Nature metabolism最新文献

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Ketogenic diet-induced bile acids protect against obesity through reduced calorie absorption 生酮饮食诱导胆汁酸通过减少热量吸收防止肥胖
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-06-27 DOI: 10.1038/s42255-024-01072-1
Xiao Li, Jie Yang, Xiaofeng Zhou, Chen Dai, Mengmeng Kong, Linshan Xie, Chenglin Liu, Yilian Liu, Dandan Li, Xiaonan Ma, Yuxiang Dai, Yan Sun, Zhijie Jian, Xiaohuan Guo, Xu Lin, Yixue Li, Liang Sun, Xin Liu, Li Jin, Huiru Tang, Yan Zheng, Shangyu Hong
{"title":"Ketogenic diet-induced bile acids protect against obesity through reduced calorie absorption","authors":"Xiao Li, Jie Yang, Xiaofeng Zhou, Chen Dai, Mengmeng Kong, Linshan Xie, Chenglin Liu, Yilian Liu, Dandan Li, Xiaonan Ma, Yuxiang Dai, Yan Sun, Zhijie Jian, Xiaohuan Guo, Xu Lin, Yixue Li, Liang Sun, Xin Liu, Li Jin, Huiru Tang, Yan Zheng, Shangyu Hong","doi":"10.1038/s42255-024-01072-1","DOIUrl":"10.1038/s42255-024-01072-1","url":null,"abstract":"The low-carbohydrate ketogenic diet (KD) has long been practiced for weight loss, but the underlying mechanisms remain elusive. Gut microbiota and metabolites have been suggested to mediate the metabolic changes caused by KD consumption, although the particular gut microbes or metabolites involved are unclear. Here, we show that KD consumption enhances serum levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA) in mice to decrease body weight and fasting glucose levels. Mechanistically, KD feeding decreases the abundance of a bile salt hydrolase (BSH)-coding gut bacterium, Lactobacillus murinus ASF361. The reduction of L. murinus ASF361 or inhibition of BSH activity increases the circulating levels of TDCA and TUDCA, thereby reducing energy absorption by inhibiting intestinal carbonic anhydrase 1 expression, which leads to weight loss. TDCA and TUDCA treatments have been found to protect against obesity and its complications in multiple mouse models. Additionally, the associations among the abovementioned bile acids, microbial BSH and metabolic traits were consistently observed both in an observational study of healthy human participants (n = 416) and in a low-carbohydrate KD interventional study of participants who were either overweight or with obesity (n = 25). In summary, we uncover a unique host–gut microbiota metabolic interaction mechanism for KD consumption to decrease body weight and fasting glucose levels. Our findings support TDCA and TUDCA as two promising drug candidates for obesity and its complications in addition to a KD. A ketogenic diet can reduce calorie absorption and protect against obesity by inducing changes to the gut microbiota and the bile acid pool.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 7","pages":"1397-1414"},"PeriodicalIF":18.9,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141461812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The hidden impact of in-source fragmentation in metabolic and chemical mass spectrometry data interpretation 源内碎片对代谢和化学质谱数据解读的隐性影响
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-06-25 DOI: 10.1038/s42255-024-01076-x
Martin Giera, Aries Aisporna, Winnie Uritboonthai, Gary Siuzdak
{"title":"The hidden impact of in-source fragmentation in metabolic and chemical mass spectrometry data interpretation","authors":"Martin Giera, Aries Aisporna, Winnie Uritboonthai, Gary Siuzdak","doi":"10.1038/s42255-024-01076-x","DOIUrl":"10.1038/s42255-024-01076-x","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 9","pages":"1647-1648"},"PeriodicalIF":18.9,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Optimizing the design of time-restricted eating human trials 优化限时进食人体试验的设计
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-06-21 DOI: 10.1038/s42255-024-01073-0
Krista A. Varady, Lisa S. Chow
{"title":"Optimizing the design of time-restricted eating human trials","authors":"Krista A. Varady, Lisa S. Chow","doi":"10.1038/s42255-024-01073-0","DOIUrl":"10.1038/s42255-024-01073-0","url":null,"abstract":"Time-restricted eating has become a popular diet for weight management and has spurred tremendous interest in the scientific community. The translation of results from TRE trials heavily depends on trial design. In this Comment, we provide general guidelines on optimizing the design and performance of time-restricted eating trials in human participants.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 8","pages":"1423-1425"},"PeriodicalIF":18.9,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141435849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The sphingosine-1-phosphate receptor 1 mediates the atheroprotective effect of eicosapentaenoic acid 鞘氨醇-1-磷酸受体 1 介导二十碳五烯酸的动脉粥样硬化保护作用
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-06-21 DOI: 10.1038/s42255-024-01070-3
Ting Zhou, Jie Cheng, Shuo He, Chao Zhang, Ming-Xin Gao, Li-Jun Zhang, Jin-Peng Sun, Yi Zhu, Ding Ai
{"title":"The sphingosine-1-phosphate receptor 1 mediates the atheroprotective effect of eicosapentaenoic acid","authors":"Ting Zhou, Jie Cheng, Shuo He, Chao Zhang, Ming-Xin Gao, Li-Jun Zhang, Jin-Peng Sun, Yi Zhu, Ding Ai","doi":"10.1038/s42255-024-01070-3","DOIUrl":"10.1038/s42255-024-01070-3","url":null,"abstract":"Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been associated with potential cardiovascular benefits, partly attributed to their bioactive metabolites. However, the underlying mechanisms responsible for these advantages are not fully understood. We previously reported that metabolites of the cytochrome P450 pathway derived from eicosapentaenoic acid (EPA) mediated the atheroprotective effect of ω-3 PUFAs. Here, we show that 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and its receptor, sphingosine-1-phosphate receptor 1 (S1PR1), in endothelial cells (ECs) can inhibit oscillatory shear stress- or tumor necrosis factor-α-induced endothelial activation in cultured human ECs. Notably, the atheroprotective effect of 17,18-EEQ and purified EPA is circumvented in male mice with endothelial S1PR1 deficiency. Mechanistically, the anti-inflammatory effect of 17,18-EEQ relies on calcium release-mediated endothelial nitric oxide synthase (eNOS) activation, which is abolished upon inhibition of S1PR1 or Gq signaling. Furthermore, 17,18-EEQ allosterically regulates the conformation of S1PR1 through a polar interaction with Lys34Nter. Finally, we show that Vascepa, a prescription drug containing highly purified and stable EPA ethyl ester, exerts its cardiovascular protective effect through the 17,18-EEQ–S1PR1 pathway in male and female mice. Collectively, our findings indicate that the anti-inflammatory effect of 17,18-EEQ involves the activation of the S1PR1–Gq–Ca2+–eNOS axis in ECs, offering a potential therapeutic target against atherosclerosis. The sphingosine-1-phosphate receptor 1 mediates the inhibitory effect of eicosapentaenoic acid on endothelial activation and atherogenesis, furthering our understanding of the cardioprotective role of omega-3 polyunsaturated fatty acids.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 8","pages":"1566-1583"},"PeriodicalIF":18.9,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141435857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Gut–liver highway of ALDH2 in drinking 饮水中 ALDH2 的肠道-肝脏高速公路
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-06-20 DOI: 10.1038/s42255-024-01071-2
Subhash C. Pandey, Emir Malovic
{"title":"Gut–liver highway of ALDH2 in drinking","authors":"Subhash C. Pandey, Emir Malovic","doi":"10.1038/s42255-024-01071-2","DOIUrl":"10.1038/s42255-024-01071-2","url":null,"abstract":"In this issue of Nature Metabolism, Fu et al. show that genetic deletion of aldehyde dehydrogenase 2 (ALDH2) simultaneously in the gut and liver synergistically regulates acetaldehyde (AcH) levels and alcohol consumption.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 7","pages":"1202-1203"},"PeriodicalIF":18.9,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Coordinated action of a gut–liver pathway drives alcohol detoxification and consumption 肠道-肝脏途径的协调作用推动酒精解毒和消费
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-06-20 DOI: 10.1038/s42255-024-01063-2
Yaojie Fu, Bryan Mackowiak, Yu-Hong Lin, Luca Maccioni, Taylor Lehner, Hongna Pan, Yukun Guan, Grzegorz Godlewski, Hongkun Lu, Cheng Chen, Shoupeng Wei, Dechun Feng, Janos Paloczi, Huiping Zhou, Pal Pacher, Li Zhang, George Kunos, Bin Gao
{"title":"Coordinated action of a gut–liver pathway drives alcohol detoxification and consumption","authors":"Yaojie Fu, Bryan Mackowiak, Yu-Hong Lin, Luca Maccioni, Taylor Lehner, Hongna Pan, Yukun Guan, Grzegorz Godlewski, Hongkun Lu, Cheng Chen, Shoupeng Wei, Dechun Feng, Janos Paloczi, Huiping Zhou, Pal Pacher, Li Zhang, George Kunos, Bin Gao","doi":"10.1038/s42255-024-01063-2","DOIUrl":"10.1038/s42255-024-01063-2","url":null,"abstract":"Alcohol use disorder (AUD) affects millions of people worldwide, causing extensive morbidity and mortality with limited pharmacological treatments. The liver is considered as the principal site for the detoxification of ethanol metabolite, acetaldehyde (AcH), by aldehyde dehydrogenase 2 (ALDH2) and as a target for AUD treatment, however, our recent data indicate that the liver only plays a partial role in clearing systemic AcH. Here we show that a liver–gut axis, rather than liver alone, synergistically drives systemic AcH clearance and voluntary alcohol drinking. Mechanistically, we find that after ethanol intake, a substantial proportion of AcH generated in the liver is excreted via the bile into the gastrointestinal tract where AcH is further metabolized by gut ALDH2. Modulating bile flow significantly affects serum AcH level and drinking behaviour. Thus, combined targeting of liver and gut ALDH2, and manipulation of bile flow and secretion are potential therapeutic strategies to treat AUD. Fu, Mackowiak et al. show that cooperative action of the liver and the gut, rather than the liver alone, drives acetaldehyde clearance after alcohol consumption and modulates drinking behaviour.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 7","pages":"1380-1396"},"PeriodicalIF":18.9,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tissue-resident bacteria in metabolic diseases: emerging evidence and challenges 代谢性疾病中的组织驻留细菌:新证据与挑战
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-06-19 DOI: 10.1038/s42255-024-01065-0
Lucas Massier, Niculina Musat, Michael Stumvoll, Valentina Tremaroli, Rima Chakaroun, Peter Kovacs
{"title":"Tissue-resident bacteria in metabolic diseases: emerging evidence and challenges","authors":"Lucas Massier, Niculina Musat, Michael Stumvoll, Valentina Tremaroli, Rima Chakaroun, Peter Kovacs","doi":"10.1038/s42255-024-01065-0","DOIUrl":"10.1038/s42255-024-01065-0","url":null,"abstract":"Although the impact of the gut microbiome on health and disease is well established, there is controversy regarding the presence of microorganisms such as bacteria and their products in organs and tissues. However, recent contamination-aware findings of tissue-resident microbial signatures provide accumulating evidence in support of bacterial translocation in cardiometabolic disease. The latter provides a distinct paradigm for the link between microbial colonizers of mucosal surfaces and host metabolism. In this Perspective, we re-evaluate the concept of tissue-resident bacteria including their role in metabolic low-grade tissue and systemic inflammation. We examine the limitations and challenges associated with studying low bacterial biomass samples and propose experimental and analytical strategies to overcome these issues. Our Perspective aims to encourage further investigation of the mechanisms linking tissue-resident bacteria to host metabolism and their potentially actionable health implications for prevention and treatment. In this Perspective, the role of tissue-resident bacteria in metabolic diseases is discussed and the experimental challenges that this emerging field is facing are highlighted.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 7","pages":"1209-1224"},"PeriodicalIF":18.9,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer LKB1 和 KEAP1 的同时缺失可增强 KRAS 突变肺癌中 SHMT 介导的抗氧化防御能力
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-06-14 DOI: 10.1038/s42255-024-01066-z
Hyun Min Lee, Nefertiti Muhammad, Elizabeth L. Lieu, Feng Cai, Jiawei Mu, Yun-Sok Ha, Guoshen Cao, Chamey Suchors, Kenneth Joves, Constantinos Chronis, Kailong Li, Gregory S. Ducker, Kellen Olszewski, Ling Cai, Derek B. Allison, Sara E. Bachert, William R. Ewing, Harvey Wong, Hyosun Seo, Isaac Y. Kim, Brandon Faubert, James Kim, Jiyeon Kim
{"title":"Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer","authors":"Hyun Min Lee, Nefertiti Muhammad, Elizabeth L. Lieu, Feng Cai, Jiawei Mu, Yun-Sok Ha, Guoshen Cao, Chamey Suchors, Kenneth Joves, Constantinos Chronis, Kailong Li, Gregory S. Ducker, Kellen Olszewski, Ling Cai, Derek B. Allison, Sara E. Bachert, William R. Ewing, Harvey Wong, Hyosun Seo, Isaac Y. Kim, Brandon Faubert, James Kim, Jiyeon Kim","doi":"10.1038/s42255-024-01066-z","DOIUrl":"10.1038/s42255-024-01066-z","url":null,"abstract":"Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine–glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)–NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies. Lee et al. identify SHMT and one-carbon metabolism as a metabolic vulnerability conferred by LKB1 and KEAP1 loss in KRAS-mutant lung cancer.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 7","pages":"1310-1328"},"PeriodicalIF":18.9,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141319849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Coenzyme A biosynthesis: mechanisms of regulation, function and disease 辅酶 A 的生物合成:调节机制、功能和疾病
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-06-13 DOI: 10.1038/s42255-024-01059-y
Samuel A. Barritt, Sarah E. DuBois-Coyne, Christian C. Dibble
{"title":"Coenzyme A biosynthesis: mechanisms of regulation, function and disease","authors":"Samuel A. Barritt, Sarah E. DuBois-Coyne, Christian C. Dibble","doi":"10.1038/s42255-024-01059-y","DOIUrl":"10.1038/s42255-024-01059-y","url":null,"abstract":"The tricarboxylic acid cycle, nutrient oxidation, histone acetylation and synthesis of lipids, glycans and haem all require the cofactor coenzyme A (CoA). Although the sources and regulation of the acyl groups carried by CoA for these processes are heavily studied, a key underlying question is less often considered: how is production of CoA itself controlled? Here, we discuss the many cellular roles of CoA and the regulatory mechanisms that govern its biosynthesis from cysteine, ATP and the essential nutrient pantothenate (vitamin B5), or from salvaged precursors in mammals. Metabolite feedback and signalling mechanisms involving acetyl-CoA, other acyl-CoAs, acyl-carnitines, MYC, p53, PPARα, PINK1 and insulin- and growth factor-stimulated PI3K–AKT signalling regulate the vitamin B5 transporter SLC5A6/SMVT and CoA biosynthesis enzymes PANK1, PANK2, PANK3, PANK4 and COASY. We also discuss methods for measuring CoA-related metabolites, compounds that target CoA biosynthesis and diseases caused by mutations in pathway enzymes including types of cataracts, cardiomyopathy and neurodegeneration (PKAN and COPAN). This Review summarizes the fundamental aspects related to coenzyme A synthesis and its implications as a central molecule in metabolism.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 6","pages":"1008-1023"},"PeriodicalIF":18.9,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141315733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes GIPR 遗传变异的特征揭示了 β-arrestin 对代谢表型的贡献
IF 18.9 1区 医学
Nature metabolism Pub Date : 2024-06-13 DOI: 10.1038/s42255-024-01061-4
Hüsün S. Kizilkaya, Kimmie V. Sørensen, Jakob S. Madsen, Peter Lindquist, Jonathan D. Douros, Jette Bork-Jensen, Alessandro Berghella, Peter A. Gerlach, Lærke S. Gasbjerg, Jacek Mokrosiński, Stephanie A. Mowery, Patrick J. Knerr, Brian Finan, Jonathan E. Campbell, David A. D’Alessio, Diego Perez-Tilve, Felix Faas, Signe Mathiasen, Jørgen Rungby, Henrik T. Sørensen, Allan Vaag, Jens S. Nielsen, Jens-Christian Holm, Jeannet Lauenborg, Peter Damm, Oluf Pedersen, Allan Linneberg, Bolette Hartmann, Jens J. Holst, Torben Hansen, Shane C. Wright, Volker M. Lauschke, Niels Grarup, Alexander S. Hauser, Mette M. Rosenkilde
{"title":"Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes","authors":"Hüsün S. Kizilkaya, Kimmie V. Sørensen, Jakob S. Madsen, Peter Lindquist, Jonathan D. Douros, Jette Bork-Jensen, Alessandro Berghella, Peter A. Gerlach, Lærke S. Gasbjerg, Jacek Mokrosiński, Stephanie A. Mowery, Patrick J. Knerr, Brian Finan, Jonathan E. Campbell, David A. D’Alessio, Diego Perez-Tilve, Felix Faas, Signe Mathiasen, Jørgen Rungby, Henrik T. Sørensen, Allan Vaag, Jens S. Nielsen, Jens-Christian Holm, Jeannet Lauenborg, Peter Damm, Oluf Pedersen, Allan Linneberg, Bolette Hartmann, Jens J. Holst, Torben Hansen, Shane C. Wright, Volker M. Lauschke, Niels Grarup, Alexander S. Hauser, Mette M. Rosenkilde","doi":"10.1038/s42255-024-01061-4","DOIUrl":"10.1038/s42255-024-01061-4","url":null,"abstract":"Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system. Molecular pharmacological characterization and association testing of human GIPR genetic variants with follow-up analysis in mice shows that β-arrestins regulate GIPR signalling and thereby strongly contribute to metabolic outcomes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 7","pages":"1268-1281"},"PeriodicalIF":18.9,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01061-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141315587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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