npj Metabolic Health and Disease最新文献

{"title":"High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice.","authors":"Ivar van Galen, Maria B Birkisdóttir, Rutger A Ozinga, Renata M C Brandt, Sander Barnhoorn, Sandra Imholz, Conny T van Oostrom, Ricfrid W G N van der Marel, Kimberly Smit, Yvonne M A Rijksen, Erwin Reiling, Harry van Steeg, Jan H J Hoeijmakers, Martijn E T Dollé, Wilbert P Vermeij","doi":"10.1038/s44324-025-00064-3","DOIUrl":"10.1038/s44324-025-00064-3","url":null,"abstract":"<p><p>Dietary composition can significantly influence health and lifespan, however, robust knowledge on which food components, at what concentration exert which long-term health effects is still incomplete. Here, we explored the effects of dietary protein intake on <i>Ercc1</i> ^Δ/- DNA-repair-deficient mice, which are an excellent model for accelerated ageing and are hyperresponsive to the anti-ageing effect of dietary restriction. Restricting dietary protein by 50% extended lifespan in male mice, but not in females. Restricting protein levels beyond 80% improved various neurological health parameters, while a further reduction to 95% affected appetite and became distinctly detrimental. Conversely, a near doubling of protein intake and isocaloric compensatory lowering with carbohydrates significantly shortened lifespan in both sexes. Gene expression analysis of liver from mice on a high-protein, low-carbohydrate diet to those on high-carbohydrate, low-protein revealed increased expression of oxidative phosphorylation, enrichment of processes associated with tissue injury, inflammation, and gene-length-dependent transcriptional decline (GLTD), recently shown to reflect DNA damage accumulation causing transcription stress, and cellular ageing. Finally, GLTD was also identified by reanalysis of publicly available data of wild-type mice, rats and humans on high-protein diets, suggesting that increased dietary protein enhances GLTD and accelerates systemic ageing. Together, our findings have implications for nutritional guidelines for progeroid DNA-repair-deficient human syndromes, warrant the use of excessive protein intake for sustaining health, and suggests GLTD as a sensitive read-out of overall health and predictor of biological ageing.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 ","pages":"20"},"PeriodicalIF":0.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145391","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 gene expression through protein-metabolite interactions.","authors":"Maximilian Hornisch, Ilaria Piazza","doi":"10.1038/s44324-024-00047-w","DOIUrl":"10.1038/s44324-024-00047-w","url":null,"abstract":"<p><p>Organisms have to adapt to changes in their environment. Cellular adaptation requires sensing, signalling and ultimately the activation of cellular programs. Metabolites are environmental signals that are sensed by proteins, such as metabolic enzymes, protein kinases and nuclear receptors. Recent studies have discovered novel metabolite sensors that function as gene regulatory proteins such as chromatin associated factors or RNA binding proteins. Due to their function in regulating gene expression, metabolite-induced allosteric control of these proteins facilitates a crosstalk between metabolism and gene expression. Here we discuss the direct control of gene regulatory processes by metabolites and recent progresses that expand our abilities to systematically characterize metabolite-protein interaction networks. Obtaining a profound map of such networks is of great interest for aiding metabolic disease treatment and drug target identification.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"7"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575043","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":"Calcium-mediated regulation of mitophagy: implications in neurodegenerative diseases.","authors":"Fivos Borbolis, Christina Ploumi, Konstantinos Palikaras","doi":"10.1038/s44324-025-00049-2","DOIUrl":"10.1038/s44324-025-00049-2","url":null,"abstract":"<p><p>Calcium signaling plays a pivotal role in diverse cellular processes through precise spatiotemporal regulation and interaction with effector proteins across distinct subcellular compartments. Mitochondria, in particular, act as central hubs for calcium buffering, orchestrating energy production, redox balance and apoptotic signaling, among others. While controlled mitochondrial calcium uptake supports ATP synthesis and metabolic regulation, excessive accumulation can trigger oxidative stress, mitochondrial membrane permeabilization, and cell death. Emerging findings underscore the intricate interplay between calcium homeostasis and mitophagy, a selective type of autophagy for mitochondria elimination. Although the literature is still emerging, this review delves into the bidirectional relationship between calcium signaling and mitophagy pathways, providing compelling mechanistic insights. Furthermore, we discuss how disruptions in calcium homeostasis impair mitophagy, contributing to mitochondrial dysfunction and the pathogenesis of common neurodegenerative diseases.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"4"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257769","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":"Ultra-processed food consumption affects structural integrity of feeding-related brain regions independent of and via adiposity.","authors":"Filip Morys, Arsene Kanyamibwa, Daniel Fängström, Max Tweedale, Alexandre Pastor-Bernier, Houman Azizi, Lang Liu, Annette Horstmann, Alain Dagher","doi":"10.1038/s44324-025-00056-3","DOIUrl":"https://doi.org/10.1038/s44324-025-00056-3","url":null,"abstract":"<p><p>Consumption of ultra-processed foods (UPFs) increases overall caloric intake and is associated with obesity, cardiovascular disease, and brain pathology. There is scant evidence as to why UPF consumption leads to increased caloric intake and whether the negative health consequences are due to adiposity or characteristics of UPFs. Using the UK Biobank sample, we probed the associations between UPF consumption, adiposity, metabolism, and brain structure. Our analysis reveals that high UPF intake is linked to adverse adiposity and metabolic profiles, alongside cellularity changes in feeding-related subcortical brain areas. These are partially mediated by dyslipidemia, systemic inflammation and body mass index, suggesting that UPFs exert effects on the brain beyond just contributing to obesity. This dysregulation of the network of subcortical feeding-related brain structures may create a self-reinforcing cycle of increased UPF consumption.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"13"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11978510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035572","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":"Pulling back the mitochondria's iron curtain.","authors":"Shani Ben Zichri-David, Liraz Shkuri, Tslil Ast","doi":"10.1038/s44324-024-00045-y","DOIUrl":"10.1038/s44324-024-00045-y","url":null,"abstract":"<p><p>Mitochondrial functionality and cellular iron homeostasis are closely intertwined. Mitochondria are biosynthetic hubs for essential iron cofactors such as iron-sulfur (Fe-S) clusters and heme. These cofactors, in turn, enable key mitochondrial pathways, such as energy and metabolite production. Mishandling of mitochondrial iron is associated with a spectrum of human pathologies ranging from rare genetic disorders to common conditions. Here, we review mitochondrial iron utilization and its intersection with disease.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"6"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575041","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":"Periodic dietary restriction of animal products induces metabolic reprogramming in humans with effects on cardiometabolic health.","authors":"Konstantinos Rouskas, Ozvan Bocher, Alexandros Simistiras, Christina Emmanouil, Panagiotis Mantas, Anargyros Skoulakis, Young-Chan Park, Alexandros Dimopoulos, Stavros Glentis, Gabi Kastenmüller, Eleftheria Zeggini, Antigone S Dimas","doi":"10.1038/s44324-025-00057-2","DOIUrl":"https://doi.org/10.1038/s44324-025-00057-2","url":null,"abstract":"<p><p>Dietary interventions constitute powerful approaches for disease prevention and treatment. However, the molecular mechanisms through which diet affects health remain underexplored in humans. Here, we compare plasma metabolomic and proteomic profiles between dietary states for a unique group of individuals who alternate between omnivory and restriction of animal products for religious reasons. We find that short-term restriction drives reductions in levels of lipid classes and of branched-chain amino acids, not detected in a control group of individuals, and results in metabolic profiles associated with decreased risk for all-cause mortality. We show that 23% of proteins whose levels are affected by dietary restriction are druggable targets and reveal that pro-longevity hormone FGF21 and seven additional proteins (FOLR2, SUMF2, HAVCR1, PLA2G1B, OXT, SPP1, HPGDS) display the greatest magnitude of change. Through Mendelian randomization we demonstrate potentially causal effects of FGF21 and HAVCR1 on risk for type 2 diabetes, of HPGDS on BMI, and of OXT on risk for lacunar stroke. Collectively, we find that restriction-associated reprogramming improves metabolic health and emphasise high-value targets for pharmacological intervention.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"14"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036846","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":"AMPK phosphosite profiling by label-free mass spectrometry reveals a multitude of mTORC1-regulated substrates.","authors":"William J Smiles, Ashley J Ovens, Dingyi Yu, Naomi X Y Ling, Andrea C Poblete Goycoolea, Kaitlin R Morrison, Emmanuel O Murphy, Astrid Glaser, Sophie F Monks O'Byrne, Scott Taylor, Alistair M Chalk, Carl R Walkley, Luke M McAloon, John W Scott, Bruce E Kemp, Ashfaqul Hoque, Christopher G Langendorf, Janni Petersen, Sandra Galic, Jonathan S Oakhill","doi":"10.1038/s44324-025-00052-7","DOIUrl":"10.1038/s44324-025-00052-7","url":null,"abstract":"<p><p>The nutrient-sensitive protein kinases AMPK and mTORC1 form a fundamental negative feedback loop that governs cell growth and proliferation. mTORC1 phosphorylates α2-S345 in the AMPK αβγ heterotrimer to suppress its activity and promote cell proliferation under nutrient stress conditions. Whether AMPK contains other functional mTORC1 substrates is unknown. Using mass spectrometry, we generated precise stoichiometry profiles of phosphorylation sites across all twelve AMPK complexes expressed in proliferating human cells and identified seven sites displaying sensitivity to pharmacological mTORC1 inhibition. These included the abundantly phosphorylated residues β1-S182 and β2-S184, which were confirmed as mTORC1 substrates on purified AMPK, and four residues in the unique γ2 N-terminal extension. β-S182/184 phosphorylation was elevated in α1-containing complexes relative to α2, an effect attributed to the α-subunit serine/threonine-rich loop. Mutation of β1-S182 to non-phosphorylatable Ala had no effect on basal and ligand-stimulated AMPK activity; however, β2-S184A mutation increased nuclear AMPK activity, enhanced cell proliferation under nutrient stress and altered expression of genes implicated in glucose metabolism and Akt signalling. Our results indicate that mTORC1 directly or indirectly phosphorylates multiple AMPK residues that may contribute to metabolic rewiring in cancerous cells.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"8"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575037","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":"Reversal of metformin's anti-proliferative effect in fission yeast <i>efr3</i> and <i>dnm1</i> (DRP1) mutants with elongated mitochondria.","authors":"Ari Gillespie, Anne-Sophie Mehdorn, Tiffany Q Lim, Tingting Wang, Bridget A Mooney, Ashley J Ovens, Ayla Orang, Jonathan S Oakhill, Michael Z Michael, Janni Petersen","doi":"10.1038/s44324-024-00048-9","DOIUrl":"10.1038/s44324-024-00048-9","url":null,"abstract":"<p><p>Metformin is a well-tolerated drug frequently prescribed for managing type 2 diabetes. Extended metformin use has been linked to a significant decrease in cancer incidence across both diabetic and non-diabetic populations. Here we investigate the anti-proliferative effects of metformin on fission yeast <i>S. pombe</i>. Our findings demonstrate that metformin's inhibitory impact on cell proliferation is effective in the absence of AMP-activated protein kinase (AMPK). Using an unbiased genetic screen we identified the plasma membrane signalling scaffold Efr3, critical for phosphatidylinositol signalling and the generation of PI4Ps, as a key determinant of resistance to the anti-proliferative effect of metformin. Deletion of <i>efr3</i> resulted in both AMPK-dependent and AMPK-independent resistance to metformin. We show that Efr3 does not influence cell proliferation by controlling Ras1 activity or its cellular localization in yeast. We observe that <i>dnm1</i> (DRP1) mutants with elongated mitochondria are also resistant to the anti-proliferative effect of metformin and that metformin treatment promotes mitochondrial fusion. Metabolic measurements after prolonged metformin exposure demonstrated a reduction in respiration in both wild type and the <i>efr3</i> deletion, however, that reduction is less pronounced in the <i>efr3</i> deletion, which also contained elongated mitochondria. It is likely that mitochondrial fusion enhances yeast fitness in response to metformin exposure. Together we provide a new perspective on the cellular response to metformin.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"5"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485196","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":"Reshaping lipid metabolism with long-term alternate day feeding in type 2 diabetes mice.","authors":"Eleni Beli, Yuanqing Yan, Leni Moldovan, Todd A Lydic, Preethi Krishman, Sarah A Tersey, Yaqian Duan, Tatiana E Salazar, James M Dominguez, Dung V Nguyen, Abigail Cox, Sergio Li Calzi, Craig Beam, Raghavendra G Mirmira, Carmella Evans-Molina, Julia V Busik, Maria B Grant","doi":"10.1038/s44324-024-00039-w","DOIUrl":"10.1038/s44324-024-00039-w","url":null,"abstract":"<p><p>Strategies to improve metabolic health include calorie restriction, time restricted eating and fasting several days per week or month. These approaches have demonstrated benefits for individuals experiencing obesity, metabolic syndrome, and prediabetes. However, their impact on established diabetes remains incompletely studied. The chronicity of type 2 diabetes (T2D) requires that interventions must be undertaken for extended periods of time, typically the entire lifetime of the individual. In this study, we examined the impact of intermittent fasting (IF), with an every-other-day protocol for a duration of 6 months in a murine model of T2D, the db/db (D) mouse on metabolism and liver steatosis. We compared D-IF mice with diabetic ad-libitum (AL; D-AL), control-IF (C-IF) and control-AL (C-AL) cohorts. We demonstrated using lipidomic, microbiome, metabolomic and liver transcriptomic studies that chronic IF improved carbohydrate utilization and glucose homeostasis without weight loss and reduced white adipose tissue inflammation and significantly impacted lipid metabolism in the liver. Microbiome studies and predicted functional analysis of gut microbiota showed that IF increased beneficial bacteria involved in sphingolipid (SL) metabolism. The metabolomic studies showed that oxidation of lipid species and ceramide levels were reduced in D-IF compared to D-AL. The liver lipidomic analysis and liver microarray confirmed a reduction in overall lipid content in D-IF mice compared to D-AL mice, especially in the feeding state as well as an overall reduction in oxidized lipids and ceramides. These studies support that long-term IF can improve glucose homeostasis and dramatically altered lipid metabolism in the absence of weight loss.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"3"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257770","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":"Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression.","authors":"Sandesh J Marathe, Emily W Grey, Margaret S Bohm, Sydney C Joseph, Arvind V Ramesh, Matthew A Cottam, Kamran Idrees, Kathryn E Wellen, Alyssa H Hasty, Jeffrey C Rathmell, Liza Makowski","doi":"10.1038/s44324-025-00054-5","DOIUrl":"https://doi.org/10.1038/s44324-025-00054-5","url":null,"abstract":"<p><p>Medical therapeutics for weight loss are changing the landscape of obesity but impacts on obesity-associated cancer remain unclear. We report that in pre-clinical models with significant retatrutide (RETA, LY3437943)-induced weight loss, pancreatic cancer engraftment was reduced, tumor onset was delayed, and progression was attenuated resulting in a 14-fold reduction in tumor volume compared to only 4-fold reduction in single agonist semaglutide-treated mice. Despite weight re-gain after RETA withdrawal, the anti-tumor benefits of RETA persisted. Remarkably, RETA-induced protection extends to a lung cancer model with 50% reduced tumor engraftment, significantly delayed tumor onset, and mitigated tumor progression, with a 17-fold reduction in tumor volume compared to controls. RETA induced immune reprogramming systemically and in the tumor microenvironment with durable anti-tumor immunity evidenced by elevated circulating IL-6, increased antigen presenting cells, reduced immunosuppressive cells, and activation of pro-inflammatory pathways. In sum, our findings suggest that patients with RETA-mediated weight loss may also benefit from reduced cancer risk and improved outcomes.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"10"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653109","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}