Metabolism: clinical and experimental最新文献

{"title":"BMAL2 controls adipose tissue inflammation and metabolic adaptation during obesity","authors":"Morgane A. Philippe ,&nbsp;Blandine Fruchet ,&nbsp;Lucie Cagninacci ,&nbsp;Lucie Beaudoin ,&nbsp;Alexis Gadault ,&nbsp;Bastien Aznar ,&nbsp;Nicolas Venteclef ,&nbsp;Etienne Challet ,&nbsp;Agnès Lehuen ,&nbsp;Ute C. Rogner ,&nbsp;Amine Toubal","doi":"10.1016/j.metabol.2025.156396","DOIUrl":"10.1016/j.metabol.2025.156396","url":null,"abstract":"<div><div>Contemporary lifestyle modifications such as changes in nutritional and sleep/wake rhythms increase the risk of metabolic and inflammatory complications linked to obesity, including type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). BMAL2 (Brain and Muscle ARNT Like Protein 2) is a transcription factor belonging to the circadian clock transcriptional feedback loop which synchronizes internal biological rhythms to environment. In humans, reduced expression in white adipose tissue (WAT) and specific polymorphisms of <em>BMAL2</em> are associated with obesity and T2D. In this study we report that <em>Bmal2</em> deletion in mice leads to increased body weight gain during diet-induced obesity. Loss of BMAL2 triggers the inflammatory response by increasing <em>Tnfα</em> expression and modifying adipocyte progenitor fate. This results in reduced lipid storage capacity within the WAT and increased ectopic storage in the liver. These functional and structural alterations culminate in the onset of hepatic steatosis and insulin resistance in liver and WAT. Overall, our investigations underscore the role of BMAL2 in the development and function of adipocytes, as well as in their inflammatory potential within the WAT. Our findings contribute to the understanding of the role of circadian clock genes in obesity and interconnected metabolic complications.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156396"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124807","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":"Enhancing cardiac serine biosynthesis mitigates the progression of dilated cardiomyopathy in mice","authors":"Maryam Kay ,&nbsp;Anne-Maj Samuelsson ,&nbsp;Nike Bharucha ,&nbsp;Xueyi Li ,&nbsp;Rohin Ramchandani ,&nbsp;Rachel E. Baum ,&nbsp;Diego Ruiz Arvizo ,&nbsp;Aurélie Laguerre ,&nbsp;Sherin Lajevardi ,&nbsp;Shrikaar Kambhampati ,&nbsp;Christian M. Metallo ,&nbsp;Michael S. Kapiloff ,&nbsp;Ioannis Karakikes","doi":"10.1016/j.metabol.2025.156395","DOIUrl":"10.1016/j.metabol.2025.156395","url":null,"abstract":"<div><div>Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. However, disease-modifying therapies remain limited. Metabolic dysfunction has emerged as a key driver of DCM pathogenesis, and impaired serine biosynthesis, catalyzed by the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH), has recently been identified as a potential therapeutic target. Here, we evaluated the therapeutic potential of increasing serine biosynthesis through AAV9-mediated PHGDH gene augmentation in a transgenic TM54 mouse model of DCM with established pathology. Longitudinal echocardiography showed preserved systolic function and prevented ventricular dilatation in TM54 mice treated with AAV9-PHGDH compared to AAV9-GFP controls. Histological analysis revealed reduced myocardial fibrosis and cardiomyocyte hypertrophy in AAV9-PHGDH-treated TM54 hearts, indicating a reversal of pathological remodeling. Metabolic profiling, including targeted metabolomics and in vivo ¹³C-glucose tracing analysis, revealed that serine levels increased in hearts treated with AAV9-PHGDH, accompanied by decreases in glucose-derived pyruvate and lactate. At the same time, mitochondrial oxidative metabolism remained intact, indicating a shift of glycolytic carbon towards serine biosynthesis. Collectively, these findings show that enhancing cardiac serine synthesis through PHGDH gene augmentation therapy preserves contractile function and mitigates disease progression in vivo, suggesting a novel metabolic therapeutic strategy for DCM.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156395"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102795","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 steatosis associates with leukopoietic activity and atherosclerotic inflammation: mechanistic insights into cardiovascular risk","authors":"Shady Abohashem ,&nbsp;Wesam Aldosoky ,&nbsp;Taimur Abbasi ,&nbsp;Tawseef Dar ,&nbsp;Robert Rollings ,&nbsp;Brian Tung ,&nbsp;Basma Hammad ,&nbsp;Fatima Saeed ,&nbsp;Abdelrahman Ali ,&nbsp;Richard A.P. Takx ,&nbsp;Brian B. Ghoshhajra ,&nbsp;Ahmed Tawakol ,&nbsp;Michael T. Osborne","doi":"10.1016/j.metabol.2025.156427","DOIUrl":"10.1016/j.metabol.2025.156427","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Hepatic steatosis (HS) is associated with an increased risk of major adverse cardiovascular events (MACE). However, the underlying mechanisms linking HS to MACE remain incompletely understood. This study aimed to investigate the role of the leukopoietic-arterial axis in mediating the relationship between imaging markers of HS and MACE.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods and materials&lt;/h3&gt;&lt;div&gt;This longitudinal retrospective cohort study included 445 individuals without active cancer, liver disease or alcohol abuse, or baseline cardiovascular disease who underwent clinical &lt;sup&gt;18&lt;/sup&gt;F-FDG-PET/CT imaging. Hepatic glucose uptake (HGU), uptake in the bone marrow (BM) and spleen (as a marker of leukopoiesis), and activity in the aorta (as a measure of arterial inflammation, ArtI) were evaluated. Hepatic and splenic attenuations were analyzed to assess hepatic attenuation index (HAI) and determine nonalcoholic fatty liver disease (NAFLD) status. Metabolic Dysfunction Associated Steatotic Liver disease (MASLD) was defined based on NAFLD status and other metabolic criteria. MACE was adjudicated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In fully adjusted models, HGU associated with heightened BM (standardized β [95 % confidence interval]: 0.353 [0.276, 0.430], &lt;em&gt;p&lt;/em&gt; &lt; 0.001) and spleen activities (0.548 [0.475, 0.621], &lt;em&gt;p&lt;/em&gt; &lt; 0.001) as well as ArtI (0.529 [0.453, 0.605], &lt;em&gt;p&lt;/em&gt; &lt; 0.001). Similar associations were observed for HAI and MASLD or NAFLD status. Notably, these associations remained significant after adjusting for other confounders and among individuals without MASLD/NAFLD. A total of 28 individuals developed MACE over 4 years median follow-up. Furthermore, the leukopoietic-arterial activity mediated the link between imaging markers of HS (i.e., HGU, HAI, MASLD) and MACE, (&lt;em&gt;p&lt;/em&gt; &lt; 0.05).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Our study suggests an important role for the leukopoietic-arterial axis in HS and MACE. These findings may inform therapeutic avenues for reducing the cardiovascular risk associated with HS.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Structured abstract&lt;/h3&gt;&lt;div&gt;This study examines the connection between hepatic steatosis (HS) and major adverse cardiovascular events (MACE) through the leukopoietic-arterial axis. Among 445 patients without history of liver disease or alcohol abuse, imaging markers of hepatic steatosis (i.e., hepatic glucose uptake (HGU)), and metabolic dysfunction associated steatotic liver disease (MASLD), associated with increased activity in bone marrow and spleen, and atherosclerotic plaques. These associations persisted irrespective of MASLD status and after adjusting for relevant confounders. Heightened uptake in leukopoietic tissues and the arteries mediated the relationship between HS markers (i.e., HGU, MASLD) and MACE development. These findings shed light on novel mechanistic pathways and potential targets for interventions to reduce the burden of HS-related CVD.&lt;/di","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156427"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452265","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":"Phenome-wide associations of coffee intake in the human phenotype project","authors":"Jin Dai ,&nbsp;Wen Dai ,&nbsp;Yoriko Heianza ,&nbsp;Lu Qi","doi":"10.1016/j.metabol.2025.156412","DOIUrl":"10.1016/j.metabol.2025.156412","url":null,"abstract":"<div><h3>Objective</h3><div>Coffee is one of the most widely consumed beverages globally and has been linked to favorable health outcomes. However, its system-wide relationships with human biology and the underlying mechanisms remain poorly characterized. This study aimed to investigate the relationship between coffee consumption and continuous glucose monitoring (CGM) metrics and other biological systems in healthy adults.</div></div><div><h3>Research design and methods</h3><div>In the Human Phenotype Project, 8666 generally healthy Israeli adults provided two weeks of real-time dietary logs, from which coffee intake was estimated. Participants wore CGM devices throughout this period, and multimodal data spanning 11 additional systems (e.g., gut microbiome, serum lipidomics, and body composition) were collected. We employed machine learning approaches to quantify the extent to which each system reflected coffee intake. We performed linear regression to identify individual traits associated with coffee intake, with false discovery rates &lt; 0.05 considered significant.</div></div><div><h3>Results</h3><div>This cross-sectional study identified continuously-monitored glucose regulation and gut microbial composition as the most reflective systems of coffee intake, with further analyses revealing favorable glycemic profiles spanning diverse aspects of glucose regulation with increasing coffee intake, and <em>Clostridium phoceensis</em> (i.e., <em>Lawsonibacter asaccharolyticus</em>) as the most significant species positively associated with coffee intake. Additionally, coffee intake was favorably associated with traits across body composition, serum lipidomics, and hepatic, hematopoietic, and renal systems.</div></div><div><h3>Conclusions</h3><div>This study found that habitual coffee intake was linked to multifaceted favorable glucose control captured by CGM and favorable profiles across multiple biological systems, providing mechanistic insights that may guide precision nutrition strategies for diabetes prevention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156412"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232946","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":"NSD2 exacerbates metabolic dysfunction-associated steatotic liver disease progression by suppressing TFEB-mediated autophagy-lysosomal pathway","authors":"Yuan Qiao ,&nbsp;Yijia Zhang ,&nbsp;Cuiting Sun ,&nbsp;Qi Jin ,&nbsp;Peng Qu ,&nbsp;Zecheng Li ,&nbsp;Yang Qiu ,&nbsp;Hua Meng ,&nbsp;Dantao Peng ,&nbsp;Liang Peng","doi":"10.1016/j.metabol.2025.156416","DOIUrl":"10.1016/j.metabol.2025.156416","url":null,"abstract":"<div><h3>Objectives</h3><div>Impaired autophagy is increasingly recognized as a key contributor to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, its underlying molecular mechanisms remain largely undefined. Emerging evidence implicates epigenetic regulators in modulating autophagic pathways in metabolic diseases. Therefore, this study aimed to elucidate the role of a histone methyltransferase, nuclear receptor binding SET domain protein 2 (NSD2), in regulating autophagy and its contribution to MASLD progression.</div></div><div><h3>Methods</h3><div>NSD2 expression levels were evaluated in liver tissues from patients with MASLD and mouse models. Functional studies were conducted using hepatocyte-specific <em>Nsd2</em> knockout and overexpression mouse models, along with cleavage under targets and tagmentation analysis in hepatocyte cell lines. Additionally, the effects of pharmacological NSD2 inhibition using NSC663284 were evaluated in human liver organoids. Autophagy, hepatic steatosis, and related epigenetic changes were assessed through molecular and histological techniques.</div></div><div><h3>Results</h3><div>NSD2 expression was markedly elevated in both patient livers and murine models, correlating positively with disease severity. Hepatic NSD2 deficiency alleviated diet-induced autophagy impairment and steatosis, while NSD2 overexpression exacerbated these pathologies. Mechanistically, NSD2 epigenetically suppressed TFEB transcription by promoting trimethylation of histone H4 at lysine 20, impairing autophagy. Pharmacological inhibition of NSD2 with NSC663284 similarly alleviated hepatic steatosis in human liver organoids.</div></div><div><h3>Conclusion</h3><div>NSD2 acts as a key epigenetic suppressor of TFEB-mediated autophagy in the liver, promoting lipid accumulation and MASLD progression. Targeting NSD2 represents a promising therapeutic strategy for MASLD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156416"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275315","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":"Semaglutide, the first approved GLP-1 receptor agonist for the management of metabolic dysfunction-associated steatohepatitis","authors":"Chrysoula Boutari ,&nbsp;Michael A. Hill ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2025.156397","DOIUrl":"10.1016/j.metabol.2025.156397","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156397"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232989","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":"Administration of the KCa channel activator SKA-31 improves long-term endothelial function, blood pressure regulation and cardiac performance in rats with type 2 diabetes","authors":"Ramesh C. Mishra ,&nbsp;Rayan Khaddaj Mallat ,&nbsp;Cini M. John ,&nbsp;Darrell D. Belke ,&nbsp;Liam Hamm ,&nbsp;Latika Singh ,&nbsp;Taeyoeb Kim ,&nbsp;Grace George ,&nbsp;Yong-Xiang Chen ,&nbsp;Heike Wulff ,&nbsp;Andrew P. Braun","doi":"10.1016/j.metabol.2025.156410","DOIUrl":"10.1016/j.metabol.2025.156410","url":null,"abstract":"<div><h3>Objective</h3><div>Our goal in the present study was to examine whether long-term administration of the selective K_Ca channel activator SKA-31 would mitigate the development/severity of type 2 diabetes (T2D)-associated cardiovascular (CV) complications in adult male Goto-Kakizaki (GK) rats with spontaneous T2D.</div></div><div><h3>Methods</h3><div>Adult male T2D GK rats instrumented with radio-telemeters were administered either vehicle or the K_Ca channel activator SKA-31 (10 mg/kg) at ~14 weeks of age by daily intraperitoneal injection for 12 consecutive weeks. <em>In vivo</em> and <em>ex vivo</em> analyses of CV function, immune system status, vascular signaling and metabolic hormones were performed following treatment.</div></div><div><h3>Results</h3><div>Vehicle-treated T2D GK rats exhibited gradual increases in systolic and diastolic blood pressure, whereas SKA-31 administration led to lower mean arterial pressure, along with improvements in cardiac function (i.e., ejection fraction, fractional shortening) and structure (i.e., end systolic and diastolic volumes), as determined by echocardiography. SKA-31 treatment <em>in vivo</em> further improved vascular endothelial function in small mesenteric arteries, as determined by arterial pressure myography, and increased the protein expression of vasodilatory signaling molecules in the vascular wall. Prolonged SKA-31 treatment did not impair vasodilatory responsiveness in skeletal muscle and coronary arteries, elicit a pro-inflammatory profile in T2D GK rats or produce any adverse histological effects in brain, kidney or liver.</div></div><div><h3>Conclusions</h3><div>The results of our study demonstrate that low-dose administration of the K_Ca channel activator SKA-31 improved CV function in an established rat model of spontaneous T2D and reveal a potential novel strategy to oppose CV-related morbidity in T2D.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156410"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225658","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":"Angiopoietin-like protein 8 mediates inflammation and fibrosis of tubular cells in diabetic kidney disease progression by interacting with Akt2","authors":"Limeng Pan ,&nbsp;Yi He ,&nbsp;Yuxi Xiang ,&nbsp;Beibei Mao ,&nbsp;Xiaoyu Meng ,&nbsp;Yaming Guo ,&nbsp;Zhihan Wang ,&nbsp;Ranran Kan ,&nbsp;Siyi Wang ,&nbsp;Xuhang Shen ,&nbsp;Tianrong Pan ,&nbsp;Zhelong Liu ,&nbsp;Junhui Xie ,&nbsp;Yan Yang ,&nbsp;Danpei Li ,&nbsp;Xuefeng Yu","doi":"10.1016/j.metabol.2025.156418","DOIUrl":"10.1016/j.metabol.2025.156418","url":null,"abstract":"<div><h3>Background and aims</h3><div>Angiopoietin-like protein 8 (ANGPTL8), an important regulator of glucose and lipid metabolism, has recently been shown to be associated with renal function decline in patients with diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain unclear. This study aimed to elucidate the novel role of ANGPTL8 in DKD progression.</div></div><div><h3>Methods</h3><div>The renal expression of ANGPTL8 was measured in patients and murine models with DKD. Proximal tubule-specific <em>Angptl8</em> knockout mice were generated to elucidate the role of ANGPTL8 in the pathogenesis of DKD. <em>In vitro</em>, ANGPTL8 was inhibited in human proximal tubular epithelial cells (PTECs) under high glucose plus palmitic acid (HGPA) stress. ANGPTL8 interacting proteins were screened using the human proteome microarray and validated by complementary interaction assays. Functional validation employed the Akt2 small interfering RNA and the specific Akt2 inhibitor <em>in vitro</em> and proximal tubule-specific <em>Akt2</em> knockout mice <em>in vivo</em>.</div></div><div><h3>Results</h3><div>ANGPTL8 expression was significantly increased in renal proximal tubules during DKD. Proximal tubule-specific <em>Angptl8</em> knockout ameliorated tubular injury and reduced tubular inflammation and fibrosis in DKD mice. <em>In vitro</em>, ANGPTL8 inhibition protected human PTECs against HGPA-induced inflammation and epithelial-mesenchymal transition (EMT). Mechanistically, intracellular ANGPTL8 directly binds to and activates Akt2, triggering downstream NF-κB pathway activation and GSK3β inhibition. Akt2 inhibition abolished ANGPTL8's pathogenic effects <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate for the first time that elevated tubular ANGPTL8 promotes tubular inflammation and fibrosis during DKD by interacting with Akt2, highlighting the ANGPTL8-Akt2 axis as a promising target to prevent DKD progression.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156418"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329578","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":"Serotonin 2C receptors inhibit hypothalamic CRH neurons to suppress appetite","authors":"Eun-Seon Yoo ,&nbsp;Jieun Yu ,&nbsp;Moonsun Sa ,&nbsp;C. Justin Lee ,&nbsp;Jong-Woo Sohn","doi":"10.1016/j.metabol.2025.156431","DOIUrl":"10.1016/j.metabol.2025.156431","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objectives&lt;/h3&gt;&lt;div&gt;The serotonin 2C receptor (&lt;em&gt;Htr2c&lt;/em&gt;) is one of the plausible targets for the development of appetite suppressants. Previous studies have demonstrated the complexity of neuronal circuitry underlying the appetite-suppressing effects of &lt;em&gt;Htr2c&lt;/em&gt; stimulation. To develop a safe and effective anti-obesity medication targeting &lt;em&gt;Htr2c&lt;/em&gt;, we need to better understand how &lt;em&gt;Htr2c&lt;/em&gt; agonists suppress appetite. In this study, we focused on the effects of &lt;em&gt;Htr2c&lt;/em&gt; agonists on corticotropin-releasing hormone (CRH) neurons to identify the contribution of humoral components to the suppression of fasting-induced food intake.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We used the &lt;em&gt;Crh&lt;/em&gt;-ires-cre mice to fluorescently label CRH neurons for whole-cell patch-clamp recordings (&lt;em&gt;Crh&lt;/em&gt;-ires-cre::tdTomato mice) and to delete &lt;em&gt;Htr2c&lt;/em&gt; selectively in CRH neurons by breeding with &lt;em&gt;Htr2c&lt;/em&gt;&lt;sup&gt;flox/Y&lt;/sup&gt; mice (&lt;em&gt;Crh&lt;/em&gt;-ires-cre::&lt;em&gt;Htr2c&lt;/em&gt;&lt;sup&gt;flox/Y&lt;/sup&gt; mice). We also injected &lt;em&gt;Htr2c&lt;/em&gt;-targeting short hairpin RNA (shRNA) into the paraventricular nucleus of the hypothalamus (PVH) of &lt;em&gt;Crh&lt;/em&gt;-ires-cre mice to knock down &lt;em&gt;Htr2c&lt;/em&gt; selectively in CRH neurons within the PVH (CRH&lt;sup&gt;PVH&lt;/sup&gt; neurons). Using these model mice, we tested the effects of WAY161503, a selective &lt;em&gt;Htr2c&lt;/em&gt; agonist, on CRH neuronal activity &lt;em&gt;ex vivo&lt;/em&gt; as well as fasting-induced food intake and plasma corticosterone (CORT) levels &lt;em&gt;in vivo&lt;/em&gt;.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;WAY161503 inhibited the activity of CRH&lt;sup&gt;PVH&lt;/sup&gt; neurons. The appetite-suppressing effects of WAY161503 were significantly attenuated when &lt;em&gt;Htr2c&lt;/em&gt; was deleted selectively in CRH&lt;sup&gt;PVH&lt;/sup&gt; neurons. On the other hand, WAY161503 promoted the reduction of plasma CORT levels during fasting-induced refeeding &lt;em&gt;via Htr2c&lt;/em&gt; expressed by CRH&lt;sup&gt;PVH&lt;/sup&gt; neurons. Importantly, when mice were pretreated with RU486, a glucocorticoid receptor antagonist that blocks CORT action, WAY161503 suppressed food intake whether CRH&lt;sup&gt;PVH&lt;/sup&gt; neurons expressed functional &lt;em&gt;Htr2c&lt;/em&gt; or not. Finally, we characterized the expression of single-minded 1 (&lt;em&gt;Sim1&lt;/em&gt;) messenger RNA (mRNA), &lt;em&gt;Crh&lt;/em&gt; mRNA, and &lt;em&gt;Htr2c&lt;/em&gt; mRNA in PVH neurons, which may help to explain the effects of &lt;em&gt;Htr2c&lt;/em&gt; stimulation on fasting-induced refeeding.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Our results demonstrate that &lt;em&gt;Htr2c&lt;/em&gt; expression in the CRH&lt;sup&gt;PVH&lt;/sup&gt; neurons is necessary for the appetite-suppressing effects of WAY161503 during fasting-induced refeeding. Importantly, we found that WAY161503 suppresses the hypothalamic-pituitary-adrenal (HPA) axis and promotes the reduction of plasma CORT levels, thereby enabling the appetite-suppressing effects of &lt;em&gt;Htr2c&lt;/em&gt; stimulation during fasting-induced refeeding. To our knowledge, this study is the first to highlight the necessity of coordination between n","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156431"},"PeriodicalIF":11.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471536","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":"The intersection of exercise, nitric oxide, and metabolism: Unraveling the role of eNOS in skeletal muscle and beyond","authors":"Pierre-Anne R. Laird ,&nbsp;Rebecca M. Wall ,&nbsp;Siobhan M. Craige","doi":"10.1016/j.metabol.2025.156360","DOIUrl":"10.1016/j.metabol.2025.156360","url":null,"abstract":"<div><div>Exercise protects against several diseases including cardiometabolic disorders. However, the molecular mechanisms driving these adaptations remain incompletely defined. Endothelial nitric oxide synthase (eNOS), a key source of nitric oxide (NO), is implicated in regulating glucose uptake, fatty acid metabolism, and mitochondrial remodeling in response to exercise. eNOS is expressed in both endothelial and non-endothelial cells and its effects on metabolism are multifaceted. Notably, eNOS is highly expressed in endothelial cells which are ubiquitous throughout all organ systems allowing them to closely integrate with surrounding cell types. This unique feature of the endothelium enables eNOS to influence both local microenvironments and signaling across organ systems. This review summarizes current findings on the role of eNOS-derived NO in exercise metabolism. Evidence suggests eNOS contributes to improved metabolic flexibility, enhanced mitochondrial function, and tissue crosstalk. However, data across experimental models remain mixed, with both supportive and conflicting results. Collectively, the literature indicates that eNOS plays a central, though context-dependent, role in facilitating exercise-induced metabolic benefits. Identifying the specific mechanisms and tissue contributions of eNOS activity remains an important area for future investigation, with potential relevance to metabolic disease prevention and treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156360"},"PeriodicalIF":11.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765087","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}