Metabolism: clinical and experimental最新文献

{"title":"ZBED3 exacerbates hyperglycemia by promoting hepatic gluconeogenesis through CREB signaling","authors":"Yuan-yuan Luo ,&nbsp;Chang-shun Ruan ,&nbsp;Fu-zhen Zhao ,&nbsp;Min Yang ,&nbsp;Wei Cui ,&nbsp;Xi Cheng ,&nbsp;Xiao-he Luo ,&nbsp;Xian-xiang Zhang ,&nbsp;Cheng Zhang","doi":"10.1016/j.metabol.2024.156049","DOIUrl":"10.1016/j.metabol.2024.156049","url":null,"abstract":"<div><h3>Background</h3><div>Elevated hepatic glucose production (HGP) is a prominent manifestation of impaired hepatic glucose metabolism in individuals with diabetes. Increased hepatic gluconeogenesis plays a pivotal role in the dysregulation of hepatic glucose metabolism and contributes significantly to fasting hyperglycemia in diabetes. Previous studies have identified zinc-finger BED domain-containing 3 (<em>ZBED3</em>) as a risk gene for type 2 diabetes (T2DM), and its single nucleotide polymorphism (SNPs) is closely associated with the fasting blood glucose level, suggesting a potential correlation between ZBED3 and the onset of diabetes. This study primarily explores the effect of ZBED3 on hepatic gluconeogenesis and analyzes the relevant signaling pathways that regulate hepatic gluconeogenesis.</div></div><div><h3>Methods</h3><div>The expression level of ZBED3 was assessed in the liver of insulin-resistant (IR)-related disease. RNA-seq and bioinformatics analyses were employed to examine the ZBED3-related pathway that modulated HGP. To investigate the role of ZBED3 in hepatic gluconeogenesis, the expression of ZBED3 was manipulated by upregulation or silencing using adeno-associated virus (AAV) in mouse primary hepatocytes (MPHs) and HHL-5 cells. In vivo, hepatocyte-specific ZBED3 knockout mice were generated. Moreover, AAV8 was employed to achieve hepatocyte-specific overexpression and knockdown of ZBED3 in C57BL/6 and db/db mice. Immunoprecipitation and mass spectrometry (IP-MS) analyses were employed to identify proteins that interacted with ZBED3. Co-immunoprecipitation (co-IP), glutathione S-transferase (GST) - pulldown, and dual-luciferase reporter assays were conducted to further elucidate the underlying mechanism of ZBED3 in regulating hepatic gluconeogenesis.</div></div><div><h3>Results</h3><div>The expression of ZBED3 in the liver of IR-related disease models was found to be increased. Under the stimulation of glucagon, ZBED3 promoted the expression of hepatic gluconeogenesis-related genes <em>PGC1A</em>, <em>PCK1</em>, <em>G6PC</em>, thereby increasing HGP. Consistently, the rate of hepatic gluconeogenesis was found to be elevated in mice with hepatocyte-specific overexpression of ZBED3 and decreased in those with ZBED3 knockout. Additionally, the knockdown of ZBED3 in the liver of db/db mice resulted in a reduction in hepatic gluconeogenesis. Moreover, the study revealed that ZBED3 facilitated the nuclear translocation of protein arginine methyltransferases 5 (PRMT5) to influence the regulation of PRMT5-mediated symmetrical dimethylation of arginine (s-DMA) of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), which in turn affects the phosphorylation of CREB and ultimately promotes HGP.</div></div><div><h3>Conclusions</h3><div>This study indicates that ZBED3 promotes hepatic gluconeogenesis and serves as a critical regulator of the progression of diabetes.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156049"},"PeriodicalIF":10.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504212","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":"Impaired unsaturated fatty acid elongation alters mitochondrial function and accelerates metabolic dysfunction-associated steatohepatitis progression","authors":"Adrien Vouilloz ,&nbsp;Thibaut Bourgeois ,&nbsp;Marc Diedisheim ,&nbsp;Thomas Pilot ,&nbsp;Antoine Jalil ,&nbsp;Naig Le Guern ,&nbsp;Victoria Bergas ,&nbsp;Noéline Rohmer ,&nbsp;Florence Castelli ,&nbsp;Damien Leleu ,&nbsp;Alexis Varin ,&nbsp;Jean-Paul Pais de Barros ,&nbsp;Pascal Degrace ,&nbsp;Mickael Rialland ,&nbsp;Camille Blériot ,&nbsp;Nicolas Venteclef ,&nbsp;Charles Thomas ,&nbsp;David Masson","doi":"10.1016/j.metabol.2024.156051","DOIUrl":"10.1016/j.metabol.2024.156051","url":null,"abstract":"<div><h3>Background and aims</h3><div>Although qualitative and quantitative alterations in liver Polyunsaturated Fatty Acids (PUFAs) are observed in MASH in humans, a causal relationship of PUFAs biosynthetic pathways is yet to be clarified. ELOVL5, an essential enzyme in PUFA elongation regulates hepatic triglyceride metabolism. Nonetheless, the long-term consequences of elongase disruption, particularly in murine models of MASH, have not been evaluated.</div></div><div><h3>Approach &amp; results</h3><div>In humans, transcriptomic data indicated that PUFAs biosynthesis enzymes and notably ELOVL5 were induced during MASH progression. Moreover, gene module association determination revealed that ELOVL5 expression was associated with mitochondrial function in both humans and mice. WT and <em>Elovl5</em>-deficient mice were fed a high-fat, high-sucrose (HF/HS) diet for four months. <em>Elovl5</em> deficiency led to limited systemic metabolic alterations but significant hepatic phenotype was observed in <em>Elovl5</em>−/− mice after the HF/HS diet, including hepatomegaly, pronounced macrovesicular and microvesicular steatosis, hepatocyte ballooning, immune cell infiltration, and fibrosis. Lipid analysis confirmed hepatic triglyceride accumulation and a reshaping of FA profile. Transcriptomic analysis indicated significant upregulation of genes involved in immune cell recruitment and fibrosis, and downregulation of genes involved in oxidative phosphorylation in <em>Elovl5</em>−/− mice. Alterations of FA oxidation and energy metabolism were confirmed by non-targeted metabolomic approach. Analysis of mitochondrial function in <em>Elovl5</em>−/− mice showed morphological alterations, qualitative cardiolipin changes with an enrichment in species containing shorter unsaturated FAs, and decreased activity of I and III respiratory chain complexes.</div></div><div><h3>Conclusion</h3><div>Enhanced susceptibility to diet-induced MASH and fibrosis in <em>Elovl5</em>−/− mice is intricately associated with disruptions in mitochondrial homeostasis, stemming from a profound reshaping of mitochondrial lipids, notably cardiolipins.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156051"},"PeriodicalIF":10.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504211","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":"NPRC promotes hepatic steatosis via USP30-mediated deubiquitination of C/EBPβ","authors":"Feng Jiang,&nbsp;Xinmiao Li,&nbsp;Lifan Lin,&nbsp;Mengyuan Li,&nbsp;Jianjian Zheng","doi":"10.1016/j.metabol.2024.156050","DOIUrl":"10.1016/j.metabol.2024.156050","url":null,"abstract":"<div><h3>Background and aims</h3><div>Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition characterised by dysregulated lipid metabolism. The role of Natriuretic Peptide Receptor C (NPRC), a receptor responsible for clearing natriuretic peptides, in MAFLD remains elusive. Therefore, the aim of the present study was to elucidate the role of NPRC in MAFLD progression.</div></div><div><h3>Approach and results</h3><div>This study demonstrated that NPRC enhanced lipid metabolism reprogramming and accelerated MAFLD progression. Mechanistic investigations, including proteomic and ubiquitination analyses, revealed that elevated NPRC levels stabilized the C/EBPβ protein, leading to excessive lipid accumulation. The DNA-binding domain (DBD) of C/EBPβ interacted with the deubiquitinase USP30, a key regulator that inhibited K149-specific K48-linked polyubiquitination of C/EBPβ. Importantly, the ANPR region of NPRC bound to USP30, facilitating the deubiquitination of C/EBPβ. Furthermore, virtual screening identified punicalin, a natural compound, as a potential inhibitor of NPRC expression, which may reduce hepatic lipid accumulation, inflammation and fibrosis.</div></div><div><h3>Conclusions</h3><div>Our findings indicate that NPRC recruits USP30 to mediate the deubiquitination of C/EBPβ, driving lipid metabolism reprogramming. Targeting NPRC could represent a promising therapeutic approach for MAFLD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156050"},"PeriodicalIF":10.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470017","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 “Increased adrenal steroidogenesis and suppressed corticosteroid responsiveness in critical COVID-19” [Metabolism volume 160 (2024) 155980]","authors":"Tian-Zi Wen ,&nbsp;Tian-Ran Li ,&nbsp;Xin-Yu Chen ,&nbsp;He-Yuan Chen ,&nbsp;Shuai Wang ,&nbsp;Wen-Juan Fu ,&nbsp;Shi-Qi Xiao ,&nbsp;Jie Luo ,&nbsp;Jia-Feng Huang ,&nbsp;Rui Tang ,&nbsp;Zhi-Cheng He ,&nbsp;Tao Luo ,&nbsp;Hong-Liang Zhao ,&nbsp;Cong Chen ,&nbsp;Jing-Ya Miao ,&nbsp;Qin Niu ,&nbsp;Yan Wang ,&nbsp;Xiu-Wu Bian ,&nbsp;Xiao-Hong Yao","doi":"10.1016/j.metabol.2024.156033","DOIUrl":"10.1016/j.metabol.2024.156033","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156033"},"PeriodicalIF":10.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378097","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":"Expanding diagnostic and therapeutic horizons for MASH: Comparison of the latest and conventional therapeutic approaches","authors":"Georgia Anastasiou ,&nbsp;Konstantinos Stefanakis ,&nbsp;Michael A. Hill ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2024.156044","DOIUrl":"10.1016/j.metabol.2024.156044","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"161 ","pages":"Article 156044"},"PeriodicalIF":10.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372340","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":"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}