Metabolism: clinical and experimental最新文献

{"title":"WWP1–SHARP1–C/EBPβ positive feedback loop modulates development of metabolic dysfunction–associated steatotic liver disease","authors":"Hao Chen ,&nbsp;Yuanxun Gong ,&nbsp;Fei Wu ,&nbsp;Man Wu ,&nbsp;Shu Li ,&nbsp;Bofeng Chen ,&nbsp;Jie Wang ,&nbsp;Min Qiu ,&nbsp;Ying Xu ,&nbsp;Wei Zhao ,&nbsp;Tianxing Chen","doi":"10.1016/j.metabol.2025.156271","DOIUrl":"10.1016/j.metabol.2025.156271","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Metabolic dysfunction–associated steatotic liver disease (MASLD) is a significant global health threat. The molecular mechanisms underlying regulation of MASLD remain largely unknown. This study aimed to investigate the role of the WW domain–containing ubiquitin E3 ligase 1 (WWP1)–enhancer–of–split and hairy–related protein 1 (SHARP1)–C/EBPβ signal loop in MASLD.</div></div><div><h3>Methods</h3><div><em>In vivo</em> and <em>in vitro</em> models of MASLD were established applying high–fat diet–fed (HFD) mice and free fatty acid (FFA)–treated hepatocytes. The relationships among SHARP1, WWP1, and C/EBPβ were examined using bioinformatics, immunoprecipitation, immunofluorescence, luciferase assays, chromatin immunoprecipitation. MASLD progression was evaluated based on food intake, energy expenditure, insulin resistance, hepatic steatosis, inflammation and white fat growth.</div></div><div><h3>Results</h3><div>SHARP1 were significantly reduced in the MASLD livers of mouse and human and in FA–treated hepatocytes. Hepatocyte–specific SHARP1 overexpression significantly inhibited MASLD development in HFD–fed mice. Wild–type SHARP1, but not deficient SHARP1 (SHARP1–K/R and SHARP1–P/A), was ubiquitinated and degraded by the E3 ligase WWP1. Wild–type SHARP1 was not ubiquitinated when WWP1 was deficient (WWP1–C886A, WWP1–C890A, WWP1–ΔWW3). Deficient SHARP1 exhibited better inhibitory activity against MASLD than the wild–type SHARP1. WWP1 overexpression reversed the suppression of MASLD induced by wild–type SHARP1 but did not affect that induced by deficient SHARP1. Deficient WWP1 did not inhibit the wild–type SHARP1–induced MASLD amelioration. Furthermore, in FA–treated hepatocytes, the interaction between SHARP1 and C/EBPβ weakened, resulting in more C/EBPβ binding to the <em>Wwp1</em> promoter and subsequent WWP1 upregulation. SHARP1 overexpression or WWP1 interference partially blocked the effects of C/EBPβ on MASLD. Hesperidin was identified as a novel WWP1 inhibitor, and it significantly blocked WWP1 overexpression–induced MASLD progression.</div></div><div><h3>Conclusion</h3><div>The WWP1–SHARP1–C/EBPβ signal loop accelerates MASLD progression. This study provides novel insights into novel biomarkers and treatment approaches for MASLD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156271"},"PeriodicalIF":10.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877254","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":"Fatty acid metabolism: The crossroads in intestinal homeostasis and tumor","authors":"Yao Lu ,&nbsp;Lining Chen ,&nbsp;Yingying Lin ,&nbsp;Yafei Zhang ,&nbsp;Yuqi Wang ,&nbsp;Weiru Yu ,&nbsp;Fazheng Ren ,&nbsp;Huiyuan Guo","doi":"10.1016/j.metabol.2025.156273","DOIUrl":"10.1016/j.metabol.2025.156273","url":null,"abstract":"<div><div>Fatty acids (FAs) have various functions on cell regulation considering their abundant types and metabolic pathways. In addition, the relation between FA and other nutritional metabolism makes their functions more complex. As the first place for diet-derived FA metabolism, intestine is significantly influenced despite lack of clear conclusions due to the inconsistent findings. In this review, we discuss the regulation of fatty acid metabolism on the fate of intestinal stem cells in homeostasis and disorders, and also focus on the intestinal tumor development and treatment from the aspect of gut microbiota-epithelium-immune interaction. We summarize that the balances between FA oxidation and glycolysis, between oxidative phosphorylation and ketogenesis, between catabolism and anabolism, and the specific roles of individual FA types determine the diverse effects of intestinal FA metabolism in different cases. We hope this will inspire further dissection and suggest precise dietary/metabolic intervention for different demands related to intestinal health.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156273"},"PeriodicalIF":10.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874063","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 oxidation in non-exercising healthy adults under varying dietary conditions: Physiological determinants, effects on fuel partitioning, and implications for body weight regulation","authors":"Yigit Unlu ,&nbsp;Emma J. Stinson ,&nbsp;Jonathan Krakoff ,&nbsp;Paolo Piaggi","doi":"10.1016/j.metabol.2025.156270","DOIUrl":"10.1016/j.metabol.2025.156270","url":null,"abstract":"<div><h3>Background</h3><div>Protein oxidation (PROTOX) typically accounts for the smallest fraction of daily energy expenditure (24hEE) in humans compared to carbohydrate and lipid oxidation. However, inter-individual differences in PROTOX may explain differences in fuel partitioning and body weight change. We aimed to elucidate the physiological determinants of PROTOX under controlled 24-h dietary conditions, including eucaloric feeding, fasting, and overfeeding diets with variable protein content.</div></div><div><h3>Methods</h3><div>Eighty-six weight-stable healthy volunteers with normal glucose regulation (67 M/19F; age: 37 ± 10 years; BMI: 26.7 ± 4.5 kg/m², body fat by DXA: 29.0 ± 9.8 %) underwent 24hEE measurements by whole-room calorimetry during energy balance (20 % protein, 50 % carbohydrate), different overfeeding diets (200 % of the daily eucaloric requirement), including three normal-protein (20 %) diets (balanced: 50 % carbohydrate; high-carbohydrate: 75 % carbohydrate; high-fat: 60 % fat), low-protein (3 %) and high-protein (30 %), and 24-h fasting in a randomized crossover design. Urine samples were collected during each 24-h dietary intervention for quantification of PROTOX and catecholamine excretion rates by nitrogen excretion and high-performance liquid chromatography, respectively.</div></div><div><h3>Results</h3><div>PROTOX during energy balance (mean ± SD: 372 ± 78 kcal/day) was positively associated with protein intake (<em>r</em> = 0.39, <em>p</em> &lt; 0.001), fat free mass (<em>r</em> = 0.35, p &lt; 0.001), but not with fat mass (<em>p</em> = 0.24). Higher PROTOX was associated with higher 24-h urinary norepinephrine (partial <em>r</em> = 0.27, <em>p</em> = 0.01), but not epinephrine (<em>p</em> = 0.48), excretion rates. During normal-protein diets, higher PROTOX was associated with lower lipid oxidation, but showed no association with carbohydrate oxidation. Inter-individual variability in PROTOX did not predict changes in weight or body composition over two years.</div></div><div><h3>Conclusion</h3><div>Dietary protein content, lean body mass, and sympathetic nervous system activity are key determinants of PROTOX. Although PROTOX did not predict free-living weight gain, increased PROTOX is associated with decreased lipid oxidation, underscoring its role in fuel partitioning and whole-body energy and substrate balance.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156270"},"PeriodicalIF":10.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860189","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":"Sarcopenia in Parkinson's disease: from pathogenesis to interventions","authors":"Meilin Gui ,&nbsp;Lingling Lv ,&nbsp;Shenglan Hu ,&nbsp;Lixia Qin ,&nbsp;Chunyu Wang","doi":"10.1016/j.metabol.2025.156272","DOIUrl":"10.1016/j.metabol.2025.156272","url":null,"abstract":"<div><div>Parkinson's disease (PD) and sarcopenia are prevalent age-related conditions that often coexist in affected individuals. Sarcopenia is particularly common among PD patients, with severe cases affecting approximately one in five individuals with the disease. Furthermore, sarcopenia is closely linked to the accelerated progression of PD, diminished quality of life, greater susceptibility to falls and fractures, and increased mortality risk. Although the precise mechanisms remain unclear, numerous studies suggest that factors such as the accumulation of α-Synuclein in skeletal muscle, loss of motor neurons, inflammation, phosphate toxicity, hormonal dysregulation, vitamin D deficiency, intestinal flora imbalances, and dysfunction of the gut-muscle-brain axis contribute to sarcopenia in PD. Understanding these mechanisms provides valuable insights into the relationship between PD and sarcopenia and establishes a foundation for future research and therapeutic strategies. This review examines the mechanisms underlying sarcopenia in PD, methods for its screening and assessment, and potential avenues for future research, including strategies for risk reduction and treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156272"},"PeriodicalIF":10.8,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860190","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":"Reply to: “Unraveling sphingolipid complexity in liver fibrosis: Perspectives for future research”","authors":"Aleksandra Gruevska ,&nbsp;Fiona Oakley ,&nbsp;Zoe Hall","doi":"10.1016/j.metabol.2025.156268","DOIUrl":"10.1016/j.metabol.2025.156268","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156268"},"PeriodicalIF":10.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860191","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 “Prolonged increase in glutamate whole body and intracellular production in older adults with COPD and healthy controls post-resistance exercise” [Metabolism, Volume 168, July 2025, 156185]","authors":"Robert H. Mbilinyi ,&nbsp;Nicolaas E.P. Deutz ,&nbsp;Clayton L. Cruthirds ,&nbsp;Laura E. Ruebush ,&nbsp;Tarun Sontam ,&nbsp;Gabriella A.M. Ten Have ,&nbsp;John J. Thaden ,&nbsp;Mariëlle P.K.J. Engelen","doi":"10.1016/j.metabol.2025.156265","DOIUrl":"10.1016/j.metabol.2025.156265","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156265"},"PeriodicalIF":10.8,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826090","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":"ADH1C maintains the homeostasis of metabolic microenvironment to inhibit steatotic hepatocellular carcinoma","authors":"Kequan Xu ,&nbsp;Tiangen Wu ,&nbsp;Xiaomian Li ,&nbsp;Xiao Zhang ,&nbsp;Xinyu Liu ,&nbsp;Shuxian Ma ,&nbsp;Wenlong Dong ,&nbsp;Jialing Yang ,&nbsp;Yingyi Liu ,&nbsp;Weixian Fang ,&nbsp;Yi Ju ,&nbsp;Yiran Chen ,&nbsp;Caixia Dai ,&nbsp;Zheng Gong ,&nbsp;Wenzhi He ,&nbsp;Zan Huang ,&nbsp;Lei Chang ,&nbsp;Weijie Ma ,&nbsp;Peng Xia ,&nbsp;Xi Chen ,&nbsp;Yufeng Yuan","doi":"10.1016/j.metabol.2025.156267","DOIUrl":"10.1016/j.metabol.2025.156267","url":null,"abstract":"<div><div>Steatotic hepatocellular carcinoma (HCC) has emerged as a significant subtype of HCC. Understanding the complex tumor microenvironment in HCC is particularly important for stratifying patients and improving treatment response. In this study, we performed proteomic analysis on clinical samples of steatotic HCC and identified human-specific gene alcohol dehydrogenase 1C (ADH1C) as a key factor. ADH1C is a favorable prognostic factor in both steatotic and non-steatotic HCC. ADH1C promotes fatty acid degradation through a novel non-enzymatic function, inhibiting the development of hepatocellular carcinoma. Specifically, in vitro experiments revealed that ADH1C interacts with splicing factor retinitis pigmentosa 9 (RP9) to enhance the splicing of key transcription factor peroxisome proliferator activated receptor alpha (PPARa) pre-mRNA, which is crucial for fatty acid degradation. The regulation of the ADH1C/RP9/PPARa axis was supported by in vivo experiments and clinical relevance. This leads to a reduction in the critical metabolite palmitic acid, subsequently decreasing the palmitoylation levels of oncogenic protein TEA domain transcription factor 1 (TEAD1), thereby regulating the hippo pathway and subsequent cell proliferation inhibition. Additionally, we found that ADH1C and PPARa can serve as combined biomarkers to distinguish between patients with steatotic and non-steatotic HCC. Combination therapy targeting ADH1C and anti-programmed cell death protein 1 (PD1) enhances the response of steatotic HCC to anti- PD1 immunotherapy. Our study revealed a central role of ADH1C/PPARa in lipid metabolism and HCC suppression. Targeting lipid metabolism via ADH1C/PPARa may provide new therapeutic strategies for the treatment of liver cancer.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156267"},"PeriodicalIF":10.8,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839472","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":"Hepatic miR-93 promotes the pathogenesis of metabolic dysfunction-associated steatotic liver disease by suppressing SIRT1","authors":"Yo Han Lee ,&nbsp;Jinyoung Lee ,&nbsp;Joonho Jeong ,&nbsp;Kieun Park ,&nbsp;Bukyung Baik ,&nbsp;Yuseong Kwon ,&nbsp;Kimyeong Kim ,&nbsp;Keon Woo Khim ,&nbsp;Haneul Ji ,&nbsp;Ji Young Lee ,&nbsp;Kwangho Kim ,&nbsp;Ji Won Kim ,&nbsp;Tam Dao ,&nbsp;Misung Kim ,&nbsp;Tae Young Lee ,&nbsp;Yong Ryoul Yang ,&nbsp;Haejin Yoon ,&nbsp;Dongryeol Ryu ,&nbsp;Seonghwan Hwang ,&nbsp;Haeseung Lee ,&nbsp;Jang Hyun Choi","doi":"10.1016/j.metabol.2025.156266","DOIUrl":"10.1016/j.metabol.2025.156266","url":null,"abstract":"<div><h3>Background and aims</h3><div>The molecular mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD) remain largely unclear; however, emerging evidence suggests that microRNAs (miRNAs) play a critical role in modulating transcriptional regulation of target genes involved in MASLD. This study aims to elucidate the role of miR-93 in lipid metabolism and MASLD progression.</div></div><div><h3>Methods</h3><div>We comprehensively analyzed miRNA expression profiles in liver tissues from patients with MASLD and diet-induced obese mice. miR-93 knockout (KO) mice were fed a high-fat–high-fructose (HFHFr) diet to assess the impact of miR-93 deficiency on MASLD. Transcriptome analysis was performed to elucidate the molecular mechanisms and role of miR-93 in MASLD. Additionally, we employed a high-throughput screening system to identify drugs capable of modulating miR-93 expression.</div></div><div><h3>Results</h3><div>miR-93 was significantly upregulated in the livers of patients with MASLD and diet-induced obese mice. miR-93 KO mice exhibited reduced hepatic steatosis. Specifically, miR-93 deficiency upregulated genes involved in fatty acid oxidation and downregulated genes associated with cholesterol biosynthesis. Sirtuin 1 (SIRT1) was identified as a direct target of miR-93, and miR-93 KO enhanced SIRT1 expression and activated the LKB1-AMPK signaling pathway. Niacin treatment downregulated miR-93, ameliorating hepatic steatosis by enhancing SIRT1 activity.</div></div><div><h3>Conclusions</h3><div>These findings implicate miR-93 as a novel therapeutic target for MASLD. The study demonstrates the therapeutic potential of niacin in modulating the miR-93/SIRT1 axis, providing a new potential treatment for MASLD, a disease with limited current treatment options.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156266"},"PeriodicalIF":10.8,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839536","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":"UBC9 ameliorates diabetic cardiomyopathy by modulating cardiomyocyte mitophagy through NEDD4/RUNX2/PSEN2 axis","authors":"Hanlin Wu ,&nbsp;Zheming Yang ,&nbsp;Ting Zhou ,&nbsp;Jing Wang ,&nbsp;Yuxin Bu ,&nbsp;Haixu Song ,&nbsp;Chenghui Yan ,&nbsp;Dan Liu ,&nbsp;Yaling Han","doi":"10.1016/j.metabol.2025.156264","DOIUrl":"10.1016/j.metabol.2025.156264","url":null,"abstract":"<div><h3>Aim</h3><div>Diabetic cardiomyopathy (DCM) is one of the most significant cardiovascular complications in patients with diabetes. Ubiquitin conjugating enzyme 9 (UBC9) is the only SUMO-E2 enzyme that plays a key role in cardiomyocytes homeostasis. This study aimed to elucidate the roles and mechanisms of UBC9 in DCM development.</div></div><div><h3>Methods</h3><div>We established cardiomyocyte-specific UBC9 knockout mice and UBC9-overexpressing mice in vivo. A DCM model was established by feeding a high-fat diet and administering a low-dose streptozotocin injection. Proteomics, H&amp;E staining, Sirius Red staining, WGA staining, real-time PCR, and western blotting were performed to examine fibrosis, hypertrophy, and mitophagy in the myocardium. Neonatal mouse cardiomyocytes (NMCMs) were cultured in vitro and stimulated with palmitic acid, UBC9 overexpression adenovirus, and small interfering RNA to establish UBC9 overexpression or knockdown NMCMs. Real-time PCR, western blotting, and immunoprecipitation were employed to examine the roles and mechanisms of UBC9 in cardiomyocyte mitophagy.</div></div><div><h3>Results</h3><div>The transcription and protein levels of UBC9 were significantly decreased in the myocardium of DCM mice. Cardiomyocyte-specific UBC9 knockout aggravated cardiac dysfunction, myocardial fibrosis, hypertrophy, and impaired mitophagy. Conversely, UBC9 overexpression produced opposite effects. UBC9 protected cardiomyocyte mitophagy independently of SUMOylation. UBC9 exerted protective effects against defective cardiomyocyte mitophagy by directly binding to NEDD4, enhancing RUNX2 ubiquitination and degradation, which in turn increased PSEN2 expression. Moreover, the impact of UBC9 on cardiomyocyte mitophagy was reversed upon PSEN2 knockdown.</div></div><div><h3>Conclusions</h3><div>UBC9 alleviated DCM development through the NEDD4/RUNX2/PSEN2 pathway. These findings offer novel insights into the potential of UBC9 as a therapeutic target for DCM.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156264"},"PeriodicalIF":10.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829119","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":"Mechanical activation of adipose tissue macrophages mediated by Piezo1 protects against diet-induced obesity by regulating sympathetic activity","authors":"Shaoqiu Leng ,&nbsp;Xiaoyu Zhang ,&nbsp;Ruxia Zhao ,&nbsp;Nan Jiang ,&nbsp;Xinyue Liu ,&nbsp;Xin Li ,&nbsp;Qi Feng ,&nbsp;Zi Sheng ,&nbsp;Shuwen Wang ,&nbsp;Jun Peng ,&nbsp;Xiang Hu","doi":"10.1016/j.metabol.2025.156262","DOIUrl":"10.1016/j.metabol.2025.156262","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity-induced mechanical changes in white adipose tissue (WAT), including adipocyte hypertrophy and fibrosis, are hypothesized to alter adipose tissue macrophage (ATM) function through mechanosensitive pathways. This study aimed to determine whether the mechanosensor Piezo1 in ATMs regulates obesity-associated metabolic dysfunction and thermogenesis.</div></div><div><h3>Methods</h3><div>To investigate macrophage Piezo1 in obesity, myeloid-specific Piezo1-deficient mice (<em>Piezo1</em>^∆lyz2) and littermate controls (<em>Piezo1</em>^flox/+) were fed a high-fat diet (HFD) to induce obesity for 12 weeks. Metabolic assessments (GTT/ITT), tissue analyses (H&amp;E staining, micro-CT), and RNA-seq were performed. Bone marrow transplantation and co-culture experiments (BMDMs with 3T3L1 adipocytes/PC12 neurons) were performed to evaluate macrophage-adipocyte/neuron crosstalk. Sympathetic activity was tested via cold exposure, NE measurement, and 6-OHDA/αMPT denervation. Molecular mechanisms were investigated using ChIP-qPCR.</div></div><div><h3>Results</h3><div><em>Piezo1</em>^∆lyz2 mice exhibited aggravated HFD-induced obesity and insulin resistance despite reduced pro-inflammatory responses. Piezo1 deficiency in ATMs suppressed Slit3–ROBO1 signaling, leading to diminished NE secretion and impaired thermogenesis. Pharmacological inhibition of NE release (6-OHDA) or ROBO1 knockdown (shROBO1) abolished thermogenic disparities between <em>Piezo1</em>^∆lyz2 and control mice. Mechanistically, Piezo1 activation triggered SP1 nuclear translocation, directly binding to the Slit3 promoter to drive Slit3 transcription and secretion.</div></div><div><h3>Conclusion</h3><div>Piezo1 in ATMs mitigates obesity progression by promoting Slit3–ROBO1-dependent NE secretion and thermogenesis, independent of its pro-inflammatory role. This mechanosensitive pathway links WAT mechanical remodeling to metabolic regulation, which may offer a novel approach for managing obesity.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156262"},"PeriodicalIF":10.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143823272","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}