Life metabolism最新文献

{"title":"Keeping up with the nicotinamides: NADP(H), the forgotten circadian cofactor that keeps metabolic time.","authors":"Lauren Palluth, Joseph S Takahashi, Carla B Green","doi":"10.1093/lifemeta/loaf034","DOIUrl":"10.1093/lifemeta/loaf034","url":null,"abstract":"<p><p>The hierarchical relationship between the core circadian clock of the suprachiasmatic nucleus and peripheral clocks throughout the body is tightly regulated. Nicotinamide adenine dinucleotide phosphate (NADP(H)) is a rhythmic cofactor used in hundreds of metabolic reactions. The cellular NADP(H) pool is not only regulated by several clock-controlled enzymes, but also responsive to peripheral \"zeitgebers\" such as food intake and oxidative stress. This positions NADP(H) as a potential harbinger between core and peripheral metabolic rhythms. While discussion in recent years has focused on its unphosphorylated counterpart, NAD(H), this review aims to highlight the roles of NADP(H) in circadian metabolism. This review discusses the multilayered regulation of cellular NADP(H), how the total pool size, redox ratio, and rhythmicity of NADP(H) impact core and peripheral rhythms, and how disruption of its rhythmic regulation can lead to metabolic disease.</p>","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":"4 6","pages":"loaf034"},"PeriodicalIF":6.3,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12507031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Weight loss maintenance after tirzepatide cessation in people with overweight/obesity: a real-world follow-up of the phase 3 SURMOUNT-CN trial.","authors":"Congling Chen, Zhen Ying, Qi Tang, Lin Zhao, Yibing Lu, Xiaofang Fan, Lan Xu, Si Si, Yuanyuan Li, Jiawei Xu, Yihua Wang, Yu Dong, Xiaoying Li, Ying Chen","doi":"10.1093/lifemeta/loaf024","DOIUrl":"10.1093/lifemeta/loaf024","url":null,"abstract":"<p><p>Tirzepatide, a dual GIP/GLP-1 receptor agonist, has shown unprecedented efficacy in weight loss and improving metabolic parameters in clinical trials. However, the durability of these benefits after treatment cessation remains poorly understood. This study aimed to investigate the effect of tirzepatide cessation on body weight change in people with obesity or overweight. This real-world, observational 26-week follow-up study included participants who completed 52 weeks' study treatment during SURMOUNT-CN (NCT05024032). The analysis excluded participants who received anti-obesity medications or bariatric procedures during the 26-week follow-up. Key outcomes were the changes in body weight and waist circumference after 26 weeks, from treatment cessation (Week 52) and trial baseline (Week 0), by the SURMOUNT-CN treatment groups (tirzepatide 10 or 15 mg, or placebo). Overall, 152 participants were included (tirzepatide 10 mg: <i>n</i> = 57; tirzepatide 15 mg: <i>n </i>= 51; placebo: <i>n </i>= 44). Following treatment cessation (Week 52), the mean (SD) percentage changes in body weight at Week 78 were 9.1% (7.4), 12.3% (9.9), and 1.8% (5.2), and the absolute changes in waist circumference were 2.9 cm (7.5), 5.5 cm (6.5) and -0.5 cm (5.6), in tirzepatide 10 and 15 mg, and placebo groups, respectively. From trial baseline to Week 78, the mean (SD) net percentage weight changes were -8.7% (6.9), -10.6% (10.2), and -2.5% (7.0), and the changes in waist circumference were -10.5 cm (8.1), -10.6 cm (9.3) and -4.0 cm (7.2), in the tirzepatide 10 and 15 mg, and placebo groups, respectively. At Week 78, residual improvements in multiple cardiometabolic indicators were evident in the tirzepatide groups. Despite weight gain following tirzepatide cessation, participants achieved a large net weight loss and reduction in waist circumference from trial baseline to Week 78, with residual improvements in several cardiometabolic indicators.</p>","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":"4 5","pages":"loaf024"},"PeriodicalIF":6.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147791391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural insights into RAB7A activation: a mammalian perspective on the MON1A-CCZ1 GEF complex.","authors":"","doi":"10.1093/lifemeta/loaf021","DOIUrl":"10.1093/lifemeta/loaf021","url":null,"abstract":"","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":"4 5","pages":"loaf021"},"PeriodicalIF":6.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147791335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MDVs bridge metabolite signals to mitochondrial fitness.","authors":"Guang Lu, Han-Ming Shen","doi":"10.1093/lifemeta/loaf022","DOIUrl":"10.1093/lifemeta/loaf022","url":null,"abstract":"","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":"4 5","pages":"loaf022"},"PeriodicalIF":6.3,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147791255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatially segregated multiomics decodes metformin-mediated function-specific metabolic characteristics in diabetic kidney disease.","authors":"Shi Qiu, Dandan Xie, Sifan Guo, Zhibo Wang, Xian Wang, Ying Cai, Chunsheng Lin, Hong Yao, Yu Guan, Qiqi Zhao, Qiang Yang, Yiqiang Xie, Songqi Tang, Aihua Zhang","doi":"10.1093/lifemeta/loaf019","DOIUrl":"10.1093/lifemeta/loaf019","url":null,"abstract":"<p><p>Understanding the specific metabolic changes in multiple regions of the kidney is crucial to revealing the underlying mechanism and developing effective targets for diabetic nephropathy (DN). In this study, integrated spatially resolved metabolomics and proteomics combined with mass spectrometry imaging (MSI) revealed a multi-scale region profile of the diabetic kidney. Based on anatomic location, spatial metabolomics revealed eight region-specific metabolite biomarkers uniquely localized to kidney segments, which were closely correlated to the clinical parameters of patients with DN. Specifically, treatment with metformin (MET) enriched inosinic acid, adenosine 3',5'-diphosphate, nicotinamide adenine dinucleotide (NADH), and hydrated NADH (NADHX) levels in the cortex (Cor) and the outer stripe of kidney medulla (OM) anatomical subregions, while in the inner stripe of kidney medulla (IM) segmentation, the p-cresol sulfate level was downregulated. Comparing differently expressed proteins in each region showed that nephrosis 2 (Nphs2) was the highest loading feature. A further region-specific analysis of pathway enrichment characteristics indicated that the purine and ether lipid metabolism pathways were enriched in the Cor and OM regions, whereas the pantothenate and coenzyme A (CoA) biosynthesis pathways were mainly enriched in the IM region in response to MET treatment. Taken together, the spatially segregated metabolomics and proteomics studies reveal MET-mediated proteins and function-specific therapeutic pathways related to the anatomical multiregion of diabetic mouse kidneys.</p>","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":"4 5","pages":"loaf019"},"PeriodicalIF":6.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147791352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyaluronidase-1 mediates postprandial suppression of hepatic gluconeogenesis.","authors":"Xi Chen, Sophie Dogné, Yanru Deng, Huiqiao Li, Jieyi Meng, Charlise Giang, Jan-Bernd Funcke, Leon G Straub, Michelle Dias, Sundararajah Thevananther, Qiang Tong, Abu Hena Mostafa Kamal, Chandra Shekar R Ambati, Yu'e Liu, Nagireddy Putluri, Xia Gao, Miao-Hsueh Chen, Dongyin Guan, Hari Krishna Yalamanchili, Shangang Zhao, Nathalie Caron, Yi Zhu","doi":"10.1093/lifemeta/loaf016","DOIUrl":"10.1093/lifemeta/loaf016","url":null,"abstract":"<p><p>Hepatic gluconeogenesis is a critical process that generates glucose from non-carbohydrate precursors during fasting to support vital organs like the brain and red blood cells. Postprandially, this process is rapidly suppressed to allow for glucose storage as glycogen and lipids in the liver. Failure to suppress gluconeogenesis after meals leads to elevated postprandial glucose levels, a key feature of type 2 diabetes. This dynamic switch is regulated by insulin and glucagon, but insulin resistance impairs this regulation. In this study, we identified a novel mechanism involving postprandial circulating hyaluronan (HA) and lysosomal hyaluronidase-1 (HYAL1) that suppresses hepatic gluconeogenesis by rewiring hepatic metabolism and mitochondrial function. <i>Hyal1</i> knockout (<i>Hyal1</i> KO) mice exhibited increased gluconeogenesis, while liver-specific <i>Hyal1</i> overexpression (Liv-<i>Hyal1</i>) mice showed reduced gluconeogenic activity. Transcriptomic analysis revealed minimal changes in liver gene expression due to <i>Hyal1</i> deletion, but metabolomic profiling demonstrated that <i>Hyal1</i> overexpression mitigated high-fat diet (HFD)-induced elevations in gluconeogenic pathway metabolites. Mechanistically, HYAL1-mediated HA digestion activates a feedback loop in HA synthesis, repartitioning the cellular uridine diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) pool. This reduces O-linked N-acetylglucosamine modification (O-GlcNAcylation) of mitochondrial ATP synthase subunits, decreasing ATP production and suppressing gluconeogenesis. Importantly, this pathway remains intact in the livers of HFD-fed, insulin-resistant mice. In summary, our findings reveal a new postprandial mechanism for regulating hepatic gluconeogenesis, highlighting the potential of enhancing postprandial HA levels or hepatic HYAL1 activity as a therapeutic strategy for managing excessive gluconeogenesis in insulin-resistant conditions, such as type 2 diabetes.</p>","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":"4 5","pages":"loaf016"},"PeriodicalIF":6.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147791262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.","authors":"Jack Devine, Anna S Monzel, David Shire, Ayelet M Rosenberg, Alex Junker, Alan A Cohen, Martin Picard","doi":"10.1093/lifemeta/loaf012","DOIUrl":"10.1093/lifemeta/loaf012","url":null,"abstract":"<p><p>Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have consistently high, while others show consistently low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic assays in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mitochondrial DNA (mtDNA) density was correlated between tissues (median <i>r</i> = -0.01 to 0.16), indicating that animals with high mitochondrial content or capacity in one tissue may have low content or capacity in other tissues. Similarly, RNA sequencing (RNAseq)-based indices of mitochondrial expression across 45 tissues from 948 women and men (genotype-tissue expression [GTEx]) showed only small to moderate coherence between some tissues, such as between brain regions (<i>r</i> = 0.26), but not between brain-body tissue pairs (<i>r</i> = 0.01). The mtDNA copy number (mtDNAcn) also lacked coherence across human tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were partially attributable to (i) tissue-specific activation of energy sensing pathways, including the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the integrated stress response (ISR), and other molecular regulators of mitochondrial biology, and (ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with distinct mitochondrial distribution strategies that map onto distinct clinical phenotypes. These data raise the possibility that tissue-specific energy sensing pathways may contribute to idiosyncratic mitochondrial distribution patterns among individuals.</p>","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":"4 3","pages":"loaf012"},"PeriodicalIF":6.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of DNA translocation of chromatin remodeler enzyme Chd1 by exit DNA unwrapping.","authors":"Yuanyuan Tian, Qi Jia, Meijing Li, Youyang Sia, Pengjing Hu, Kangjing Chen, Ming Li, Xueming Li, Zigang Xu, Lin Ma, Youpi Ye, Ying Lu, Zhucheng Chen","doi":"10.1093/lifemeta/loaf013","DOIUrl":"10.1093/lifemeta/loaf013","url":null,"abstract":"<p><p>Nucleosomes are the fundamental unit of chromatin. Chromatin remodeler plays a crucial role in the regulation of gene expression in eukaryotes. It is involved in important physiological processes, such as development, immune response, and metabolic regulation. During gene expression regulation, chromatin remodelers slide nucleosomes along genomic DNA and play a major role in chromatin organization. Chd1 senses the extranucleosomal linker DNA and controls nucleosome spacing in cells. However, the mechanism of linker DNA sensing by Chd1 is not completely understood. Here, we report the cryo-electron microscope (cryoEM) structures of Chd1 engaging nucleosomes in different states. Chd1 induces two exit-DNA conformations, either fully wrapped or partially unwrapped states. Notably, in the unwrapped conformation, the exit DNA interacts with a positively charged loop of the motor, named the exit-DNA binding loop, and traps Chd1 in the closed state in the ATPase cycle, suggesting attenuation of its remodeling activity. Explored single-molecule fluorescence resonance energy transfer (smFRET) and biochemical data supported the regulation of Chd1 remodeling activity by the exit-DNA conformations, which is important for the linker DNA sensitivity. Mutants of the Chd1 exit-DNA binding loop compromised nucleosome organization in yeast cells. Together, our findings provide valuable insights into Chd1 regulation by exit DNA unwrapping. These results provide a new perspective for the study of cell development and metabolism.</p>","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":"4 3","pages":"loaf013"},"PeriodicalIF":0.0,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transporters in vitamin uptake and cellular metabolism: impacts on health and disease.","authors":"Yaxuan Yuan, Ligong Chen","doi":"10.1093/lifemeta/loaf008","DOIUrl":"10.1093/lifemeta/loaf008","url":null,"abstract":"<p><p>Vitamins are vital nutrients essential for metabolism, functioning as coenzymes, antioxidants, and regulators of gene expression. Their absorption and metabolism rely on specialized transport proteins that ensure bioavailability and cellular utilization. Water-soluble vitamins, including B-complex and vitamin C, are transported by solute carrier (SLC) family proteins and ATP-binding cassette (ABC) transporters for efficient uptake and cellular distribution. Fat-soluble vitamins (A, D, E, and K) rely on lipid-mediated pathways through proteins like scavenger receptor class B type I (SR-BI), CD36, and Niemann-Pick C1-like 1 (NPC1L1), integrating their absorption with lipid metabolism. Defective vitamin transporters are associated with diverse metabolic disorders, including neurological, hematological, and mitochondrial diseases. Advances in structural and functional studies of vitamin transporters highlight their tissue-specific roles and regulatory mechanisms, shedding light on their impact on health and disease. This review emphasizes the significance of vitamin transporters and their potential as therapeutic targets for deficiencies and related chronic conditions.</p>","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":"4 3","pages":"loaf008"},"PeriodicalIF":0.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary sulfur amino acid restriction improves metabolic health by reducing fat mass.","authors":"Chenhao Xin, Mingcheng Cai, Qianxi Jia, Rong Huang, Rui Li, Junyao Wang, Zi Li, Qiang Zhao, Tianyi Liu, Weidong Zhuang, Jinyu Zhou, Shengxian Li, Yongzhen Tao, Lin Wang, Lifeng Yang","doi":"10.1093/lifemeta/loaf009","DOIUrl":"10.1093/lifemeta/loaf009","url":null,"abstract":"<p><p>Diet interventions such as calorie restriction or time-restricted feeding offer potential for weight management, but long-term success is often hindered by poor adherence due to the rewarding effects of sugars. In this study, we demonstrate that sulfur amino acid restriction (SAAR) diets promote rapid fat loss without impairing appetite and physiological locomotion, outperforming diets with restricted branched-chain amino acids. Weekly cycling of SAAR diets preserves metabolic benefits, such as reduced fat mass and improved glucose sensitivity. Metabolic analysis and <i>in vivo</i> isotope tracing revealed a shift toward carbohydrate oxidation in white and brown adipose tissue (WAT and BAT), and liver during the SAAR diet refeeding state, leading to decreased <i>de novo</i> lipogenesis. Enhanced lipolysis and fatty acid oxidation were observed in the heart, brain, BAT, lungs, etc. The reintroduction of methionine or cystine negated these metabolic benefits. Further ¹³C and ²H tracing experiments indicated that cystine, rather than its derivatives like taurine or H₂S, directly regulates adiposity. In a high-fat diet model, SAAR diet led to sustained fat mass reduction, regardless of the timing of intervention. Additionally, cystine levels correlated positively with body mass index (BMI) and total triglycerides in diabetic patients. Our findings highlight SAAR diet as a promising strategy for long-term weight control by modulating systemic glucose and lipid metabolism homeostasis.</p>","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":"4 3","pages":"loaf009"},"PeriodicalIF":0.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}