Nature metabolism最新文献

{"title":"Career pathways, part 16","authors":"Cholsoon Jang, Min-Dian Li","doi":"10.1038/s42255-024-01192-8","DOIUrl":"https://doi.org/10.1038/s42255-024-01192-8","url":null,"abstract":"In this instalment of our Career Pathways series, Cholsoon Jang and Min-Dian Li share how curiosity from a very early age has driven their scientific journeys.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934887","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}

{"title":"The hepatic clock synergizes with HIF-1α to regulate nucleotide availability during liver damage repair","authors":"Linyuan Peng, Siliang Xiang, Tianzhi Wang, Mei Yang, Yajun Duan, Xiaoyu Ma, Su Li, Cong Yu, Xin Zhang, Haiyang Hu, Zuojun Liu, Jie Sun, Chunmeng Sun, Chen Wang, Baohua Liu, Zhongyuan Wang, Minxian Qian","doi":"10.1038/s42255-024-01184-8","DOIUrl":"https://doi.org/10.1038/s42255-024-01184-8","url":null,"abstract":"<p>Nucleotide availability is crucial for DNA replication and repair; however, the coordinating mechanisms in vivo remain unclear. Here, we show that the circadian clock in the liver controls the activity of the pentose phosphate pathway (PPP) to support de novo nucleotide biosynthesis for DNA synthesis demands. We demonstrate that disrupting the hepatic clock by genetic manipulation or mistimed feeding impairs PPP activity in male mice, leading to nucleotide imbalance. Such defects not only elicit DNA replication stress to limit liver regeneration after resection but also allow genotoxin-induced hepatocyte senescence and STING signalling-dependent inflammation. Mechanistically, the molecular clock activator BMAL1 synergizes with hypoxia-inducible factor-1α (HIF-1α) to regulate the transcription of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD), which is enhanced during liver regeneration. Overexpressing G6PD restores the compromised regenerative capacity of the BMAL1- or HIF-1α-deficient liver. Moreover, boosting G6PD expression genetically or through preoperative intermittent fasting potently facilitates liver repair in normal mice. Hence, our findings highlight the physiological importance of the hepatic clock and suggest a promising pro-regenerative strategy.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"28 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934990","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}

{"title":"Making sense of gene expression control by flux sensing","authors":"Bas Teusink, Robert Planqué, Frank J. Bruggeman","doi":"10.1038/s42255-024-01182-w","DOIUrl":"https://doi.org/10.1038/s42255-024-01182-w","url":null,"abstract":"Cells regulate metabolic fluxes by changing enzyme levels according to their needs, but how do they regulate something that cannot be measured directly? In this issue of Nature Metabolism, Palme et al. address the fundamental question of how metabolic flux sensing is coupled to gene expression.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"25 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929419","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}

{"title":"The galactokinase enzyme of yeast senses metabolic flux to stabilize galactose pathway regulation","authors":"Julius Palme, Ang Li, Michael Springer","doi":"10.1038/s42255-024-01181-x","DOIUrl":"https://doi.org/10.1038/s42255-024-01181-x","url":null,"abstract":"<p>Nutrient sensors allow cells to adapt their metabolisms to match nutrient availability by regulating metabolic pathway expression. Many such sensors are cytosolic receptors that measure intracellular nutrient concentrations. One might expect that inducing the metabolic pathway that degrades a nutrient would reduce intracellular nutrient levels, destabilizing induction. However, in the galactose-responsive (GAL) pathway of <i>Saccharomyces cerevisiae</i>, we find that induction is stabilized by flux sensing. Previously proposed mechanisms for flux sensing postulate the existence of metabolites whose concentrations correlate with flux. The GAL pathway flux sensor uses a different principle: the galactokinase Gal1p both performs the first step in GAL metabolism and reports on flux by signalling to the GAL repressor, Gal80p. Both Gal1p catalysis and Gal1p signalling depend on the concentration of the Gal1p–GAL complex and are therefore directly correlated. Given the simplicity of this mechanism, flux sensing is probably a general feature throughout metabolic regulation.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"15 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929422","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}

{"title":"Holistic approaches to explain and combat obesity","authors":"Tobias Anker Stripp, Per Torp Sangild","doi":"10.1038/s42255-024-01197-3","DOIUrl":"https://doi.org/10.1038/s42255-024-01197-3","url":null,"abstract":"<p>Obesity is a global health problem related to the Western lifestyle. Lifestyle is biological but also non-biological, and so requires more than studies of diet, exercise and mechanisms of cellular metabolism. The recent Perspective by Magkos et al.¹ provides an excellent overview of leading causal models in metabolic obesity research and new areas for future exploration. Specifically, they contrast the energy balance model (EBM) and the carbohydrate–insulin model (CIM). The latter can be considered a version of the fuel partitioning model (FPM)². We draw attention to the need for holistic, interdisciplinary approaches, with potential new ontological perspectives, to explain and combat obesity beyond what is currently considered within said existing biological models. The World Health Organization’s 1946 definition of health as “… complete physical, mental, and social well-being” points to such a holistic understanding of health. Over the past decades, spirituality has been suggested as a necessary fourth dimension of human health³. Although Magkos et al. include “psychosocial” among “other factors” in their model, they hardly discuss mental or social factors and leave out spirituality.</p><p>Drawing on experience from palliative care, spirituality is widely defined as the “dynamic and intrinsic aspect of humanity through which persons seek ultimate meaning, purpose, and transcendence, and experience relationship to self, family, others, community, society, nature, and the significant or sacred. Spirituality is expressed through beliefs, values, traditions, and practices”⁵. Recent epidemiological studies show robust associations between spirituality and health outcomes⁶. Such relations are challenging to explain entirely by altered metabolism or psychosocial factors, and the observed effects may be partly determined by independent effects of spirituality⁷. The majority of the global population expresses faith convictions in some form (spiritual, religious, secular and/or existential)^6,7,8. Spiritual needs and expressions are common, including in modern, secular cultures⁸. Hence, personal or communal spirituality may influence how people understand and relate to their body, food and eating⁹. Beyond psychosocial issues, existential anxiety may stimulate appetite and fat storage, in line with conventional EBM and FPM theories.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"15 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916899","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}

{"title":"Pivotal role of exogenous pyruvate in human natural killer cell metabolism","authors":"Nicolas Kern Coquillat, Louis Picq, Ameline Hamond, Pierre Megy, Sarah Benezech, Annabelle Drouillard, Nina Lager-Lachaud, Edern Cahoreau, Marielle Moreau, Lucie Fallone, Anne-Laure Mathieu, Floriant Bellvert, Carine Nizard, Anne-Laure Bulteau, Thierry Walzer, Antoine Marçais","doi":"10.1038/s42255-024-01188-4","DOIUrl":"https://doi.org/10.1038/s42255-024-01188-4","url":null,"abstract":"<p>Resting natural killer (NK) cells display immediate effector functions after recognizing transformed or infected cells. The environmental nutrients and metabolic requirements to sustain these functions are not fully understood. Here, we show that NK cells rely on the use of extracellular pyruvate to support effector functions, signal transduction and cell viability. Glucose-derived carbons do not generate endogenous pyruvate. Consequently, NK cells import extracellular pyruvate that is reduced to lactate to regenerate glycolytic NAD⁺ and is oxidized in the tricarboxylic acid (TCA) cycle to produce ATP. This supports serine production through phosphoglycerate dehydrogenase, a pathway required for optimal proliferation following cytokine stimulation but dispensable for effector functions. In addition, like mouse NK cells, human NK cells rely on a citrate–malate configuration of the TCA cycle that is not fed by glutamine. Moreover, supraphysiologic pyruvate concentrations dose-dependently increase the effector functions of NK cells. Overall, this study highlights the role of exogenous pyruvate in NK cell biology, providing knowledge that could be exploited to boost NK cell potential in therapeutic settings.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"1 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917290","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}

{"title":"NUFIP1 integrates amino acid sensing and DNA damage response to maintain the intestinal homeostasis","authors":"Hui Ming, Jing Tan, Si-Yi Cao, Cheng-Ping Yu, Yu-Ting Qi, Chao Wang, Lei Zhang, Ying Liu, Jian Yuan, Miao Yin, Qun-Ying Lei","doi":"10.1038/s42255-024-01179-5","DOIUrl":"https://doi.org/10.1038/s42255-024-01179-5","url":null,"abstract":"<p>Nutrient availability strongly affects intestinal homeostasis. Here, we report that low-protein (LP) diets decrease amino acids levels, impair the DNA damage response (DDR), cause DNA damage and exacerbate inflammation in intestinal tissues of male mice with inflammatory bowel disease (IBD). Intriguingly, loss of nuclear fragile X mental retardation-interacting protein 1 (NUFIP1) contributes to the amino acid deficiency-induced impairment of the DDR in vivo and in vitro and induces necroptosis-related spontaneous enteritis. Mechanistically, phosphorylated NUFIP1 binds to replication protein A2 (RPA32) to recruit the ataxia telangiectasia and Rad3-related (ATR)–ATR-interacting protein (ATRIP) complex, triggering the DDR. Consistently, both reintroducing NUFIP1 but not its non-phospho-mutant and inhibition of necroptosis prevent bowel inflammation in male <i>Nufip1</i> conditional knockout mice. Intestinal inflammation and DNA damage in male mice with IBD can be mitigated by NUFIP1 overexpression. Moreover, NUFIP1 protein levels in the intestine of patients with IBD were found to be significantly decreased. Conclusively, our study uncovers that LP diets contribute to intestinal inflammation by hijacking NUFIP1–DDR signalling and thereby activating necroptosis.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"72 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916900","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}

{"title":"Natural killer loops: pyruvate in, lactate out","authors":"Cathal Keane, David K. Finlay","doi":"10.1038/s42255-024-01195-5","DOIUrl":"https://doi.org/10.1038/s42255-024-01195-5","url":null,"abstract":"Resting human CD56Dim natural killer cells utilize exogenous pyruvate to support energy metabolism. A new study shows that these cells take up exogenous pyruvate, which regenerates cytosolic NAD+ via metabolism to lactate to support glycolysis and fuels oxidative phosphorylation via the mitochondrial citrate–malate shuttle.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"72 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917259","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}

{"title":"Do not overlook the role of fructose in obesity","authors":"Takahiko Nakagawa, Richard J. Johnson","doi":"10.1038/s42255-024-01198-2","DOIUrl":"https://doi.org/10.1038/s42255-024-01198-2","url":null,"abstract":"<p>A recent Perspective¹ on obesity pathogenesis examined the energy balance model and carbohydrate–insulin model, discussed risk factors for weight gain and also had a goal to “discuss the importance of purported causal factors for weight gain”. However, it overlooked the important role of fructose metabolism in obesity development. There is now a wealth of data that suggests that dietary fructose, or fructose endogenously produced from glucose, may have a role in obesity². Indeed, there is evidence that fructose metabolism may play into the energy balance model by stimulating food intake and reducing resting energy metabolism by affecting brain and liver regulatory mechanisms^3,4,5,6, and that it may also induce hyperinsulinemia and insulin resistance that may account for many of the proposed effects of the carbohydrate–insulin model^7,8. These findings suggest that fructose metabolism may provide a unifying pathway linking the carbohydrate–insulin and energy balance models⁹.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"27 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916898","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}

{"title":"Cellular Feimin enhances exercise performance by suppressing muscle thermogenesis","authors":"Ying Peng, Liangjie Jia, Xiao Hu, Xiaoliu Shi, Xinlei Fang, Yifu Qiu, Zhenji Gan, Yiguo Wang","doi":"10.1038/s42255-024-01176-8","DOIUrl":"https://doi.org/10.1038/s42255-024-01176-8","url":null,"abstract":"<p>Exercise can rapidly increase core body temperature, and research has indicated that elevated internal body temperature can independently contribute to fatigue during physical activity. However, the precise mechanisms responsible for regulating thermogenesis in muscles during exercise have remained unclear. Here, we demonstrate that cellular Feimin (cFeimin) enhances exercise performance by inhibiting muscle thermogenesis during physical activity. Mechanistically, we found that AMP-activated protein kinase (AMPK) phosphorylates cFeimin and facilitates its translocation into the cell nucleus during exercise. Within the nucleus, cFeimin binds to the forkhead transcription factor FOXC2, leading to the suppressed expression of sarcolipin (<i>Sln</i>), which is a key regulator of muscle thermogenesis. In addition, our results further reveal that short-term AMPK agonist treatments can enhance exercise performance through the activation of the AMPK–cFeimin signalling pathway. In summary, these results underscore the crucial role of cFeimin in enhancing exercise performance by modulating SLN-mediated thermogenesis.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"5 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911549","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}