npj Metabolic Health and Disease最新文献

Calcium-mediated regulation of mitophagy: implications in neurodegenerative diseases.

npj Metabolic Health and Disease Pub Date : 2025-01-01 Epub Date: 2025-02-03 DOI: 10.1038/s44324-025-00049-2

Fivos Borbolis, Christina Ploumi, Konstantinos Palikaras

{"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":"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.","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}

引用次数: 0

Regulation of gene expression through protein-metabolite interactions.

npj Metabolic Health and Disease Pub Date : 2025-01-01 Epub Date: 2025-03-04 DOI: 10.1038/s44324-024-00047-w

Maximilian Hornisch, Ilaria Piazza

引用次数: 0

Pulling back the mitochondria's iron curtain.

npj Metabolic Health and Disease Pub Date : 2025-01-01 Epub Date: 2025-03-04 DOI: 10.1038/s44324-024-00045-y

Shani Ben Zichri-David, Liraz Shkuri, Tslil Ast

引用次数: 0

AMPK phosphosite profiling by label-free mass spectrometry reveals a multitude of mTORC1-regulated substrates.

npj Metabolic Health and Disease Pub Date : 2025-01-01 Epub Date: 2025-03-04 DOI: 10.1038/s44324-025-00052-7

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

{"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":"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.","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}

引用次数: 0

Reversal of metformin's anti-proliferative effect in fission yeast efr3 and dnm1 (DRP1) mutants with elongated mitochondria. 逆转二甲双胍在线粒体拉长的裂殖酵母efr3和dnm1（DRP1）突变体中的抗增殖作用。

npj Metabolic Health and Disease Pub Date : 2025-01-01 Epub Date: 2025-02-21 DOI: 10.1038/s44324-024-00048-9

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

{"title":"Reversal of metformin's anti-proliferative effect in fission yeast efr3 and dnm1 (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":"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 S. pombe. 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 efr3 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 dnm1 (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 efr3 deletion, however, that reduction is less pronounced in the efr3 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.","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}

引用次数: 0

Reshaping lipid metabolism with long-term alternate day feeding in type 2 diabetes mice.

npj Metabolic Health and Disease Pub Date : 2025-01-01 Epub Date: 2025-02-03 DOI: 10.1038/s44324-024-00039-w

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

{"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":"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.","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}

引用次数: 0

Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression.

npj Metabolic Health and Disease Pub Date : 2025-01-01 Epub Date: 2025-03-14 DOI: 10.1038/s44324-025-00054-5

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

{"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":"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.","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}

引用次数: 0

Intermittent fasting as a treatment for obesity in young people: a scoping review 间歇性禁食作为治疗年轻人肥胖的一种方法：范围综述

npj Metabolic Health and Disease Pub Date : 2024-12-30 DOI: 10.1038/s44324-024-00041-2

Jomanah Bakhsh, Sarah-Jeanne Salvy, Alaina P. Vidmar

{"title":"Intermittent fasting as a treatment for obesity in young people: a scoping review","authors":"Jomanah Bakhsh, Sarah-Jeanne Salvy, Alaina P. Vidmar","doi":"10.1038/s44324-024-00041-2","DOIUrl":"10.1038/s44324-024-00041-2","url":null,"abstract":"Intermittent fasting focuses on the timing of eating rather than diet quality or energy intake, with evidence supporting its effects on weight loss and improvements in cardiometabolic outcomes in adults with obesity. However, there is limited evidence for its feasibility and efficacy in young people. To address this, a scoping review was conducted to examine intermittent fasting regimens in individuals aged 10 to 25 for the treatment of obesity focusing on methodology, intervention parameters, outcomes, adherence, feasibility, and efficacy. Due to the paucity of evidence in this age group, to adequately assess feasibility and adherence, all published studies of intermittent fasting in this age category, regardless of weight status and treatment intention, were included in the review. The review included 34 studies (28 interventional studies and 6 observational studies) with 893 participants aged 12 to 25. Interventions varied with 9 studies in cohorts with obesity utilizing intermittent fasting as an obesity treatment. Thirteen studies utilized 8-h time-restricted eating. Primary outcomes included cardiometabolic risk factors (7/28), anthropometric measurements (7/28), body composition (5/28), muscular performance (4/28), feasibility (1/28), and others (4/28). All 9 studies conducted in young people with obesity reported some degree of weight loss, although the comparator groups varied significantly. This review underscores the various utilizations of intermittent fasting in this age group and highlights its potential in treating obesity. However, the findings emphasize the need for rigorous studies with standardized frameworks for feasibility to ensure comparability and determine intermittent fasting’s practicality in this age group depending on the treatment outcome of interest.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-19"},"PeriodicalIF":0.0,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00041-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906112","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}

引用次数: 0

The effect of high-sugar feeding on rodent metabolic phenotype: a systematic review and meta-analysis 高糖摄食对啮齿动物代谢表型的影响：系统回顾和荟萃分析

npj Metabolic Health and Disease Pub Date : 2024-12-30 DOI: 10.1038/s44324-024-00043-0

Sophie Lucic Fisher, G. Jean Campbell, Alistair Senior, Kim Bell-Anderson

{"title":"The effect of high-sugar feeding on rodent metabolic phenotype: a systematic review and meta-analysis","authors":"Sophie Lucic Fisher, G. Jean Campbell, Alistair Senior, Kim Bell-Anderson","doi":"10.1038/s44324-024-00043-0","DOIUrl":"10.1038/s44324-024-00043-0","url":null,"abstract":"Dietary sugar consumption has been linked to increased cardiometabolic disease risk, although it is unclear if this is independent of increases in body weight and adiposity. Additionally, many preclinical animal studies provide liquid sugar which more readily leads to excess consumption and weight gain, confounding any outcomes driven by high-sugar intake alone. To gain clarity on this, we conducted a systematic review and meta-analysis exclusively investigating the effect of isocaloric high-sugar, low-fat solid diet formulations containing fructose or sucrose, on cardiometabolic health in rodents. Overall, we found strong evidence that fructose and sucrose have effects on metabolic health, independent of body weight gain. High-sugar feeding, with fructose in particular, altered liver phenotype; ALT (d = 1.08; 0.66, 1.5), triglyceride content (d = 0.52; 0.25, 0.78), cholesterol (d = 0.59; 0.16, 1.03) and liver mass (d = 0.93; 0.37, 1.48), and glucose tolerance; fasting glucose (d = 0.60; 0.18, 1.01) and fasting insulin (d = 0.42; 0.07, 0.77) but not body weight or energy intake. Our review also highlights the lack of data reported on adiposity and in female rodents. This is the first meta-analysis to synthesise all current rodent solid diet high-sugar studies, while adjusting them for confounders (fat content, time spent on diet and age started on diet) and suggests that high-sugar dietary intake and composition alters metabolic health of mice regardless of weight gain.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-13"},"PeriodicalIF":0.0,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00043-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906125","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}

引用次数: 0

Chain splitting of insulin: an underlying mechanism of insulin resistance? 胰岛素链分裂：胰岛素抵抗的潜在机制？

npj Metabolic Health and Disease Pub Date : 2024-12-18 DOI: 10.1038/s44324-024-00042-1

Christian N. Cramer, František Hubálek, Christian Lehn Brand, Hans Helleberg, Peter Kurtzhals, Jeppe Sturis

引用次数: 0