Molecular Metabolism最新文献

{"title":"Physical training reduces cell senescence and associated insulin resistance in skeletal muscle","authors":"Agnieszka Podraza-Farhanieh ,&nbsp;Rosa Spinelli ,&nbsp;Federica Zatterale ,&nbsp;Annika Nerstedt ,&nbsp;Silvia Gogg ,&nbsp;Matthias Blüher ,&nbsp;Ulf Smith","doi":"10.1016/j.molmet.2025.102130","DOIUrl":"10.1016/j.molmet.2025.102130","url":null,"abstract":"<div><h3>Background</h3><div>Cell senescence (CS) is a key aging process that leads to irreversible cell cycle arrest and an altered secretory phenotype. In skeletal muscle (SkM), the accumulation of senescent cells contributes to sarcopenia. Despite exercise being a known intervention for maintaining SkM function and metabolic health, its effects on CS remain poorly understood.</div></div><div><h3>Objectives</h3><div>This study aimed to investigate the impact of exercise on CS in human SkM by analyzing muscle biopsies from young, normal-weight individuals and middle-aged individuals with obesity, both before and after exercise intervention.</div></div><div><h3>Methods</h3><div>Muscle biopsies were collected from both groups before and after an exercise intervention. CS markers, insulin sensitivity (measured with euglycemic clamp), and satellite cell markers were analyzed. Additionally, <em>in vitro</em> experiments were conducted to evaluate the effects of cellular senescence on human satellite cells, focusing on key regulatory genes and insulin signaling.</div></div><div><h3>Results</h3><div>Individuals with obesity showed significantly elevated CS markers, along with reduced expression of <em>GLUT4</em> and <em>PAX7</em>, indicating impaired insulin action and regenerative potential. Exercise improved insulin sensitivity, reduced CS markers, and activated satellite cell response in both groups. In vitro experiments revealed that senescence downregulated key regulatory genes in satellite cells and impaired insulin signaling by reducing the Insulin Receptor β-subunit.</div></div><div><h3>Conclusions</h3><div>These findings highlight the role of CS in regulating insulin sensitivity in SkM and underscore the therapeutic potential of exercise in mitigating age- and obesity-related muscle dysfunction. Targeting CS through exercise or senolytic agents could offer a promising strategy for improving metabolic health and combating sarcopenia, particularly in at-risk populations.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102130"},"PeriodicalIF":7.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701080","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":"Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice","authors":"L. Stilgenbauer ,&nbsp;Q. Chen ,&nbsp;D. Pungi ,&nbsp;N. James ,&nbsp;H. Jayarathne ,&nbsp;L. Koshko ,&nbsp;S. Scofield ,&nbsp;K. Zhang ,&nbsp;M. Sadagurski","doi":"10.1016/j.molmet.2025.102128","DOIUrl":"10.1016/j.molmet.2025.102128","url":null,"abstract":"<div><h3>Background</h3><div>Chronic high-fat diet (HFD) feeding triggers hypothalamic inflammation and systemic metabolic dysfunction associated with endoplasmic reticulum (ER) stress. Glial cells, specifically microglia and astrocytes, are central mediators of hypothalamic inflammation. However, the role of Inositol-Requiring Enzyme 1α (IRE1α), a primary ER stress sensor, in glial cells and its contributions to metabolic dysfunction remains elusive.</div></div><div><h3>Objectives</h3><div>To investigate the role of IRE1α in microglia in mediating HFD-induced metabolic dysfunction.</div></div><div><h3>Methods</h3><div>Using novel conditional knockout mouse models (CX3CR1^GFPΔIRE1 and TMEM119^ERΔIRE1), we deleted IRE1α in immune cells or exclusively in microglia and studied its impact on metabolic health and hypothalamic transcriptional changes in mice fed with HFD for 16 weeks.</div></div><div><h3>Results</h3><div>Deleting IRE1α in microglia significantly reduced LPS-induced pro-inflammatory cytokine gene expression <em>in vitro</em>. IRE1α deletion in microglia protected male mice from HFD-induced obesity, glucose intolerance, and hypothalamic inflammation, with no metabolic benefits observed in female mice. RNA-sequencing revealed significant transcriptional reprogramming of the hypothalamus, including upregulation of genes related to mitochondrial fatty acid oxidation, metabolic adaptability, and anti-inflammatory responses.</div></div><div><h3>Conclusions</h3><div>Our findings reveal that IRE1α-mediated ER stress response in microglia significantly contributes to hypothalamic inflammation and systemic metabolic dysfunction in response to HFD, particularly in males, demonstrating an important role of microglial ER stress response in diet-induced obesity and metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102128"},"PeriodicalIF":7.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692818","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":"No UCP1 in the kidney","authors":"Celso Pereira Batista Sousa-Filho,&nbsp;Natasa Petrovic","doi":"10.1016/j.molmet.2025.102127","DOIUrl":"10.1016/j.molmet.2025.102127","url":null,"abstract":"<div><h3>Objectives</h3><div>Several recent studies have indicated the presence of UCP1 in the kidney, challenging the paradigm that UCP1 is only found in brown and beige adipocytes and broadening the (patho)physiological significance of UCP1. The kidney localization has been the direct result of immunohistochemical investigations and an inferred outcome from multiple lines of reporter mice. These findings require confirmation and further physiological characterization.</div></div><div><h3>Methods</h3><div>We examined UCP1 expression in the kidney using immunohistochemistry and qPCR. Transversal sections through or near the kidney hilum, consistently including perirenal brown fat and adjacent kidney tissue, were analyzed with four UCP1 antibodies.</div></div><div><h3>Results</h3><div>In addition to detecting UCP1 in perirenal adipose tissue, we observed distinct immunopositive structures in the kidney with our in-house UCP1-antibody, ‘C10’, in apparent agreement with earlier reports. To corroborate this, we tested the C10-antibody on kidney sections from UCP1-ablated mice but found equal reactivity in these UCP1-negative tissues. We then tested the widely used antibody ab10983, previously employed in kidney studies. Also here, the positive signal persisted in UCP1-ablated mice, clearly invalidating earlier findings. UCP1 qPCR studies also failed to detect UCP1 mRNA above background. Finally, two highly specific antibodies, E9Z2V and EPR20381, accurately detected UCP1 in perirenal adipose tissue but showed no signal in the kidney.</div></div><div><h3>Conclusions</h3><div>When appropriate controls are implemented, there is no evidence for the presence of UCP1 in the kidney. Consequently, this conclusion also implies that the results from UCP1 reporter mice, specifically regarding kidney expression of the UCP1 gene – though possibly applicable to other tissues – require reconfirmation before being accepted as evidence for the presence of UCP1 in non-adipose tissues.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102127"},"PeriodicalIF":7.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692821","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":"Peptidylglycine alpha-amidating monooxygenase is important in mice for beta-cell cilia formation and insulin secretion but promotes diabetes risk through beta-cell independent mechanisms","authors":"Yi-Chun Chen ,&nbsp;Nils E. Bäck ,&nbsp;Jenicia Zhen ,&nbsp;Lena Xiong ,&nbsp;Mitsuhiro Komba ,&nbsp;Anna L. Gloyn ,&nbsp;Patrick E. MacDonald ,&nbsp;Richard E. Mains ,&nbsp;Betty A. Eipper ,&nbsp;C. Bruce Verchere","doi":"10.1016/j.molmet.2025.102123","DOIUrl":"10.1016/j.molmet.2025.102123","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objectives&lt;/h3&gt;&lt;div&gt;Carriers of &lt;em&gt;PAM&lt;/em&gt; (peptidylglycine alpha-amidating monooxygenase) coding variant alleles have reduced insulinogenic index, higher risk of developing type 2 diabetes (T2D), and islets from heterozygous carriers of the &lt;em&gt;PAM&lt;/em&gt; p.Asp563Gly variant display reduced insulin secretion. Exactly how global PAM deficiency contributes to hyperglycemia remains unclear. PAM is the only enzyme capable of converting glycine-extended peptide hormones into amidated products. Like neuropeptide Y (NPY), α-melanocyte stimulating hormone (αMSH), and glucagon-like peptide 1 (GLP-1), islet amyloid polypeptide (IAPP), a beta cell peptide that forms islet amyloid in type 2 diabetes, is a PAM substrate. We hypothesized that Pam deficiency limited to beta cells would lead to reduced insulin secretion, prevent the production of amidated IAPP, and reveal the extent to which loss of Pam in β-cells could accelerate the onset of hyperglycemia in mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;PAM activity was assessed in human islets from donors based on their &lt;em&gt;PAM&lt;/em&gt; genotype. We generated beta cell-specific &lt;em&gt;Pam&lt;/em&gt; knockout (&lt;em&gt;Ins1&lt;/em&gt;&lt;sup&gt;Cre/+&lt;/sup&gt;, &lt;em&gt;Pam&lt;/em&gt;&lt;sup&gt;&lt;em&gt;fl/fl&lt;/em&gt;&lt;/sup&gt;; β&lt;em&gt;Pam&lt;/em&gt;KO) mice and performed islet culture, histological, and metabolic assays to evaluate the physiological roles of Pam in beta cells. We analyzed human IAPP (hIAPP) amyloid fibril forming kinetics using synthetic amidated and non-amidated hIAPP peptides, and generated hIAPP knock-in beta cell-specific &lt;em&gt;Pam&lt;/em&gt; knockout (&lt;em&gt;hIAPP&lt;/em&gt;&lt;sup&gt;w/w&lt;/sup&gt; β&lt;em&gt;Pam&lt;/em&gt;KO) mice to determine the impact of hIAPP amidation on islet amyloid burden, islet graft survival, and glucose tolerance.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;PAM enzyme activity was significantly reduced in islets from donors with the &lt;em&gt;PAM&lt;/em&gt; p. Asp563Gly T2D-risk allele. Islets from β&lt;em&gt;Pam&lt;/em&gt;KO mice had impaired second-phase glucose- and KCl-induced insulin secretion. Beta cells from β&lt;em&gt;Pam&lt;/em&gt;KO mice had larger dense-core granules and fewer and shorter cilia. Interestingly, non-amidated hIAPP was less fibrillogenic &lt;em&gt;in vitro&lt;/em&gt;, and high glucose-treated &lt;em&gt;hIAPP&lt;/em&gt;&lt;sup&gt;w/w&lt;/sup&gt; β&lt;em&gt;Pam&lt;/em&gt;KO islets had reduced amyloid burden. Despite these changes in beta cell function, β&lt;em&gt;Pam&lt;/em&gt;KO mice were not more susceptible to diet-induced hyperglycemia. &lt;em&gt;In vitro&lt;/em&gt; beta cell death and &lt;em&gt;in vivo&lt;/em&gt; islet graft survival remained comparable between &lt;em&gt;hIAPP&lt;/em&gt;&lt;sup&gt;w/w&lt;/sup&gt; β&lt;em&gt;Pam&lt;/em&gt;KO and &lt;em&gt;hIAPP&lt;/em&gt;&lt;sup&gt;w/w&lt;/sup&gt; islets. Surprisingly, aged &lt;em&gt;hIAPP&lt;/em&gt;&lt;sup&gt;w/w&lt;/sup&gt; β&lt;em&gt;Pam&lt;/em&gt;KO mice had improved insulin secretion and glucose tolerance.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Eliminating &lt;em&gt;Pam&lt;/em&gt; expression only in beta cells leads to morphological changes in insulin granules, reduced insulin secretion, reduced hIAPP amyloid burden and altered ciliogenesis. However, in mice beta-cell &lt;em&gt;Pam&lt;/em&gt; deficiency has no impact on","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"96 ","pages":"Article 102123"},"PeriodicalIF":7.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692823","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}

{"title":"Aregs-IGFBP3-mediated SMC-like cells apoptosis impairs beige adipocytes formation in aged mice","authors":"Shifeng Wang ,&nbsp;Yuanxu Cui ,&nbsp;Limei Wang ,&nbsp;Chun Feng ,&nbsp;Yifei Sun ,&nbsp;Bangyun Huo ,&nbsp;Honglu Jiang ,&nbsp;Mingyu Zhao ,&nbsp;Yingying Tu ,&nbsp;Qiyue Wang ,&nbsp;Yutao Yang ,&nbsp;Qiang Zhang","doi":"10.1016/j.molmet.2025.102125","DOIUrl":"10.1016/j.molmet.2025.102125","url":null,"abstract":"<div><div>Aging is associated with a decline in the browning capacity of white adipose tissue (WAT), contributing to metabolic dysfunction. Beige adipocytes, which dissipate excess energy as heat, are a key feature of this process. In this study, we investigate the role of adipose stem and progenitor cells (ASPCs), specifically the Aregs (CD142+) subpopulation, in regulating beige adipocyte formation in aged mice under cold stimulation. Our findings reveal that Aregs significantly increase in the subcutaneous WAT (sWAT) of aged mice following cold exposure. We further demonstrate that Aregs secrete insulin-like growth factor binding protein 3 (IGFBP3), which appears to play a pivotal role in the cross-talk between adipogenesis-regulatory cells (Aregs) and smooth muscle cell-like (SMC-like) cells, thereby leading to the inhibition of beige adipocytes formation. Functional enrichment analysis highlighted the activation of TGFβ, MAPK and p53 signaling pathways in SMC-like cells, all of which are known to induce cell apoptosis and fibrosis. Moreover, IGFBP3 was found to interact with receptors and signaling molecules, including Egfr, Irf1 and Cdkn1a, in SMC-like cells, enhancing their apoptosis. Co-culture experiments confirmed that IGFBP3 significantly suppressed the formation of beige adipocytes, further corroborating its role in impairing browning. Overall, our study provides novel insights into the molecular mechanisms by which Aregs and IGFBP3 contribute to the age-related decline in WAT browning. These findings suggest potential therapeutic targets for reversing impaired WAT browning in aging and related metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"95 ","pages":"Article 102125"},"PeriodicalIF":7.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674398","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":"Glucagon-like peptide-2 pharmacotherapy activates hepatic Farnesoid X receptor-signaling to attenuate resection-associated bile acid loss in mice","authors":"Johannes Reiner ,&nbsp;Nooshin Mohebali ,&nbsp;Jens Kurth ,&nbsp;Maria Witte ,&nbsp;Cornelia Prehn ,&nbsp;Tobias Lindner ,&nbsp;Peggy Berlin ,&nbsp;Nagi Elleisy ,&nbsp;Robert H. Förster ,&nbsp;Alexander Cecil ,&nbsp;Robert Jaster ,&nbsp;Jerzy Adamski ,&nbsp;Sarah M. Schwarzenböck ,&nbsp;Brigitte Vollmar ,&nbsp;Bernd J. Krause ,&nbsp;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}

{"title":"Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis","authors":"Amanda K. Casey ,&nbsp;Nathan M. Stewart ,&nbsp;Naqi Zaidi ,&nbsp;Hillery F. Gray ,&nbsp;Hazel A. Fields ,&nbsp;Masahiro Sakurai ,&nbsp;Carlos A. Pinzon-Arteaga ,&nbsp;Bret M. Evers ,&nbsp;Jun Wu ,&nbsp;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>^{<em>R371S</em>} 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>^{<em>R371S</em>} mice appeared normal at birth, adult <em>mFicD</em>^{<em>R371S</em>} mice displayed disturbed pancreatic islet organization that progressed with age. <em>mFicD</em>^{<em>R371S</em>} 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}

{"title":"Apolipoprotein A-IV is induced by high-fat diets and mediates positive effects on glucose and lipid metabolism","authors":"Anne-Marie Lundsgaard ,&nbsp;Rita Del Giudice ,&nbsp;Josephine M. Kanta ,&nbsp;Mark Larance ,&nbsp;Sarah L. Armour ,&nbsp;Amalie London ,&nbsp;Michael M. Richter ,&nbsp;Nicoline R. Andersen ,&nbsp;Trine S. Nicolaisen ,&nbsp;Christian S. Carl ,&nbsp;Kim A. Sjøberg ,&nbsp;Kirstine Nyvold Bojsen-Møller ,&nbsp;Jakob G. Knudsen ,&nbsp;Jens O. Lagerstedt ,&nbsp;Andreas M. Fritzen ,&nbsp;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}

{"title":"Glucose-dependent insulinotropic polypeptide (GIP)","authors":"Timo D. Müller ,&nbsp;Alice Adriaenssens ,&nbsp;Bo Ahrén ,&nbsp;Matthias Blüher ,&nbsp;Andreas L. Birkenfeld ,&nbsp;Jonathan E. Campbell ,&nbsp;Matthew P. Coghlan ,&nbsp;David D'Alessio ,&nbsp;Carolyn F. Deacon ,&nbsp;Stefano DelPrato ,&nbsp;Jonathan D. Douros ,&nbsp;Daniel J. Drucker ,&nbsp;Natalie S. Figueredo Burgos ,&nbsp;Peter R. Flatt ,&nbsp;Brian Finan ,&nbsp;Ruth E. Gimeno ,&nbsp;Fiona M. Gribble ,&nbsp;Matthew R. Hayes ,&nbsp;Christian Hölscher ,&nbsp;Jens J. Holst ,&nbsp;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 ,&nbsp;Weisheng Lu ,&nbsp;Yong Xu ,&nbsp;Alexei Morozov ,&nbsp;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}