Metabolism: clinical and experimental最新文献

{"title":"Disruption of branched-chain amino acid homeostasis promotes the progression of DKD via enhancing inflammation and fibrosis-associated epithelial-mesenchymal transition","authors":"Xiaoqing Deng ,&nbsp;Chao Tang ,&nbsp;Ting Fang ,&nbsp;Ting Li ,&nbsp;Xiaoyu Li ,&nbsp;Yajin Liu ,&nbsp;Xuejiao Zhang ,&nbsp;Bei Sun ,&nbsp;Haipeng Sun ,&nbsp;Liming Chen","doi":"10.1016/j.metabol.2024.156037","DOIUrl":"10.1016/j.metabol.2024.156037","url":null,"abstract":"<div><h3>Background and aims</h3><div>The disrupted homeostasis of branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) has been strongly correlated with diabetes with a potential causal role. However, the relationship between BCAAs and diabetic kidney disease (DKD) remains to be established. Here, we show that the elevated BCAAs from BCAAs homeostatic disruption promote DKD progression unexpectedly as an independent risk factor.</div></div><div><h3>Methods and results</h3><div>Similar to other tissues, the suppressed BCAAs catabolic gene expression and elevated BCAAs abundance were detected in the kidneys of type 2 diabetic mice and individuals with DKD. Genetic and nutritional studies demonstrated that the elevated BCAAs from systemic disruption of BCAAs homeostasis promoted the progression of DKD. Of note, the elevated BCAAs promoted DKD progression without exacerbating diabetes in the animal models of type 2 DKD. Mechanistic studies demonstrated that the elevated BCAAs promoted fibrosis-associated epithelial-mesenchymal transition (EMT) by enhancing the activation of proinflammatory macrophages through mTOR signaling. Furthermore, pharmacological enhancement of systemic BCAAs catabolism using small molecule inhibitor attenuated type 2 DKD. Finally, the elevated BCAAs also promoted DKD progression in type 1 diabetic mice without exacerbating diabetes.</div></div><div><h3>Conclusion</h3><div>BCAA homeostatic disruption serves as an independent risk factor for DKD and restoring BCAA homeostasis pharmacologically or dietarily represents a promising therapeutic strategy to ameliorate the progression of DKD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"162 ","pages":"Article 156037"},"PeriodicalIF":10.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350220","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":"Subphenotypes of body composition and their association with cardiometabolic risk – Magnetic resonance imaging in a population-based sample","authors":"Elena Grune ,&nbsp;Johanna Nattenmüller ,&nbsp;Lena S. Kiefer ,&nbsp;Jürgen Machann ,&nbsp;Annette Peters ,&nbsp;Fabian Bamberg ,&nbsp;Christopher L. Schlett ,&nbsp;Susanne Rospleszcz","doi":"10.1016/j.metabol.2024.156130","DOIUrl":"10.1016/j.metabol.2024.156130","url":null,"abstract":"<div><h3>Background</h3><div>For characterizing health states, fat distribution is more informative than overall body size. We used population-based whole-body magnetic resonance imaging (MRI) to identify distinct body composition subphenotypes and characterize associations with cardiovascular disease (CVD) risk.</div></div><div><h3>Methods</h3><div>Bone marrow, visceral, subcutaneous, cardiac, renal, hepatic, skeletal muscle and pancreatic adipose tissue were measured by MRI in <em>n</em> = 299 individuals from the population-based KORA cohort. Body composition subphenotypes were identified by data-driven k-means clustering. CVD risk was calculated by established scores.</div></div><div><h3>Results</h3><div>We identified five body composition subphenotypes, which differed substantially in CVD risk factor distribution and CVD risk. Compared to reference subphenotype I with favorable risk profile, two high-risk phenotypes, III&amp;V, had a 3.8-fold increased CVD risk. High-risk subphenotype III had increased bone marrow and skeletal muscle fat (26.3 % vs 11.4 % in subphenotype I), indicating ageing effects, whereas subphenotype V showed overall high fat contents, and particularly elevated pancreatic fat (25.0 % vs 3.7 % in subphenotype I), indicating metabolic impairment. Subphenotype II had a 2.7-fold increased CVD risk, and an unfavorable fat distribution, probably smoking-related, while BMI was only slightly elevated. Subphenotype IV had a 2.8-fold increased CVD risk with comparably young individuals, who showed high blood pressure and hepatic fat (17.7 % vs 3.0 % in subphenotype I).</div></div><div><h3>Conclusions</h3><div>Whole-body MRI can identify distinct body composition subphenotypes associated with different degrees of cardiometabolic risk. Body composition profiling may enable a more comprehensive risk assessment than individual fat compartments, with potential benefits for individualized prevention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156130"},"PeriodicalIF":10.8,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914456","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":"PPARα-ERRα crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression","authors":"Milton Boaheng Antwi ,&nbsp;Sander Lefere ,&nbsp;Dorien Clarisse ,&nbsp;Lisa Koorneef ,&nbsp;Anneleen Heldens ,&nbsp;Louis Onghena ,&nbsp;Kylian Decroix ,&nbsp;Daria Fijalkowska ,&nbsp;Jonathan Thommis ,&nbsp;Madeleine Hellemans ,&nbsp;Anne Hoorens ,&nbsp;Anja Geerts ,&nbsp;Lindsey Devisscher ,&nbsp;Karolien De Bosscher","doi":"10.1016/j.metabol.2024.156128","DOIUrl":"10.1016/j.metabol.2024.156128","url":null,"abstract":"<div><h3>Background and aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent liver disease worldwide, continues to rise. More effective therapeutic strategies are urgently needed. We investigated how targeting two key nuclear receptors involved in hepatic energy metabolism, peroxisome proliferator-activated receptor alpha (PPARα) and estrogen-related receptor alpha (ERRα), ameliorates MASLD.</div></div><div><h3>Methods</h3><div>The PPARα agonist pemafibrate and/or ERRα inverse agonist C29 were administered in a short- and long-term Western diet plus fructose model, and a diabetic-background streptozotocin-Western diet model (STZ-WD). Liver and adipose tissue morphology, histological samples, serum metabolites, RNA and protein levels were analysed and scanning electron microscopy was performed. In addition, we performed cell-based assays and immunohistochemistry and immunofluorescence stainings with light and super-resolution confocal microscopy of healthy, MASLD and MASH human livers.</div></div><div><h3>Results</h3><div>The ligand combinations' efficacy was highlighted by reduced liver steatosis across all mouse models, alongside improvements in body weight, inflammation, and fibrosis in both long-term models. Additionally, tumour formation was prevented in the STZ-WD mice model. Cell-based assays demonstrated that ERRα inhibits PPARα's activity, explaining why ERRα blockage improves inflammatory and lipid metabolism gene profiles and enhances lipid-lowering effects. Complementary RNA sequencing and shotgun proteomics, combined with enrichment analysis, jointly identified downregulated serum amyloid A1/A2 as essential components underlying the combination treatment's effectiveness. MASLD/MASH patient livers showed reduced PPARα and increased ERRα levels supporting disrupted NR crosstalk in the hepatocyte nucleus.</div></div><div><h3>Conclusion</h3><div>Our study supports that dual nuclear receptor targeting, which simultaneously increases PPARα and diminishes ERRα activity, may represent a viable novel strategy against MASLD.</div></div><div><h3>Impact and implications</h3><div>Our research introduces a novel therapeutic strategy against MASLD by simultaneously increasing PPARα activity while diminishing ERRα activity. With PPARα agonists already tested in phase III clinical trials, ERRα ligands/modulators need further (clinical) development to make our findings applicable to both MASLD patients and physicians.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156128"},"PeriodicalIF":10.8,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915469","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":"CD36-mediated uptake of oxidized LDL induces double-negative regulatory T cell ferroptosis in metabolic dysfunction-associated steatotic liver disease","authors":"Yunxiong Wei ,&nbsp;Yuan Jiang ,&nbsp;Jingjing Zhu ,&nbsp;Zihan Zhang ,&nbsp;Mengyi Li ,&nbsp;Shimeng Zheng ,&nbsp;Xiyu Wang ,&nbsp;Jie Sun ,&nbsp;Changying Li ,&nbsp;Wen Shi ,&nbsp;Songlin Wang ,&nbsp;Xinjuan Liu ,&nbsp;Minjie Lin ,&nbsp;Zhongtao Zhang ,&nbsp;Dong Zhang ,&nbsp;Guangyong Sun","doi":"10.1016/j.metabol.2024.156127","DOIUrl":"10.1016/j.metabol.2024.156127","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic alterations have been shown to instigate liver inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying mechanism is not fully elucidated. During MASLD progression, intrahepatic CD3⁺TCRαβ⁺CD4⁻CD8⁻ double negative T regulatory cells (DNT) decrease cell survival and immunosuppressive function, leading to aggravated liver inflammation. In this study, we aim to reveal the underlying mechanisms that cause changes in DNT during MASLD progression.</div></div><div><h3>Methods</h3><div>The correlation of serum oxidized low-density lipoprotein (oxLDL) levels and DNT from patients with MASLD and MASLD mouse models were evaluated. The mechanisms of oxLDL affecting DNT survival and function were explored through transcriptome sequencing analysis, flow cytometry, and CUT &amp; TAG experiments.</div></div><div><h3>Results</h3><div>Serum oxLDL levels are negative correlated with survival and functional molecule expression of circulating DNT in patients with MASLD and intrahepatic DNT in MASLD mouse models. Mechanistically, oxLDL increases DNT CD36 expression through the NF-κB pathway, leading to enhanced uptake of oxLDL and subsequent occurrence of ferroptosis and functional impairment. oxLDL enhances ferroptosis in DNT by upregulating acyl-CoA synthetase long chain family member 4 expression. By transferring CD36^−/− DNT into MASLD mice, we observe a significant reduction in ferroptosis and improved immune regulation in CD36^−/− DNT compared to wild type DNT. This improvement in DNT results in a notable enhancement of therapeutic efficacy against MASLD.</div></div><div><h3>Conclusion</h3><div>oxLDL induces a decline in the survival and immune regulatory function of DNT, subsequently weakening their role in maintaining liver immune homeostasis in MASLD. Specific targeting of CD36 to prevent ferroptosis in DNT may provide a novel therapeutic approach for the treatment of MASLD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156127"},"PeriodicalIF":10.8,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915465","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":"Serum miR-365b-5p/miR-222-5p as a potential diagnostic biomarker for long-term weight loss in patients with morbid obesity after bariatric surgery","authors":"Virginia Mela ,&nbsp;Flores Martín-Reyes ,&nbsp;Wilfredo Oliva-Olivera ,&nbsp;Antonio Cantarero-Cuenca ,&nbsp;Ana Sánchez-García ,&nbsp;Raquel Sancho-Marín ,&nbsp;Andrés González-Jimenez ,&nbsp;Mónica Tomé ,&nbsp;Francisco J. Moreno-Ruiz ,&nbsp;Rocío Soler-Humanes ,&nbsp;José L. Fernández-Serrano ,&nbsp;Pilar Sanchez-Gallegos ,&nbsp;Jose M Martínez-Moreno ,&nbsp;Francisco J. Tinahones ,&nbsp;Eduardo García-Fuentes ,&nbsp;Lourdes Garrido-Sánchez","doi":"10.1016/j.metabol.2024.156129","DOIUrl":"10.1016/j.metabol.2024.156129","url":null,"abstract":"<div><h3>Background</h3><div>The successful weight loss following bariatric surgery is not achieved in all patients with morbid obesity (MO). This study aims to determine whether a serum miRNA profile can predict this outcome.</div></div><div><h3>Design</h3><div>Thirty-three patients with MO were classified in “Good Responders” (GR, percentage of excess weight loss (%EWL) ≥ 50 %) or “Non-Responders” (NR, %EWL &lt; 50 %) according to the %EWL 5–8 year following bariatric surgery. Baseline serum miRNA sequencing was performed to find predictor biomarkers and human adipocyte culture were performed to determine their effect.</div></div><div><h3>Results</h3><div>Fifty-six differentially expressed miRNAs were found between GR and NR. Logistic regression models showed two miRNAs, hsa-miR-365b-5p (upregulated in GR) and hsa-miR-222-5p (upregulated in NR) associated to %EWL. Receiver operating characteristic curves showed that the combination of these miRNAs was the best serum miRNAs profile that distinguished between GR and NR. The experimentally validated target genes of these miRNAs were involved in processes related to the response to stress, cell cycle, transduction, and development and proliferation processes. The in vitro expression of six genes involved in adipogenesis and adipocyte differentiation (STAT3, ILR7, PARP1, SOD2, FGF2 and TMEM18) was downregulated in lipogenic and upregulated in lipolitic conditions in human adipocytes incubated with the combination of a hsa-miR-365b-5p mimic and a hsa-miR-222-5p inhibitor.</div></div><div><h3>Conclusions</h3><div>Baseline serum hsa-miR-365b-5p and hsa-miR-222-5p were able to predict %EWL 5–8 years following bariatric surgery. The combination of these potential predictive biomarkers was involved in regulating the expression levels of genes associated with obesity. However, these effects could be modified depending of other stimuli.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156129"},"PeriodicalIF":10.8,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914455","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":"Hypothalamic SIRT1-mediated regulation of the hormonal trigger of ovulation and its repression in energy deficit","authors":"María J. Vazquez ,&nbsp;Silvia Daza-Dueñas ,&nbsp;Inmaculada Velasco ,&nbsp;Francisco Ruiz-Pino ,&nbsp;María J. Sanchez-Tapia ,&nbsp;María Manfredi-Lozano ,&nbsp;Carmen Torres-Granados ,&nbsp;Alexia Barroso ,&nbsp;Juan Roa ,&nbsp;Miguel A. Sánchez-Garrido ,&nbsp;Carlos Dieguez ,&nbsp;Alejandro Lomniczi ,&nbsp;Rubén Nogueiras ,&nbsp;Manuel Tena-Sempere","doi":"10.1016/j.metabol.2024.156125","DOIUrl":"10.1016/j.metabol.2024.156125","url":null,"abstract":"<div><div>Female reproduction is highly sensitive to body energy stores; persistent energy deficit, as seen in anorexia or strenuous exercise, is known to suppress ovulation via ill-defined mechanisms. We report herein that hypothalamic SIRT1, a key component of the epigenetic machinery that links nutritional status and puberty onset via modulation of <em>Kiss1</em>, plays a critical role in the control of the preovulatory surge of gonadotropins, i.e., the hormonal trigger of ovulation, and its repression by conditions of energy deficit. Kiss1 neurons in the preoptic area, with proven roles in the control of ovulation, express <em>Sirt1</em> mRNA. Reciprocal changes in hypothalamic SIRT1 content and <em>Kiss1</em> expression were observed during the pre-ovulatory phase in adult female rats. Central activation of SIRT1 reduced <em>Kiss1</em> expression in the rostral hypothalamus, and attenuated the preovulatory surge, while blockade of central SIRT1 augmented it. Conditions of energy deficit enhanced hypothalamic SIRT1 activity and caused suppression of the pre-ovulatory surge and ovulation, which could be rescued by central SIRT1 inhibition. In turn, virogenetic induction of SIRT1 in rostral hypothalamic Kiss1 neurons in adult female mice disrupted ovarian cyclicity and suppressed reproductive indices, despite preserved body weight. Our data document the prominent function of hypothalamic SIRT1 as a key modulator of Kiss1 neurons and the hormonal surge driving ovulation in adulthood, with a major role in its inhibition during conditions of energy insufficiency.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156125"},"PeriodicalIF":10.8,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910043","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":"Identifying proteins and pathways associated with multimorbidity in 53,026 adults","authors":"Yi-Lin Chen ,&nbsp;Jia You ,&nbsp;Yu Guo ,&nbsp;Yi Zhang ,&nbsp;Bing-Ran Yao ,&nbsp;Ji-Jing Wang ,&nbsp;Shi-Dong Chen ,&nbsp;Yi-Jun Ge ,&nbsp;Liu Yang ,&nbsp;Xin-Rui Wu ,&nbsp;Bang-Sheng Wu ,&nbsp;Ya-Ru Zhang ,&nbsp;Qiang Dong ,&nbsp;Jian-Feng Feng ,&nbsp;Mei Tian ,&nbsp;Wei Cheng ,&nbsp;Jin-Tai Yu","doi":"10.1016/j.metabol.2024.156126","DOIUrl":"10.1016/j.metabol.2024.156126","url":null,"abstract":"<div><h3>Background and aims</h3><div>Multimorbidity, the coexistence of multiple chronic diseases, is a rapidly expanding global health challenge, carrying profound implications for patients, caregivers, healthcare systems, and society. Investigating the determinants and drivers underlying multiple chronic diseases is a priority for disease management and prevention.</div></div><div><h3>Method</h3><div>This prospective cohort study analyzed data from the 53,026 participants in the UK Biobank from baseline (2006 to 2010) across 13.3 years of follow-up. Using Cox proportional hazards regression model, we characterized shared and unique associations across 38 incident outcomes (31 chronic diseases, 6 system mortality and all-cause mortality). Furthermore, ordinal regression models were used to assess the association between protein levels and multimorbidity (0–1, 2, 3–4, or ≥ 5 chronic diseases). Functional and tissue enrichment analysis were employed for multimorbidity-associated proteins. The upstream regulators of above proteins were identified.</div></div><div><h3>Results</h3><div>We demonstrated 972 (33.3 %) proteins were shared across at least two incident chronic diseases after Bonferroni correction (P &lt; 3.42 × 10⁻⁷, 93.3 % of those had consistent effects directions), while 345 (11.8 %) proteins were uniquely linked to a single chronic disease. Remarkably, GDF15, PLAUR, WFDC2 and AREG were positively associated with 20–24 incident chronic diseases (hazards ratios: 1.21–3.77) and showed strong associations with multimorbidity (odds ratios: 1.33–1.89). We further identified that protein levels are explained by common risk factors, especially renal function, liver function, inflammation, and obesity, providing potential intervention targets. Pathway analysis has underscored the pivotal role of the immune response, with the top three transcription factors associated with proteomics being NFKB1, JUN and RELA.</div></div><div><h3>Conclusions</h3><div>Our results enhance the understanding of the biological basis underlying multimorbidity, offering biomarkers for disease identification and novel targets for therapeutic intervention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156126"},"PeriodicalIF":10.8,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910044","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":"A3AR antagonism mitigates metabolic dysfunction-associated steatotic liver disease by exploiting monocyte-derived Kupffer cell necroptosis and inflammation resolution","authors":"Jeong-Su Park ,&nbsp;Yuan-Qiang Ma ,&nbsp;Feng Wang ,&nbsp;Hwan Ma ,&nbsp;Guoyan Sui ,&nbsp;Nodir Rustamov ,&nbsp;Minyeong Han ,&nbsp;Yejin Son ,&nbsp;Chun-Woong Park ,&nbsp;Sang-Bae Han ,&nbsp;Jin Tae Hong ,&nbsp;Lak Shin Jeong ,&nbsp;Jin Lee ,&nbsp;Yoon Seok Roh","doi":"10.1016/j.metabol.2024.156114","DOIUrl":"10.1016/j.metabol.2024.156114","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Metabolic dysfunction-associated steatotic liver (MASLD) progression is driven by chronic inflammation and fibrosis, largely influenced by Kupffer cell (KC) dynamics, particularly replenishment of pro-inflammatory monocyte-derived KCs (MoKCs) due to increased death of embryo-derived KCs. Adenosine A3 receptor (A3AR) plays a key role in regulating metabolism and immune responses, making it a promising therapeutic target. This study aimed to investigate the impact of selective A3AR antagonism for regulation of replenished MoKCs, thereby improving MASLD.</div></div><div><h3>Approach &amp; results</h3><div>A3AR expression was significantly elevated in KCs from both patients with MASLD and fast-food diet (FFD)-fed mice. A3AR knockout (KO) mice displayed marked improvements in hepatic inflammation and fibrosis along with a reduction in CLEC4F-positive KCs. The spatial transcriptomics of these KCs revealed disrupted mitochondrial integrity, increased oxidative stress, and enhanced cell death due to A3AR deletion. Similarly, in vivo FM101 treatment, a highly potent and selective antagonist of A3AR with a truncated 4′-thioadenosine structure, mitigated FFD-induced MASLD in mice. Mechanistically, FM101 induces β-arrestin2-mediated A3AR degradation, leading to mitochondrial dysfunction-mediated necroptosis in KCs. Consistently, A3AR was highly expressed in monocyte-derived macrophages in MASLD patients, with strong correlations with macrophage activation and monocyte chemoattractant gene sets. Thus, FM101 induced necroptosis in pro-inflammatory MoKCs, facilitating anti-inflammatory effects.</div></div><div><h3>Conclusions</h3><div>This study demonstrated that inhibiting A3AR via FM101 or genetic deletion alleviates MASLD by inducing mitochondrial dysfunction and subsequent necroptosis in MoKCs, establishing FM101 as a promising therapeutic strategy for MASLD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156114"},"PeriodicalIF":10.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895816","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":"Retraction notice “to Loss of mitochondrial adaptation associates with deterioration of mitochondrial turnover and structure in metabolic dysfunction-associated steatotic liver disease” [Metabolism 151 (2024) 155762]","authors":"Theresia Sarabhai ,&nbsp;Sabine Kahl ,&nbsp;Sofiya Gancheva ,&nbsp;Lucia Mastrototaro ,&nbsp;Bedair Dewidar ,&nbsp;Dominik Pesta ,&nbsp;Jacqueline M. Ratter-Rieck ,&nbsp;Pavel Bobrov ,&nbsp;Kay Jeruschke ,&nbsp;Irene Esposito ,&nbsp;Matthias Schlensak ,&nbsp;Michael Roden","doi":"10.1016/j.metabol.2024.156107","DOIUrl":"10.1016/j.metabol.2024.156107","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156107"},"PeriodicalIF":10.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895793","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":"Effect of glucagon-like peptide-1 receptor agonists and co-agonists on body composition: Systematic review and network meta-analysis","authors":"Paschalis Karakasis ,&nbsp;Dimitrios Patoulias ,&nbsp;Nikolaos Fragakis ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2024.156113","DOIUrl":"10.1016/j.metabol.2024.156113","url":null,"abstract":"<div><h3>Background and aims</h3><div>While glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively reduce body weight, their impact on lean mass remains uncertain. This meta-analysis evaluated the effects of GLP-1RAs and GLP-1/GIP receptor dual agonists (GLP-1/GIP-RAs) on body composition, focusing on total weight, fat mass, and lean mass in adults with diabetes and/or overweight/obesity.</div></div><div><h3>Methods</h3><div>A systematic search of Medline, Embase, and the Cochrane Library was conducted through November 12, 2024. Data were analyzed using random-effects pairwise and network meta-analyses to compare interventions with placebo or active comparators.</div></div><div><h3>Results</h3><div>Twenty-two randomized controlled trials (2258 participants) were included. GLP-1RAs significantly reduced total body weight (MD -3.55 kg, 95 %-CI [−4.81, −2.29]), fat mass (MD -2.95 kg, 95 %-CI [−4.11, −1.79]), and lean mass (MD -0.86 kg, 95 %-CI [−1.30, −0.42]), with lean mass loss comprising approximately 25 % of the total weight loss. However, the relative lean mass, defined as percentage change from baseline, was unaffected. Liraglutide, at 3.0 mg weekly or 1.8 mg daily, was the only GLP-1RA to achieve significant weight reduction without significantly reducing lean mass. Tirzepatide (15 mg weekly) and semaglutide (2.4 mg weekly) were the most effective for weight and fat mass reduction but were among the least effective in preserving lean mass.</div></div><div><h3>Conclusions</h3><div>Potent GLP-1 RAs, such as tirzepatide and semaglutide, demonstrate greater overall weight loss but are associated with a significant reduction in lean mass.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"164 ","pages":"Article 156113"},"PeriodicalIF":10.8,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886041","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}