npj Metabolic Health and Disease最新文献

{"title":"Thyroid hormone receptor beta (THRB) dependent regulation of diurnal hepatic lipid metabolism in adult male mice","authors":"Leonardo Vinicius Monteiro de Assis, Lisbeth Harder, Julica Inderhees, Olaf Jöhren, Jens Mittag, Henrik Oster","doi":"10.1038/s44324-024-00023-4","DOIUrl":"10.1038/s44324-024-00023-4","url":null,"abstract":"Thyroid hormones (THs) are critical regulators of systemic energy metabolism and homeostasis. In the liver, high TH action protects against steatosis by enhancing cholesterol and triglyceride turnover, with thyroid hormone receptor beta (THRB) signaling playing a pivotal role. This study probed the potential interaction between THRB action and another critical regulator of liver energy metabolism, the circadian clock. Liver transcriptome analysis of THRB deficient (THRBKO) mice under normal chow conditions revealed a modest impact of THRB deletion. Temporal transcriptome and lipidome profiling uncovered significant alterations in diurnal metabolic rhythms attributable to THRB deficiency pointing to a pro-steatotic state with elevated levels of cholesterol, tri- and diacylglycerides, and fatty acids. These findings were confirmed by THRB agonization in hepatocytes under steatosis-promoting conditions in vitro. Integration of transcriptome profiles from THRBKO mice and mice with induced high or low TH action identified a subset of TH responsive but THRB insensitive genes implicated in immune processes. In summary, our study reveals a complex time-of-day dependent interaction of different TH-related signals in the regulation of liver physiology indicating an opportunity for chronopharmacological approaches to TH/THRB manipulation in fatty liver diseases.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00023-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973752","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":"The salivary metabolome of children and parental caregivers in a large-scale family environment study","authors":"Jason A. Rothman, Hillary L. Piccerillo, Sage J. B. Dunham, Jenna L. Riis, Douglas A. Granger, Elizabeth A. Thomas, Katrine L. Whiteson","doi":"10.1038/s44324-024-00024-3","DOIUrl":"10.1038/s44324-024-00024-3","url":null,"abstract":"Human metabolism is complex, and is impacted by genetics, cohabitation, diet, health, and environmental inputs. As such, we applied untargeted LC-MS metabolomics to 1425 saliva samples from a diverse group of elementary school-aged children and their caregivers collected during the Family Life Project, of which 1344 were paired into caregiver/child dyads. We compared metabolomes within and between homes, performed population-wide “metabotype” analyses, and measured associations between metabolites and salivary biomeasures of inflammation, antioxidant potential, environmental tobacco smoke (ETS) exposure, metabolic regulation, and heavy metals. Children and caregivers had similar salivary metabolomes, and dyad explained most metabolomic variation. Our data clustered into two groups, indicating that “metabotypes” exist across large populations. Lastly, several metabolites—putative oxidative damage-associated or pathological markers—were correlated with the above-mentioned salivary biomeasures and heavy metals. Implications of the family environment’s effects on metabolomic variation at population, dyadic, and individual levels for human health are discussed.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00024-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973743","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":"Peripheral insulin resistance attenuates cerebral glucose metabolism and impairs working memory in healthy adults","authors":"Hamish A. Deery, Emma Liang, Robert Di Paolo, Katharina Voigt, Gerard Murray, M. Navyaan Siddiqui, Gary F. Egan, Chris Moran, Sharna D. Jamadar","doi":"10.1038/s44324-024-00019-0","DOIUrl":"10.1038/s44324-024-00019-0","url":null,"abstract":"People with insulin resistance are at increased risk for cognitive decline. Insulin resistance has previously been considered primarily a condition of ageing but it is increasingly seen in younger adults. It is possible that impaired insulin function in early adulthood has both proximal effects and moderates or even accelerates changes in cerebral metabolism in ageing. Thirty-six younger (mean 27.8 years) and 43 older (mean 75.5) participants completed a battery of tests, including blood sampling, cognitive assessment and a simultaneous PET/MR scan. Cortical thickness and cerebral metabolic rates of glucose were derived for 100 regions and 17 functional networks. Older adults had lower rates of regional cerebral glucose metabolism than younger adults across the brain even after adjusting for lower cortical thickness in older adults. Higher fasting blood glucose was also associated with lower regional cerebral glucose metabolism in older adults. In younger adults, higher insulin resistance was associated with lower rates of regional cerebral glucose metabolism but this was not seen in older adults. The largest effects of insulin resistance in younger adults were in prefrontal, parietal and temporal regions; and in the control, salience ventral attention, default and somatomotor networks. Higher rates of network glucose metabolism were associated with lower reaction time and psychomotor speed. Higher levels of insulin resistance were associated with lower working memory. Our results underscore the importance of insulin sensitivity and glycaemic control to brain health and cognitive function across the adult lifespan, even in early adulthood.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00019-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141968580","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":"Autophagy and hepatic lipid metabolism: mechanistic insight and therapeutic potential for MASLD","authors":"Sana Raza, Sangam Rajak, Paul M. Yen, Rohit A. Sinha","doi":"10.1038/s44324-024-00022-5","DOIUrl":"10.1038/s44324-024-00022-5","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) originates from a homeostatic imbalance in hepatic lipid metabolism. Increased fat deposition in the liver of people suffering from MASLD predisposes them to develop further metabolic derangements, including diabetes mellitus, metabolic dysfunction-associated steatohepatitis (MASH), and other end-stage liver diseases. Unfortunately, only limited pharmacological therapies exist for MASLD to date. Autophagy, a cellular catabolic process, has emerged as a primary mechanism of lipid metabolism in mammalian hepatocytes. Furthermore, preclinical studies with autophagy modulators have shown promising results in resolving MASLD and mitigating its progress into deleterious liver pathologies. In this review, we discuss our current understanding of autophagy-mediated hepatic lipid metabolism, its therapeutic modulation for MASLD treatment, and current limitations and scope for clinical translation.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11296953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891510","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":"Some paradoxes and unresolved aspects of hepatic de novo lipogenesis","authors":"John G. Jones","doi":"10.1038/s44324-024-00020-7","DOIUrl":"10.1038/s44324-024-00020-7","url":null,"abstract":"Hepatic de novo lipogenesis (DNL) is a critical pathway in both liver intermediary metabolism and whole-body nutrient management. In the setting of excessive caloric intake, increased DNL fluxes are implicated in the pathogenesis of metabolic-associated steatotic liver disease (MASLD). As a result, there is intense interest both in the measurement of DNL activity and in gaining a better understanding on how this drives MASLD development. While much progress has been made towards these objectives, a number of intriguing uncertainties and paradoxes remain. This short perspective will focus on some of these aspects, namely a), how DNL contributes to triglyceride overload, b), the timing of DNL pathway activation with nutrient availability, c) the sources of acetyl-CoA for DNL and d), the sources of NADPH reducing equivalents for DNL. The implications of these uncertainties on pharmacological targeting of hepatic DNL activity will also be discussed.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-5"},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00020-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141968579","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":"Dysfunctional VLDL metabolism in MASLD","authors":"Urko M. Marigorta, Oscar Millet, Shelly C. Lu, José M. Mato","doi":"10.1038/s44324-024-00018-1","DOIUrl":"10.1038/s44324-024-00018-1","url":null,"abstract":"Lipidomics has unveiled the intricate human lipidome, emphasizing the extensive diversity within lipid classes in mammalian tissues critical for cellular functions. This diversity poses a challenge in maintaining a delicate balance between adaptability to recurring physiological changes and overall stability. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), linked to factors such as obesity and diabetes, stems from a compromise in the structural and functional stability of the liver within the complexities of lipid metabolism. This compromise inaccurately senses an increase in energy status, such as during fasting-feeding cycles or an upsurge in lipogenesis. Serum lipidomic studies have delineated three distinct metabolic phenotypes, or “metabotypes” in MASLD. MASLD-A is characterized by lower very low-density lipoprotein (VLDL) secretion and triglyceride (TG) levels, associated with a reduced risk of cardiovascular disease (CVD). In contrast, MASLD-C exhibits increased VLDL secretion and TG levels, correlating with elevated CVD risk. An intermediate subtype, with a blend of features, is designated as the MASLD-B metabotype. In this perspective, we examine into recent findings that show the multifaceted regulation of VLDL secretion by S-adenosylmethionine, the primary cellular methyl donor. Furthermore, we explore the differential CVD and hepatic cancer risk across MASLD metabotypes and discuss the context and potential paths forward to gear the findings from genetic studies towards a better understanding of the observed heterogeneity in MASLD.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763941","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":"Finishing the odyssey to a stem cell cure for type 1 diabetes","authors":"Lise Hunault, Daniel Hesselson","doi":"10.1038/s44324-024-00014-5","DOIUrl":"10.1038/s44324-024-00014-5","url":null,"abstract":"For over two decades pluripotent stem cells have promised a renewable source of β cells to treat patients with type 1 diabetes. Major efforts to optimize the differentiation, survival, and function of transplanted stem cell-derived tissue have recently delivered clinically meaningful metabolic benefits using a perforated encapsulation device that promotes integration with recipient vasculature under the protection of systemic immunosuppression. Despite this success, the journey is not over as a universal cure will require a larger β cell mass. Here, we summarize recent interdisciplinary advances that could maximize the functional β cell mass within transplanted devices and provide an immune privileged niche that could eliminate the need for systemic immunosuppression.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00014-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141816298","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":"Unlocking therapeutic potential: exploring cross-talk among emerging nuclear receptors to combat metabolic dysfunction in steatotic liver disease","authors":"Milton Boaheng Antwi, Ariann Jennings, Sander Lefere, Dorien Clarisse, Anja Geerts, Lindsey Devisscher, Karolien De Bosscher","doi":"10.1038/s44324-024-00013-6","DOIUrl":"10.1038/s44324-024-00013-6","url":null,"abstract":"Nuclear receptors (NRs) regulate cellular processes and serve as key targets in treating metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). Their ability to interact and influence each other’s signaling pathways introduces a complex yet underexplored dimension in the pharmacotherapy of MASLD and MASH. This review delineates the emerging NRs in this field—estrogen-related receptor alpha (ERRα), glucocorticoid receptor (GR), estrogen receptor alpha (ERα), liver receptor homolog-1 (LRH-1), and vitamin D receptor (VDR)—and their interplay with established NRs, including peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, PPARγ), farnesoid X receptor (FXR), liver X receptors (LXR), hepatocyte nuclear factor 4α (HNF4α), and thyroid hormone receptor beta (THRβ). We discuss their collective impact on hepatic lipid metabolism, inflammation, fibrosis, and glucose homeostasis. We explore recent findings on dual NR crosstalk, via direct and indirect mechanisms, and discuss the potential of targeting receptor pathways using selective agonists, inverse agonists, antagonists, or specific modulators to combat MASLD and MASH. Elucidating NR interactions opens up new avenues for targeted therapies, emphasizing the critical need for further research in the evolving field of hepatology.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00013-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141500494","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":"Serum and CSF metabolomics analysis shows Mediterranean Ketogenic Diet mitigates risk factors of Alzheimer’s disease","authors":"Annalise Schweickart, Richa Batra, Bryan J. Neth, Cameron Martino, Liat Shenhav, Anru R. Zhang, Pixu Shi, Naama Karu, Kevin Huynh, Peter J. Meikle, Leyla Schimmel, Amanda Hazel Dilmore, Kaj Blennow, Henrik Zetterberg, Colette Blach, Pieter C. Dorrestein, Rob Knight, Alzheimer’s Gut Microbiome Project Consortium, Suzanne Craft, Rima Kaddurah-Daouk, Jan Krumsiek","doi":"10.1038/s44324-024-00016-3","DOIUrl":"10.1038/s44324-024-00016-3","url":null,"abstract":"Alzheimer’s disease (AD) is influenced by a variety of modifiable risk factors, including a person’s dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD’s metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean Ketogenic Diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00016-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489061","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":"PowerAI-Diabetes: Review of glycemic and lipid variability to predict cardiovascular events in Chinese diabetic population","authors":"Sharen Lee, Tong Liu, Cheuk To Chung, Johannes Reinhold, Vassilios S. Vassiliou, Gary Tse","doi":"10.1038/s44324-024-00012-7","DOIUrl":"10.1038/s44324-024-00012-7","url":null,"abstract":"The aim of this study is to review the predictive value of visit-to-visit variability in glycaemic or lipid tests for forecasting major adverse cardiovascular events (MACE) in diabetes mellitus. Data from existing studies suggests that such variability is an independent predictor of adverse outcomes in this patient cohort. This understanding is then applied to the development of PowerAI-Diabetes, a Chinese-specific artificial intelligence-enhanced predictive model for predicting the risks of major adverse cardiovascular events and diabetic complications. The model integrates an amalgam of variables including demographics, laboratory and medication information to assess the risk of MACE. Future efforts should focus on the incorporation of treatment effects and non-traditional cardiovascular risk factors, such as social determinants of health variables, to improve the performance of predictive models.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00012-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489070","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}