Nature metabolism最新文献_第2页

Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis 胞浆内NADK对叶酸依赖的核苷酸合成是有条件必需的

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-05-02 DOI: 10.1038/s42255-025-01272-3

Kyle M. Flickinger, Carlos A. Mellado Fritz, Kimberly S. Huggler, Gina M. Wade, Gavin R. Chang, Kathryn C. Fox, Judith A. Simcox, Jason R. Cantor

{"title":"Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis","authors":"Kyle M. Flickinger, Carlos A. Mellado Fritz, Kimberly S. Huggler, Gina M. Wade, Gavin R. Chang, Kathryn C. Fox, Judith A. Simcox, Jason R. Cantor","doi":"10.1038/s42255-025-01272-3","DOIUrl":"https://doi.org/10.1038/s42255-025-01272-3","url":null,"abstract":"Nicotinamide adenine dinucleotide kinase (NADK) catalyses the phosphorylation of NAD+ to produce NAD phosphate, the oxidized form of NADPH, a cofactor that serves a critical role in driving reductive metabolism. Cancer cells co-express two distinct NAD kinases that differ by localization (NADK, cytosol; NADK2, mitochondria). CRISPR screens performed across hundreds of cancer cell lines indicate that both are dispensable for growth in conventional culture media. By contrast, NADK deletion impaired cell growth in human plasma-like medium. Here we trace this conditional NADK dependence to the availability of folic acid. NADPH is the preferred cofactor of dihydrofolate reductase (DHFR), the enzyme that mediates metabolic activation of folic acid. We find that NADK is required for enabling cytosolic NADPH-driven DHFR activity sufficient to maintain folate-dependent nucleotide synthesis under low folic acid conditions. Our results reveal a basis for conditional NADK essentiality and suggest that folate availability determines whether DHFR activity can be sustained by alternative electron donors such as NADH.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"44 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898124","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

GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice GIPR激动剂和拮抗剂通过不同的机制降低雄性小鼠的体重和食物摄入量

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-29 DOI: 10.1038/s42255-025-01294-x

Robert M. Gutgesell, Ahmed Khalil, Arkadiusz Liskiewicz, Gandhari Maity-Kumar, Aaron Novikoff, Gerald Grandl, Daniela Liskiewicz, Callum Coupland, Ezgi Karaoglu, Seun Akindehin, Russell Castelino, Fabiola Curion, Xue Liu, Cristina Garcia-Caceres, Alberto Cebrian-Serrano, Jonathan D. Douros, Patrick J. Knerr, Brian Finan, Richard D. DiMarchi, Kyle W. Sloop, Ricardo J. Samms, Fabian J. Theis, Matthias H. Tschöp, Timo D. Müller

{"title":"GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice","authors":"Robert M. Gutgesell, Ahmed Khalil, Arkadiusz Liskiewicz, Gandhari Maity-Kumar, Aaron Novikoff, Gerald Grandl, Daniela Liskiewicz, Callum Coupland, Ezgi Karaoglu, Seun Akindehin, Russell Castelino, Fabiola Curion, Xue Liu, Cristina Garcia-Caceres, Alberto Cebrian-Serrano, Jonathan D. Douros, Patrick J. Knerr, Brian Finan, Richard D. DiMarchi, Kyle W. Sloop, Ricardo J. Samms, Fabian J. Theis, Matthias H. Tschöp, Timo D. Müller","doi":"10.1038/s42255-025-01294-x","DOIUrl":"https://doi.org/10.1038/s42255-025-01294-x","url":null,"abstract":"Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. However, while GIPR agonism decreases body weight and food intake in a GLP-1R-independent manner via GABAergic GIPR+ neurons, it remains unclear whether GIPR antagonism affects energy metabolism via a similar mechanism. Here we show that the body weight and food intake effects of GIPR antagonism are eliminated in mice with global loss of either Gipr or Glp-1r but are preserved in mice with loss of Gipr in either GABAergic neurons of the central nervous system or peripherin-expressing neurons of the peripheral nervous system. Single-nucleus RNA-sequencing shows opposing effects of GIPR agonism and antagonism in the dorsal vagal complex, with antagonism, but not agonism, closely resembling GLP-1R signalling. Additionally, GIPR antagonism and GLP-1R agonism both regulate genes implicated in synaptic plasticity. Collectively, we show that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signalling.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"17 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884803","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

Unravelling the GIPR agonist versus antagonist paradox 解开GIPR激动剂与拮抗剂的悖论

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-29 DOI: 10.1038/s42255-025-01299-6

Alice E. Adriaenssens

引用次数: 0

GIPR-Ab/GLP-1 peptide–antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice GIPR- ab /GLP-1肽抗体偶联物需要脑GIPR和GLP-1R来实现肥胖小鼠的增重

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-29 DOI: 10.1038/s42255-025-01295-w

Clarissa M. Liu, Elizabeth A. Killion, Rola Hammoud, Shu-Chen Lu, Renee Komorowski, Tongyu Liu, Matt Kanke, Veena A. Thomas, Kevin Cook, Glenn N. Sivits, Aerielle B. Ben, Larissa I. Atangan, Rajaa Hussien, Amy Tang, Artem Shkumatov, Chi-Ming Li, Daniel J. Drucker, Murielle M. Véniant

{"title":"GIPR-Ab/GLP-1 peptide–antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice","authors":"Clarissa M. Liu, Elizabeth A. Killion, Rola Hammoud, Shu-Chen Lu, Renee Komorowski, Tongyu Liu, Matt Kanke, Veena A. Thomas, Kevin Cook, Glenn N. Sivits, Aerielle B. Ben, Larissa I. Atangan, Rajaa Hussien, Amy Tang, Artem Shkumatov, Chi-Ming Li, Daniel J. Drucker, Murielle M. Véniant","doi":"10.1038/s42255-025-01295-w","DOIUrl":"https://doi.org/10.1038/s42255-025-01295-w","url":null,"abstract":"Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide 1 receptor (GLP-1R) are expressed in the central nervous system (CNS) and regulate food intake. Here, we demonstrate that a peptide–antibody conjugate that blocks GIPR while simultaneously activating GLP-1R (GIPR-Ab/GLP-1) requires both CNS GIPR and CNS GLP-1R for maximal weight loss in obese, primarily male, mice. Moreover, dulaglutide produces greater weight loss in CNS GIPR knockout (KO) mice, and the weight loss achieved with dulaglutide + GIPR-Ab is attenuated in CNS GIPR KO mice. Wild-type mice treated with GIPR-Ab/GLP-1 and CNS GIPR KO mice exhibit similar changes in gene expression related to tissue remodelling, lipid metabolism and inflammation in white adipose tissue and liver. Moreover, GIPR-Ab/GLP-1 is detected in circumventricular organs in the brain and activates c-FOS in downstream neural substrates involved in appetite regulation. Hence, both CNS GIPR and GLP-1R signalling are required for the full weight loss effect of a GIPR-Ab/GLP-1 peptide–antibody conjugate.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"37 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884809","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

Intracellular metabolic gradients dictate dependence on exogenous pyruvate 细胞内代谢梯度决定了对外源性丙酮酸的依赖性

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-28 DOI: 10.1038/s42255-025-01289-8

Benjamin T. Jackson, Angela M. Montero, Sangita Chakraborty, Julia S. Brunner, Paige K. Arnold, Anna E. Bridgeman, Pavlina K. Todorova, Katrina I. Paras, Lydia W. S. Finley

{"title":"Intracellular metabolic gradients dictate dependence on exogenous pyruvate","authors":"Benjamin T. Jackson, Angela M. Montero, Sangita Chakraborty, Julia S. Brunner, Paige K. Arnold, Anna E. Bridgeman, Pavlina K. Todorova, Katrina I. Paras, Lydia W. S. Finley","doi":"10.1038/s42255-025-01289-8","DOIUrl":"https://doi.org/10.1038/s42255-025-01289-8","url":null,"abstract":"During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"84 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880755","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

Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states 在进食、禁食和饥饿状态之间的代谢转变过程中，肝细胞糖异生的空间可塑性

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-25 DOI: 10.1038/s42255-025-01269-y

Junichi Okada, Austin Landgraf, Alus M. Xiaoli, Li Liu, Maxwell Horton, Victor L. Schuster, Fajun Yang, Simone Sidoli, Yunping Qiu, Irwin J. Kurland, Carolina Eliscovich, Kosaku Shinoda, Jeffrey E. Pessin

{"title":"Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states","authors":"Junichi Okada, Austin Landgraf, Alus M. Xiaoli, Li Liu, Maxwell Horton, Victor L. Schuster, Fajun Yang, Simone Sidoli, Yunping Qiu, Irwin J. Kurland, Carolina Eliscovich, Kosaku Shinoda, Jeffrey E. Pessin","doi":"10.1038/s42255-025-01269-y","DOIUrl":"https://doi.org/10.1038/s42255-025-01269-y","url":null,"abstract":"Hepatocytes are organized along a spatial axis between the portal triad and the central vein to form functionally repetitive units known as lobules. The hepatocytes perform distinct metabolic functions depending on their location within the lobule. Single-cell analysis of hepatocytes across the liver lobule demonstrates that gluconeogenic gene expression is relatively low in the fed state and gradually increases in the periportal hepatocytes during the initial fasting period. As fasting progresses, pericentral hepatocyte gluconeogenic gene expression and gluconeogenic activity also increase and, following entry into a starvation state, the pericentral hepatocytes show similar gluconeogenic gene expression and activity to the periportal hepatocytes. In parallel, starvation suppresses canonical β-catenin signalling and modulates the expression of pericentral and periportal glutamine synthetase and glutaminase, respectively, resulting in enhanced incorporation of glutamine into glucose. Thus, hepatocyte gluconeogenic gene expression and glucose production are spatially and temporally plastic across the liver lobule, underscoring the complexity of defining hepatic insulin resistance and glucose production on a whole-organ level, as well as for a particular fasted or fed condition.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"53 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872777","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

Starvation induces metabolic hepatocyte reprogramming 饥饿诱导代谢性肝细胞重编程

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-25 DOI: 10.1038/s42255-025-01286-x

Coenraad F. Slabber, Jan S. Tchorz

引用次数: 0

Rapid modulation of gut microbiota composition by hypothalamic circuits in mice 小鼠下丘脑回路对肠道微生物群组成的快速调节

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-22 DOI: 10.1038/s42255-025-01280-3

Míriam Toledo, Sara Martínez-Martínez, Matthias Van Hul, Berta Laudo, Elena Eyre, Rudy Pelicaen, Anthony Puel, Jordi Altirriba, Alicia G. Gómez-Valadés, Julica Inderhees, Isabel Moreno-Indias, Macarena Pozo, Iñigo Chivite, Maria Milà-Guasch, Roberta Haddad-Tóvolli, Arnaud Obri, Júlia Fos-Domènech, Iasim Tahiri, Sergio R. Llana, Sara Ramírez, Erika Monelli, Markus Schwaninger, Patrice D. Cani, Rubén Nogueiras, Marc Claret

{"title":"Rapid modulation of gut microbiota composition by hypothalamic circuits in mice","authors":"Míriam Toledo, Sara Martínez-Martínez, Matthias Van Hul, Berta Laudo, Elena Eyre, Rudy Pelicaen, Anthony Puel, Jordi Altirriba, Alicia G. Gómez-Valadés, Julica Inderhees, Isabel Moreno-Indias, Macarena Pozo, Iñigo Chivite, Maria Milà-Guasch, Roberta Haddad-Tóvolli, Arnaud Obri, Júlia Fos-Domènech, Iasim Tahiri, Sergio R. Llana, Sara Ramírez, Erika Monelli, Markus Schwaninger, Patrice D. Cani, Rubén Nogueiras, Marc Claret","doi":"10.1038/s42255-025-01280-3","DOIUrl":"https://doi.org/10.1038/s42255-025-01280-3","url":null,"abstract":"In recent years, the gut microbiota and derived metabolites have emerged as relevant players in modulating several brain functions, including energy balance control1,2,3. This form of distant communication mirrors that of metabolic hormones (for example, leptin, ghrelin), which convey information about the organism’s energy status by exerting effects on diverse brain regions, including the master homeostatic centre, the hypothalamus4. However, whether the hypothalamus is also able to influence gut microbiota composition remains enigmatic. Here we present a study designed to unravel this challenging question. To this aim, we used chemogenetics5 (to selectively activate or inhibit hypothalamic pro-opiomelanocortin or agouti-related peptide neurons) or centrally administered leptin or ghrelin to male mice. Subsequently, we conducted microbiota composition analysis throughout the gut using 16S rRNA gene sequencing. Our results showed that these brain interventions significantly changed the gut microbiota in an anatomical and short-term (2–4 h) fashion. Transcriptomic analysis indicated that these changes were associated with the reconfiguration of neuronal and synaptic pathways in the duodenum concomitant with increased sympathetic tone. Interestingly, diet-induced obesity attenuated the brain-mediated changes triggered by leptin in gut microbiota communities and sympathetic activation. Our findings reveal a previously unanticipated brain–gut axis that acutely attunes microbiota composition on fast timescales, with potential implications for meal-to-meal adjustments and systemic energy balance control.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"37 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857778","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

Mind over microbiota: neurons call the shots in the gut 心智胜过微生物群：神经元在肠道中发号施令

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-22 DOI: 10.1038/s42255-025-01282-1

Wuling Zhong, Karen Wang, Amir Zarrinpar

引用次数: 0

Career pathways, part 17 职业道路，第17部分

IF 20.8 1区医学

Nature metabolism Pub Date : 2025-04-21 DOI: 10.1038/s42255-025-01288-9

Leah Gates, Benjamin P. Weaver

引用次数: 0