mice had access to a permanently locked wheel. Mice were housed under these conditions in metabolic chambers for 4 weeks in which LFD and HFD conditions were maintained. Following the exercise intervention, body composition and glucose tolerance were assessed. Wheel running during either the early or late dark phase resulted in metabolic improvements such as attenuation in body weight gain, enhanced glucose tolerance and reduced ectopic lipid deposition. However, late dark phase exercise resulted in a greater reduction in body weight gain, as well as enhanced metabolic flexibility and insulin sensitivity. Our data suggest that late dark phase versus early dark phase exercise confers greater metabolic adaptations in HFD-fed mice.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102116"},"PeriodicalIF":7.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tara L. MacDonald , Birgitta Ryback , Jéssica Aparecida da Silva Pereira , Siying Wei , Bryhan Mendez , Erica P. Cai , Yuki Ishikawa , Meagan Arbeau , Gordon Weir , Susan Bonner-Weir , Stephan Kissler , Peng Yi
{"title":"Renalase inhibition defends against acute and chronic β cell stress by regulating cell metabolism","authors":"Tara L. MacDonald , Birgitta Ryback , Jéssica Aparecida da Silva Pereira , Siying Wei , Bryhan Mendez , Erica P. Cai , Yuki Ishikawa , Meagan Arbeau , Gordon Weir , Susan Bonner-Weir , Stephan Kissler , Peng Yi","doi":"10.1016/j.molmet.2025.102115","DOIUrl":"10.1016/j.molmet.2025.102115","url":null,"abstract":"<div><h3>Objective</h3><div>Renalase (Rnls) is annotated as an oxidase enzyme. It has been implicated in Type 1 diabetes (T1D) risk via genome-wide association studies (GWAS). We previously discovered through CRISPR screening and validation experiments that Rnls inhibition prevents or delays T1D in multiple mouse models of diabetes <em>in vivo</em>, and protects pancreatic β cells against autoimmune killing, ER and oxidative stress <em>in vitro</em>. The molecular biochemistry and functions of Rnls are largely uncharted. Here we studied the mechanisms of Rnls inhibition that underlie β cell protection during diabetogenic stress.</div></div><div><h3>Methods</h3><div>Akita mice were treated with oral Pargyline (PG) <em>in vivo</em> to bind and inhibit Rnls, and pancreas or islets were harvested for β cell mass and β cell function analyses. Genetic and pharmacological tools were used to inhibit Rnls in β cell lines. RNA sequencing, metabolomics and metabolic function experiments were conducted in vitro in NIT-1 mouse β cell lines and human stem cell-derived β cells.</div></div><div><h3>Results</h3><div><em>In vivo</em>, PG improved glycemia and mildly preserved β cell mass and function in females. Genetic strategies to mutate (Rnls<sup>mut</sup>) or knockout (Rnls KO) Rnls induced a robust metabolic shift towards glycolysis in both mouse and human β cell lines, <em>in vitro</em>. Stress protection was abolished when glycolysis was blocked with 2-deoxyglucose (2-DG). Pharmacological Rnls inhibition with PG did not strongly mimic these newly identified metabolic mechanisms.</div></div><div><h3>Conclusions</h3><div>Our work illustrates a role for Rnls in regulating cell metabolism. We show that inhibiting Rnls protects against chronic stress <em>in vivo</em>, and shields against acute stress in β cell lines <em>in vitro</em> by rewiring cell metabolism towards glycolysis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102115"},"PeriodicalIF":7.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Se Seul Im , Jihyeon Seo , Ji Eun You , Hye Won Bang , YongHwan Kim , Jiyeon Kweon , Yongsub Kim , Dong-Myung Shin , Jaekyoung Son
{"title":"BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics","authors":"Se Seul Im , Jihyeon Seo , Ji Eun You , Hye Won Bang , YongHwan Kim , Jiyeon Kweon , Yongsub Kim , Dong-Myung Shin , Jaekyoung Son","doi":"10.1016/j.molmet.2025.102113","DOIUrl":"10.1016/j.molmet.2025.102113","url":null,"abstract":"<div><h3>Objectives</h3><div>Increased expression of glutaminase (GLS) has been found to correlate with more aggressive disease and poorer prognosis in patients with several types of cancer, including breast, lung, and pancreatic cancer. G9a histone methyltransferase inhibitors may have anticancer activity. The present study assessed whether BIX01294 (BIX), a G9a histone methyltransferase inhibitor, can inhibit glutaminase (GLS) in pancreatic ductal adenocarcinoma (PDAC) cells.</div></div><div><h3>Methods</h3><div>The effects of BIX on mitochondrial metabolism in PDAC cells were evaluated by targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) metabolomic analysis. To assess the impact of BIX on glutathione dynamics, real-time changes in glutathione levels were monitored by FreSHtracer-based GSH assays.</div></div><div><h3>Results</h3><div>BIX significantly inhibited the growth of PDAC cells, both in vitro and <em>in vivo</em>, and robustly induced apoptotic cell death. BIX significantly increased the cellular NADP<sup>+</sup>/NADPH ratio and decreased the ratio of reduced-to-oxidized glutathione (GSH:GSSG). In addition, BIX decreased GSH levels and increased ROS levels. N-acetyl-<span>l</span>-cysteine (NAC) supplementation dramatically rescued PDAC cells from BIX-induced apoptosis. Furthermore, BIX inhibited the transcription of GLS by inhibiting Jumonji-domain histone demethylases but not G9a histone methyltransferase. One Jumonji-domain histone demethylase, KDM6B, epigenetically regulated GLS expression by binding to the GLS gene promoter.</div></div><div><h3>Conclusions</h3><div>Collectively, these findings suggest that BIX could be a potent therapeutic agent in patients with PDAC through its inhibition of GLS-mediated cellular redox balance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"94 ","pages":"Article 102113"},"PeriodicalIF":7.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Romina Bertinat , Todd Holyoak , Rodrigo Gatica , Nery Jara , Iván González-Chavarría , Francisco Westermeier
{"title":"The neglected PCK1/glucagon (inter)action in nutrient homeostasis beyond gluconeogenesis: Disease pathogenesis and treatment","authors":"Romina Bertinat , Todd Holyoak , Rodrigo Gatica , Nery Jara , Iván González-Chavarría , Francisco Westermeier","doi":"10.1016/j.molmet.2025.102112","DOIUrl":"10.1016/j.molmet.2025.102112","url":null,"abstract":"<div><h3>Background</h3><div>Glucagon plays a central role in hepatic adaptation during fasting, with the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) traditionally associated with increased gluconeogenesis. However, recent experimental models and clinical studies have challenged this view, suggesting a more complex interplay between PCK1 and glucagon, which extends beyond gluconeogenesis and has broader implications for metabolic regulation in health and disease.</div></div><div><h3>Scope of review</h3><div>This review provides a comprehensive overview of the current evidence on the multifaceted roles of PCK1 in glucagon-dependent hepatic adaptation during fasting, which is crucial for maintaining systemic homeostasis not only of glucose, but also of lipids and amino acids. We explore the relationship between PCK1 deficiency and glucagon resistance in metabolic disorders, including inherited PCK1 deficiency and metabolic dysfunction-associated steatotic liver disease (MASLD), and compare findings from experimental animal models with whole-body or tissue-specific ablation of PCK1 or the glucagon receptor. We propose new research platforms to advance the therapeutic potential of targeting PCK1 in metabolic diseases.</div></div><div><h3>Major conclusions</h3><div>We propose that hepatic PCK1 deficiency might be an acquired metabolic disorder linking alterations in lipid metabolism with impaired glucagon signaling. Our findings highlight interesting links between glycerol, PCK1 deficiency, elevated plasma alanine levels and glucagon resistance. We conclude that the roles of PCK1 and glucagon in metabolic regulation are more complex than previously assumed. In this (un)expected scenario, hepatic PCK1 deficiency and glucagon resistance appear to exert limited control over glycemia, but have broader metabolic effects related to lipid and amino acid dysregulation. Given the shift in glucagon research from receptor inhibition to activation, we propose that a similar paradigm shift is needed in the study of hepatic PCK1. Understanding PCK1 expression and activity in the glucagon-dependent hepatic adaptation to fasting might provide new perspectives and therapeutic opportunities for metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"94 ","pages":"Article 102112"},"PeriodicalIF":7.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}