Metabolism: clinical and experimental最新文献

{"title":"Comparative efficacy of THR-β agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis","authors":"Ru-Tao Lin ,&nbsp;Qin-Mei Sun ,&nbsp;Xin Xin ,&nbsp;Cheng Han Ng ,&nbsp;Luca Valenti ,&nbsp;Yi-Yang Hu ,&nbsp;Ming-Hua Zheng ,&nbsp;Qin Feng","doi":"10.1016/j.metabol.2024.156043","DOIUrl":"10.1016/j.metabol.2024.156043","url":null,"abstract":"<div><h3>Aims</h3><div>To compare the efficacy of thyroid hormone receptor beta (THR-β) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD).</div></div><div><h3>Methods</h3><div>A database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight.</div></div><div><h3>Results</h3><div>Twenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] −51.47; 95 % confidence interval [CI]: −68.25 to −34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD −47.08; 95 % CI: −58.83 to −35.34; SUCRA 75.5), GLP-1R agonists (MD −37.36; 95 % CI: −69.52 to −5.21; SUCRA 52.3) and THR-β agonists (MD −33.20; 95 % CI: −43.90 to −22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD −9.65; 95 % CI: −19.28 to −0.01; SUCRA 82.2) vs. placebo, followed by THR-β agonists (MD −5.79; 95 % CI: −9.50 to −2.09; SUCRA 58.2), and GLP-1RAs (MD −5.58; 95 % CI: −15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-β agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-β agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-β agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism.</div></div><div><h3>Conclusion</h3><div>These results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156043"},"PeriodicalIF":10.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365795","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":"PDCD4 deficiency in hepatocytes exacerbates nonalcoholic steatohepatitis through enhanced MHC class II transactivator expression","authors":"Kaikai Lu ,&nbsp;Lei He ,&nbsp;Zizhen Guo ,&nbsp;Mengda Li ,&nbsp;Xiaona Cheng ,&nbsp;Sitong Liu ,&nbsp;Tianyun Zhang ,&nbsp;Qian Chen ,&nbsp;Rong Zhao ,&nbsp;Luyun Yang ,&nbsp;Xiaodan Wu ,&nbsp;Kexin Cheng ,&nbsp;Peihai Cao ,&nbsp;Litao Wu ,&nbsp;Muhammad Shahzad ,&nbsp;Minghua Zheng ,&nbsp;Lianying Jiao ,&nbsp;Yue Wu ,&nbsp;Dongmin Li","doi":"10.1016/j.metabol.2024.156036","DOIUrl":"10.1016/j.metabol.2024.156036","url":null,"abstract":"<div><div>Nonalcoholic steatohepatitis (NASH) is a primary cause of liver cirrhosis and hepatocellular carcinoma, presenting a significant and unmet medical challenge. The necessity to investigate the molecular mechanisms underlying NASH is highlighted by the observed decrease in programmed cell death 4 (PDCD4) expression in NASH patients, suggesting that PDCD4 may play a protective role in maintaining liver health. In this study, we identify PDCD4 as a natural inhibitor of NASH development in mice. The absence of PDCD4 leads to the spontaneous progression of NASH. Notably, PDCD4-deficient hepatocytes display elevated major histocompatibility complex class II (MHCII) expression due to CIITA activation, indicating that PCDC4 prevents the abnormal transformation of hepatocytes into antigen-presenting cells (APCs). Cell co-culture experiments reveal that hepatocytes lacking PDCD4, which resemble APCs, can directly activate CD4⁺ T cells by presenting multiple peptides, resulting in the release of inflammatory factors. Additionally, both cellular and animal studies show that CIITA promotes lipid accumulation in hepatocytes and exacerbates NASH progression. In summary, our findings reveal a novel role of PDCD4 in regulating CIITA and MHCII expression during NASH development, offering new therapeutic approaches for NASH treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156036"},"PeriodicalIF":10.8,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350222","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":"Protein kinase N1 deficiency results in upregulation of cerebral energy metabolism and is highly protective in in vivo and in vitro stroke models","authors":"Stephanie zur Nedden ,&nbsp;Motahareh S. Safari ,&nbsp;Dido Weber ,&nbsp;Louisa Kuenkel ,&nbsp;Carolin Garmsiri ,&nbsp;Luisa Lang ,&nbsp;Cyrille Orset ,&nbsp;Tom Freret ,&nbsp;Benoît Haelewyn ,&nbsp;Madlen Hotze ,&nbsp;Marcel Kwiatkowski ,&nbsp;Bettina Sarg ,&nbsp;Klaus Faserl ,&nbsp;Dragana Savic ,&nbsp;Ira-Ida Skvortsova ,&nbsp;Anne Krogsdam ,&nbsp;Sandro Carollo ,&nbsp;Zlatko Trajanoski ,&nbsp;Herbert Oberacher ,&nbsp;Dominik Zlotek ,&nbsp;Gabriele Baier-Bitterlich","doi":"10.1016/j.metabol.2024.156039","DOIUrl":"10.1016/j.metabol.2024.156039","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background and aim&lt;/h3&gt;&lt;div&gt;We recently identified protein kinase N1 (PKN1) as a master regulator of brain development. However, its function in the adult brain has not been clearly established. In this study, we assessed the cerebral energetic phenotype of wildtype (WT) and global &lt;em&gt;Pkn1&lt;/em&gt; knockout (&lt;em&gt;Pkn1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;−/−&lt;/em&gt;&lt;/sup&gt;) animals under physiological and pathophysiological conditions.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Cerebral energy metabolism was analyzed by &lt;sup&gt;13&lt;/sup&gt;C&lt;sub&gt;6&lt;/sub&gt;-glucose tracing &lt;em&gt;in vivo&lt;/em&gt; and real time seahorse analysis of extracellular acidification rates as well as mitochondrial oxygen consumption rates (OCR) of brain slice punches &lt;em&gt;in vitro&lt;/em&gt;. Isolated WT and &lt;em&gt;Pkn1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;−/−&lt;/em&gt;&lt;/sup&gt; brain mitochondria were tested for differences in OCR with different substrates. Metabolite levels were determined by mass spectrometric analysis in brain slices under control and energetic stress conditions, induced by oxygen-glucose deprivation and reperfusion, an &lt;em&gt;in vitro&lt;/em&gt; model of ischemic stroke. Differences in enzyme activities were assessed by enzymatic assays, western blotting and bulk RNA sequencing. A middle cerebral artery occlusion stroke model was used to analyze lesion volumes and functional recovery in WT and &lt;em&gt;Pkn1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;−/−&lt;/em&gt;&lt;/sup&gt; mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;&lt;em&gt;Pkn1&lt;/em&gt; deficiency resulted in a remarkable upregulation of cerebral energy metabolism, &lt;em&gt;in vivo&lt;/em&gt; and &lt;em&gt;in vitro&lt;/em&gt;. This was due to two separate mechanisms involving an enhanced glycolytic flux and higher pyruvate-induced mitochondrial OCR. Mechanistically we show that &lt;em&gt;Pkn1&lt;/em&gt;&lt;sup&gt;−/−&lt;/sup&gt; brain tissue exhibits an increased activity of the glycolysis rate-limiting enzyme phosphofructokinase. Additionally, glucose-1,6-bisphosphate levels, a metabolite that increases mitochondrial pyruvate uptake, were elevated upon &lt;em&gt;Pkn1&lt;/em&gt; deficiency. Consequently, &lt;em&gt;Pkn1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;−/−&lt;/em&gt;&lt;/sup&gt; brain slices had more ATP and a greater accumulation of ATP degradation metabolites during energetic stress. This translated into increased phosphorylation and activity of adenosine monophosphate (AMP)-activated protein kinase (AMPK) during &lt;em&gt;in vitro&lt;/em&gt; stroke. Accordingly, &lt;em&gt;Pkn1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;−/−&lt;/em&gt;&lt;/sup&gt; brain slices showed a post-ischemic transcriptional upregulation of energy metabolism pathways and &lt;em&gt;Pkn1&lt;/em&gt; deficiency was strongly protective in &lt;em&gt;in vitro&lt;/em&gt; and &lt;em&gt;in vivo&lt;/em&gt; stroke models. While inhibition of mitochondrial pyruvate uptake only moderately affected the protective phenotype, inhibition of AMPK in &lt;em&gt;Pkn1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;−/−&lt;/em&gt;&lt;/sup&gt; slices increased post-ischemic cell death &lt;em&gt;in vitro&lt;/em&gt;.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;This is the first study to comprehensively demonstrate an essential and unique role of PKN1 in cerebral energy metabolism, regulating glycolysis and mitochondrial pyruvate-induced respiration. We furt","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156039"},"PeriodicalIF":10.8,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Starvation and infection: The role of sickness-associated anorexia in metabolic adaptation during acute infection","authors":"Jessy Jindal ,&nbsp;Jennifer Hill ,&nbsp;Jodie Harte ,&nbsp;Susanna J. Dunachie ,&nbsp;Barbara Kronsteiner","doi":"10.1016/j.metabol.2024.156035","DOIUrl":"10.1016/j.metabol.2024.156035","url":null,"abstract":"<div><div>Sickness-associated anorexia, the reduction in appetite seen during infection, is a widely conserved and well-recognized symptom of acute infection, yet there is very little understanding of its functional role in recovery. Anorexic sickness behaviours can be understood as an evolutionary strategy to increase tolerance to pathogen-mediated illness. In this review we explore the evidence for mechanisms and potential metabolic benefits of sickness-associated anorexia. Energy intake can impact on the immune response, control of inflammation and tissue stress, and on pathogen fitness. Fasting mediators including hormone-sensitive lipase, peroxisome proliferator-activated receptor-alpha (PPAR-α) and ketone bodies are potential facilitators of infection recovery through multiple pathways including suppression of inflammation, adaptation to lipid utilising pathways, and resistance to pathogen-induced cellular stress. However, the effect and benefit of calorie restriction is highly heterogeneous depending on both the infection and the metabolic status of the host, which has implications regarding clinical recommendations for feeding during different infections.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156035"},"PeriodicalIF":10.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials","authors":"Zeyu Xie ,&nbsp;Guimei Zheng ,&nbsp;Zhuoru Liang ,&nbsp;Mengting Li ,&nbsp;Weishang Deng ,&nbsp;Weiling Cao","doi":"10.1016/j.metabol.2024.156038","DOIUrl":"10.1016/j.metabol.2024.156038","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This study aimed to provide evidence-based support and a reference for the efficacy and safety of seven glucagon-like peptide-1 (GLP-1) receptor agonists and polyagonists for weight loss in patients with obesity or overweight through a network meta-analysis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Relevant randomized controlled trials (RCTs) with an intervention duration of at least 16 weeks assessing seven GLP-1 receptor agonists and polyagonists (mazdutide, 6 or 4.5 mg; retatrutide, 12 or 8 mg; tirzepatide, 15 or 10 mg; liraglutide, 3.0 mg; semaglutide, 2.4 mg; orforglipron, 45 or 36 mg; and beinaglutide, 0.2 mg) in patient with obesity or overweight was searched using three databases (Cochrane Library, PubMed, and Embase) from creation to August 30, 2024. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included changes in waist circumference, hemoglobin A1c, and fasting plasma glucose level from baseline; adverse events, serious adverse events, adverse event withdrawal, and hypoglycemic events. We conducted a frequentist random-effects network meta-analysis to analyze the data extracted from the RCTs using Stata 16.1 software.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Twenty-seven RCTs of seven GLP-1 receptor agonists and polyagonists and 15,584 patients were included in the network meta-analysis. In terms of efficacy, compared with placebo, retatrutide 12 mg (−22.10 % in body weight and − 17.00 cm in waist circumference), retatrutide 8 mg (−20.70 % and − 15.90 cm), and tirzepatide 15 mg (−16.53 % and − 13.23 cm) were the three most efficacious treatments for reducing body weight and waist circumference. However, these treatments were less effective in patients with type 2 diabetes mellitus (T2DM). In addition, patients with a high body mass index (BMI) or longer treatment cycles exhibited significantly greater weight loss than those with a low BMI or shorter treatment cycles. In terms of safety, patients without T2DM had a higher incidence of adverse events than those with T2DM. None of the interventions increased the incidence of serious adverse or hypoglycemic events (˂54 mg/dL). There was no significant difference in the incidence of adverse event withdrawal for all interventions in head-to-head comparisons. In addition, disparities in race, BMI, and treatment cycles did not significantly increase the incidence of adverse events. Finally, the sensitivity and publication bias analyses indicated that the basic analysis results were reliable.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Retatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156038"},"PeriodicalIF":10.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291425","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":"Corrigendum to “PCSK7: A novel regulator of apolipoprotein B and a potential target against non-alcoholic fatty liver disease” [Metabolism Volume 150, January 2024, 155736, PMID: 7967646]","authors":"Vatsal Sachan ,&nbsp;Maïlys LeDévéhat ,&nbsp;Anna Roubtsova ,&nbsp;Rachid Essalmani ,&nbsp;Jean-Francois Laurendeau ,&nbsp;Damien Garçon ,&nbsp;Delia Susan-Sesiga ,&nbsp;Stéphanie Duval ,&nbsp;Sahar Mikaeeli ,&nbsp;Josée Hamelin ,&nbsp;Alexandra Evagelidis ,&nbsp;Michael Chong ,&nbsp;Guillaume Paré ,&nbsp;Elizabeta Chernetsova ,&nbsp;Zu-Hua Gao ,&nbsp;Isabelle Robillard ,&nbsp;Matthieu Ruiz ,&nbsp;Vincent Quoc-Huy Trinh ,&nbsp;Jennifer L. Estall ,&nbsp;May Faraj ,&nbsp;Nabil G. Seidah","doi":"10.1016/j.metabol.2024.156032","DOIUrl":"10.1016/j.metabol.2024.156032","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156032"},"PeriodicalIF":10.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0026049524002592/pdfft?md5=3d6e756d24e495614c7982067f4d793f&pid=1-s2.0-S0026049524002592-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142243134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inter-organ cross-talk in human cancer cachexia revealed by spatial metabolomics","authors":"Na Sun ,&nbsp;Tanja Krauss ,&nbsp;Claudine Seeliger ,&nbsp;Thomas Kunzke ,&nbsp;Barbara Stöckl ,&nbsp;Annette Feuchtinger ,&nbsp;Chaoyang Zhang ,&nbsp;Andreas Voss ,&nbsp;Simone Heisz ,&nbsp;Olga Prokopchuk ,&nbsp;Marc E. Martignoni ,&nbsp;Klaus-Peter Janssen ,&nbsp;Melina Claussnitzer ,&nbsp;Hans Hauner ,&nbsp;Axel Walch","doi":"10.1016/j.metabol.2024.156034","DOIUrl":"10.1016/j.metabol.2024.156034","url":null,"abstract":"<div><h3>Background</h3><div>Cancer cachexia (CCx) presents a multifaceted challenge characterized by negative protein and energy balance and systemic inflammatory response activation. While previous CCx studies predominantly focused on mouse models or human body fluids, there's an unmet need to elucidate the molecular inter-organ cross-talk underlying the pathophysiology of human CCx.</div></div><div><h3>Methods</h3><div>Spatial metabolomics were conducted on liver, skeletal muscle, subcutaneous and visceral adipose tissue, and serum from cachectic and control cancer patients. Organ-wise comparisons were performed using component, pathway enrichment and correlation network analyses. Inter-organ correlations in CCx altered pathways were assessed using Circos. Machine learning on tissues and serum established classifiers as potential diagnostic biomarkers for CCx.</div></div><div><h3>Results</h3><div>Distinct metabolic pathway alteration was detected in CCx, with adipose tissues and liver displaying the most significant (P ≤ 0.05) metabolic disturbances. CCx patients exhibited increased metabolic activity in visceral and subcutaneous adipose tissues and liver, contrasting with decreased activity in muscle and serum compared to control patients. Carbohydrate, lipid, amino acid, and vitamin metabolism emerged as highly interacting pathways across different organ systems in CCx. Muscle tissue showed decreased (P ≤ 0.001) energy charge in CCx patients, while liver and adipose tissues displayed increased energy charge (P ≤ 0.001). We stratified CCx patients by severity and metabolic changes, finding that visceral adipose tissue is most affected, especially in cases of severe cachexia. Morphometric analysis showed smaller (P ≤ 0.05) adipocyte size in visceral adipose tissue, indicating catabolic processes. We developed tissue-based classifiers for cancer cachexia specific to individual organs, facilitating the transfer of patient serum as minimally invasive diagnostic markers of CCx in the constitution of the organs.</div></div><div><h3>Conclusions</h3><div>These findings support the concept of CCx as a multi-organ syndrome with diverse metabolic alterations, providing insights into the pathophysiology and organ cross-talk of human CCx. This study pioneers spatial metabolomics for CCx, demonstrating the feasibility of distinguishing cachexia status at the organ level using serum.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156034"},"PeriodicalIF":10.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0026049524002622/pdfft?md5=402aa7309345c22a7c9b01315005ee42&pid=1-s2.0-S0026049524002622-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond glucose: The crucial role of redox signaling in β-cell metabolic adaptation","authors":"Blanka Holendová ,&nbsp;Barbora Šalovská ,&nbsp;Štěpánka Benáková ,&nbsp;Lydie Plecitá-Hlavatá","doi":"10.1016/j.metabol.2024.156027","DOIUrl":"10.1016/j.metabol.2024.156027","url":null,"abstract":"<div><h3>Objective</h3><div>Redox signaling mediated by reversible oxidative cysteine thiol modifications is crucial for driving cellular adaptation to dynamic environmental changes, maintaining homeostasis, and ensuring proper function. This is particularly critical in pancreatic β-cells, which are highly metabolically active and play a specialized role in whole organism glucose homeostasis. Glucose stimulation in β-cells triggers signals leading to insulin secretion, including changes in ATP/ADP ratio and intracellular calcium levels. Additionally, lipid metabolism and reactive oxygen species (ROS) signaling are essential for β-cell function and health.</div></div><div><h3>Methods</h3><div>We employed IodoTMT isobaric labeling combined with tandem mass spectrometry to elucidate redox signaling pathways in pancreatic β-cells.</div></div><div><h3>Results</h3><div>Glucose stimulation significantly increases ROS levels in β-cells, leading to targeted reversible oxidation of proteins involved in key metabolic pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, pyruvate metabolism, oxidative phosphorylation, protein processing in the endoplasmic reticulum (ER), and insulin secretion. Furthermore, the glucose-induced increase in reversible cysteine oxidation correlates with the presence of other post-translational modifications, including acetylation and phosphorylation.</div></div><div><h3>Conclusions</h3><div>Proper functioning of pancreatic β-cell metabolism relies on fine-tuned regulation, achieved through a sophisticated system of diverse post-translational modifications that modulate protein functions. Our findings demonstrate that glucose induces the production of ROS in pancreatic β-cells, leading to targeted reversible oxidative modifications of proteins. Furthermore, protein activity is modulated by acetylation and phosphorylation, highlighting the complexity of the regulatory mechanisms in β-cell function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156027"},"PeriodicalIF":10.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0026049524002543/pdfft?md5=285fe24b9032bafa308da0a90c761ad9&pid=1-s2.0-S0026049524002543-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of dietary modification in the prevention and management of metabolic dysfunction-associated fatty liver disease: An international multidisciplinary expert consensus","authors":"Xu-Fen Zeng ,&nbsp;Krista A. Varady ,&nbsp;Xiang-Dong Wang ,&nbsp;Giovanni Targher ,&nbsp;Christopher D. Byrne ,&nbsp;Reema Tayyem ,&nbsp;Giovanni Latella ,&nbsp;Ina Bergheim ,&nbsp;Rodrigo Valenzuela ,&nbsp;Jacob George ,&nbsp;Carolyn Newberry ,&nbsp;Ju-Sheng Zheng ,&nbsp;Elena S. George ,&nbsp;C. Wendy Spearman ,&nbsp;Meropi D. Kontogianni ,&nbsp;Danijela Ristic-Medic ,&nbsp;Wilza Arantes Ferreira Peres ,&nbsp;Gamze Yurtdaş Depboylu ,&nbsp;Wanshui Yang ,&nbsp;Xu Chen ,&nbsp;Ming-Hua Zheng","doi":"10.1016/j.metabol.2024.156028","DOIUrl":"10.1016/j.metabol.2024.156028","url":null,"abstract":"<div><p>Metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), has become the leading cause of chronic liver disease worldwide. Optimal dietary intervention strategies for MAFLD are not standardized. This study aimed to achieve consensus on prevention of MAFLD through dietary modification. A multidisciplinary panel of 55 international experts, including specialists in hepatology, gastroenterology, dietetics, endocrinology and other medical specialties from six continents collaborated in a Delphi-based consensus development process. The consensus statements covered aspects ranging from epidemiology to mechanisms, management, and dietary recommendations for MAFLD. The recommended dietary strategies emphasize adherence to a balanced diet with controlled energy intake and personalized nutritional interventions, such as calorie restriction, high-protein, or low-carbohydrate diets. Specific dietary advice encouraged increasing the consumption of whole grains, plant-based proteins, fish, seafood, low-fat or fat-free dairy products, liquid plant oils, and deeply colored fruits and vegetables. Concurrently, it advised reducing the intake of red and processed meats, saturated and trans fats, ultra-processed foods, added sugars, and alcohol. Additionally, maintaining the Mediterranean or DASH diet, minimizing sedentary behavior, and engaging in regular physical activity are recommended. These consensus statements lay the foundation for customized dietary guidelines and proposing avenues for further research on nutrition and MAFLD.</p></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156028"},"PeriodicalIF":10.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242936","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":"History and future of leptin: Discovery, regulation and signaling","authors":"Heike Münzberg,&nbsp;Steven B. Heymsfield,&nbsp;Hans-Rudolf Berthoud,&nbsp;Christopher D. Morrison","doi":"10.1016/j.metabol.2024.156026","DOIUrl":"10.1016/j.metabol.2024.156026","url":null,"abstract":"<div><p>The cloning of leptin 30 years ago in 1994 was an important milestone in obesity research. Prior to the discovery of leptin, obesity was stigmatized as a condition caused by lack of character and self-control. Mutations in either leptin or its receptor were the first single gene mutations found to cause severe obesity, and it is now recognized that obesity is caused mostly by a dysregulation of central neuronal circuits. Since the discovery of the leptin-deficient <em>obese</em> mouse (<em>ob/ob</em>) the cloning of leptin (<em>ob</em> aka <em>lep</em>) and leptin receptor (<em>db</em> aka <em>lepr</em>) genes, we have learned much about leptin and its action in the central nervous system. The first hope that leptin would cure obesity was quickly dampened because humans with obesity have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint to understand how neuronal circuits control energy homeostasis. Our expanding understanding of leptin function, interconnection of leptin signaling with other systems and impact on distinct physiological functions continues to guide and improve the development of safe and effective interventions to treat metabolic illnesses. This review highlights past concepts and current emerging concepts of the hormone leptin, leptin receptor signaling pathways and central targets to mediate distinct physiological functions.</p></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156026"},"PeriodicalIF":10.8,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154569","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}