Metabolism: clinical and experimental最新文献

{"title":"Semaglutide, the first approved GLP-1 receptor agonist for the management of metabolic dysfunction-associated steatohepatitis","authors":"Chrysoula Boutari , Michael A. Hill , 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}

{"title":"Emerging role of E4BP4/NFIL3 in metabolic homeostasis","authors":"Shuman Ran ,&nbsp;Siqi Wang ,&nbsp;Qi Jin ,&nbsp;Genzheng Liu ,&nbsp;Xiaobin Xue ,&nbsp;Peng Qu ,&nbsp;Liang Peng ,&nbsp;Hua Meng","doi":"10.1016/j.metabol.2025.156390","DOIUrl":"10.1016/j.metabol.2025.156390","url":null,"abstract":"<div><div>E4BP4/NFIL3 (E4 promoter-binding protein 4 or nuclear factor interleukin-3-regulated protein), is well-established for its association with circadian rhythm regulation and immune function. Recent advances in research have revealed its emerging and indispensable role in metabolic homeostasis, positioning it at the crossroads of circadian biology, immune responses, and metabolic balance. This review summarizes three decades of research on E4BP4/NFIL3 and explores its structural basis and regulatory functions. We synthesized current insights into the regulatory pathways that govern E4BP4/NFIL3 and discuss its central role in various metabolic scenarios, emphasizing its emerging significance as a pivotal metabolic regulator. Finally, we identify critical, unresolved questions and propose future research directions to enhance our understanding of E4BP4/NFIL3's broader implications in metabolic health.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156390"},"PeriodicalIF":11.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086404","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":"Relationship of GDF15 with hepatic mitochondrial respiration is depending on the presence of fibrosis in obese individuals","authors":"Anna Giannakogeorgou ,&nbsp;Sabine Kahl ,&nbsp;Cesare Granata ,&nbsp;Geronimo Heilmann ,&nbsp;Lucia Mastrototaro ,&nbsp;Bedair Dewidar ,&nbsp;Pavel Bobrov ,&nbsp;Irene Esposito ,&nbsp;Aslihan Yavas ,&nbsp;Sandra Trenkamp ,&nbsp;Frank A. Granderath ,&nbsp;Matthias Schlensak ,&nbsp;Christos S. Mantzoros ,&nbsp;Michael Roden ,&nbsp;Patrick Schrauwen","doi":"10.1016/j.metabol.2025.156391","DOIUrl":"10.1016/j.metabol.2025.156391","url":null,"abstract":"<div><h3>Background and purpose</h3><div>Preclinical studies reported elevated growth differentiation factor 15 (GDF15) when mitochondrial function is reduced. In humans, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) exhibit different hepatic mitochondrial adaptation. We hypothesized that circulating GDF15 differently correlates with hepatic mitochondrial respiration in obesity and/or MASLD/MASH.</div></div><div><h3>Methods</h3><div>Humans without (<em>n</em> = 20) and with biopsy-confirmed MASLD (n = 20) or MASH (n = 20) underwent hyperinsulinemic-euglycemic clamps to assess whole-body (M-value) and adipose-tissue (insulin-induced NEFA suppression) insulin sensitivity. Fasting serum GDF15 and glucagon were quantified by ELISA. Mitochondrial respiration was measured in liver obtained during bariatric surgery by high-resolution respirometry. Associations were assessed with Spearman's nonparametric correlation.</div></div><div><h3>Results</h3><div>Serum GDF15 correlated negatively with M-value (<em>r</em> = −0.35, <em>p</em> = 0.017) and NEFA suppression (<em>r</em> = −0.29, <em>p</em> = 0.046), but not with hepatic mitochondrial respiration across the whole cohort. However, correlations were found upon stratification into groups based on the presence (<em>n</em> = 37, age: 41 ± 2y, BMI: 49 ± 1 kg/m²) or absence of hepatic fibrosis (<em>n</em> = 23, 44 ± 2 years, BMI: 49 ± 1 kg/m²). In persons without fibrosis, GDF15 correlated positively with fatty acid oxidation-linked (F_P; <em>r</em> = 0.35, <em>p</em> = 0.035) and maximal coupled (FNS_P; <em>r</em> = 0.42, <em>p</em> = 0.010) mitochondrial respiration. Conversely, GDF15 correlated negatively with hepatic FN_P in persons with fibrosis (<em>r</em> = −0.48, <em>p</em> = 0.022).</div></div><div><h3>Conclusions</h3><div>In humans with obesity, serum GDF15 correlates positively with hepatic mitochondrial respiration in persons without, but negatively in persons with hepatic fibrosis. Future studies are needed to investigate whether and how GDF15 affects hepatic mitochondrial respiration in a fibrosis-dependent manner and/or, conversely, how fibrosis might modulate hepatic GDF15 secretion through altered mitochondrial function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156391"},"PeriodicalIF":11.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070041","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":"SerpinA3N in leptin-sensitive neurons is required for energy and glucose homeostasis and autonomic regulation","authors":"Deng Fu Guo ,&nbsp;Zili Luo ,&nbsp;Alexis Olson ,&nbsp;Donald A. Morgan ,&nbsp;Elizabeth A. Newell ,&nbsp;Kamal Rahmouni","doi":"10.1016/j.metabol.2025.156387","DOIUrl":"10.1016/j.metabol.2025.156387","url":null,"abstract":"<div><h3>Aims</h3><div>SerpinA3N (Serpin peptidase inhibitor clade A member 3) is a serine protease inhibitor upregulated in the hypothalamus by leptin and obesity, yet its role in physiological regulation remains poorly understood. This study aims to elucidate the role of hypothalamic SerpinA3N in regulation of energy balance, glucose homeostasis, and autonomic and cardiovascular functions.</div></div><div><h3>Methods and results</h3><div>Immunostaining revealed that SerpinA3N is primarily expressed in neurons, including those expressing the leptin receptor (LepRb). Targeted deletion of SerpinA3N in LepRb neurons reduced body weight and adiposity and improved insulin sensitivity in female mice. SerpinA3N deficiency also enhanced leptin sensitivity, evidenced by amplified leptin-induced anorexia, weight loss, and LepRb signaling in the hypothalamic arcuate nucleus. Upon exposure to an obesogenic diet, mice lacking SerpinA3N in LepRb neurons exhibited attenuated weight gain, hepatic lipid accumulation and microgliosis. Notably, SerpinA3N deletion in LepRb neurons impaired baroreflex sensitivity and elevated renal sympathetic nerve activity, with dietary obesity further exacerbating sympathetic tone.</div></div><div><h3>Conclusions</h3><div>These findings identify neuronal SerpinA3N as a key regulator of energy balance, leptin and insulin sensitivity, and autonomic function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156387"},"PeriodicalIF":11.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040726","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":"Modulating metabolism to improve the therapeutic outcomes of CAR cell therapies: From bench to bedside","authors":"Dengxiong Li ,&nbsp;Jie Wang ,&nbsp;Ruicheng Wu ,&nbsp;Qingxin Yu ,&nbsp;Fanglin Shao ,&nbsp;Dilinaer Wusiman ,&nbsp;Zhipeng Wang ,&nbsp;Zhouting Tuo ,&nbsp;Luxia Ye ,&nbsp;Yiqing Guo ,&nbsp;Koo Han Yoo ,&nbsp;Zhihong Liu ,&nbsp;William C. Cho ,&nbsp;Dechao Feng","doi":"10.1016/j.metabol.2025.156375","DOIUrl":"10.1016/j.metabol.2025.156375","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) cell therapies have emerged as a groundbreaking approach in cancer treatment, offering new hope for patients with refractory tumors. Despite their success, the therapeutic efficacy of CAR cell therapies is often undermined by metabolic factors within the tumor microenvironment (TME), which impede CAR cell function and lead to treatment resistance. Current literature has not fully explored how these metabolic processes contribute to CAR cell therapy failure, particularly in the context of solid tumors, where the TME presents unique challenges. Addressing this gap is crucial for enhancing the effectiveness of CAR cell therapies across a broader range of cancers. Here, we review the latest research on the metabolic mechanisms that influence CAR cell therapy outcomes, from preclinical studies to clinical applications. We conducted a comprehensive analysis of studies from PubMed and Web of Science, focusing on how various metabolic processes—such as hypoxia, immune cytokine signaling, glycolysis, adenine metabolism, cellular senescence, lactic acid increment, and cholesterol metabolism—affect CAR cell functions, including cytotoxicity, proliferation, stemness, and activation. Additionally, we examine how interactions between CAR cells and other components of the TME, such as tumor cells, stromal cells, and the extracellular matrix, contribute to an immune-suppressive environment that diminishes CAR cell efficacy. We also discuss potential strategies for overcoming these metabolic barriers, including the development of CAR cells with enhanced metabolic regulation, gene expression modulation, and the combination of CAR cell therapy with existing pharmacological treatments. Our findings underscore the critical role of metabolism in shaping the anti-tumor efficacy of CAR cell therapies in both hematologic and solid tumors. By targeting metabolic pathways within the TME, it is possible to enhance CAR cell infiltration, function, and persistence, thereby overcoming resistance and improving therapeutic outcomes. This approach not only addresses a key limitation in current CAR cell therapies but also paves the way for more effective cancer treatments in the future.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156375"},"PeriodicalIF":11.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961527","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":"Disruption of mitochondria-associated membranes contributes to the dysregulation of insulin secretion in undernutrition, obesity, and double burden of malnutrition","authors":"Thiago dos Reis Araujo ,&nbsp;Joel Alves da Silva Junior ,&nbsp;Bruna Lourençoni Alves ,&nbsp;Dimitrius Santiago Passos Simões Fróes Guimarães ,&nbsp;Lohanna Monali Barreto ,&nbsp;Mariana Roberta Rodrigues Muniz ,&nbsp;Jennifer Rieusset ,&nbsp;Everardo Magalhães Carneiro","doi":"10.1016/j.metabol.2025.156393","DOIUrl":"10.1016/j.metabol.2025.156393","url":null,"abstract":"<div><h3>Aims/hypothesis</h3><div>Nutritional disorders directly affect the endocrine pancreas, increasing the susceptibility to type 2 diabetes mellitus. However, the molecular mechanisms underlying these alterations remain unknown. This study aims to characterize the role of endoplasmic reticulum (ER)-mitochondria contact sites, known as mitochondrial-associated membranes (MAMs), in insulin secretion dysfunctions associated with undernutrition, obesity, and the double burden of malnutrition (DBM).</div></div><div><h3>Methods</h3><div>Rat pancreatic INS-1E β-cells were cultured in a medium without amino acids supplemented with 1 × (control) or 0.25 × (amino acid restriction) of an amino acid solution for 48 h, and then cells were exposed to a fatty acid mix for 48 h. Male C57BL/6 mice were fed a normoprotein diet (14 % protein) or protein-restricted diet (6 % protein) for 6 weeks and subsequently a high-fat diet (35 % kcal) for 12 weeks. ER-mitochondria interactions were evaluated by in situ proximity ligation assay and transmission electronic microscopy.</div></div><div><h3>Results</h3><div>Our findings indicate that protein restriction reduces ER-mitochondria contacts in pancreatic beta-cells, leading to decreased mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). In contrast, obesity increases ER-mitochondria contact points, mitochondrial metabolism, and GSIS in pancreatic beta-cells, without alterations in viability. DBM results in a significant increase in ER-mitochondria contacts, elevated mitochondrial calcium levels, increased production of reactive oxygen species, and cell death, collectively contributing to impaired GSIS response in the context of obesity.</div></div><div><h3>Conclusions/interpretation</h3><div>These data indicates that MAMs play a crucial role in GSIS during nutritional disorders such as undernutrition, obesity, and DBM. Importantly, changes in MAMs precede GSIS impairment, therefore targeting these interactions might prevent further disruption in beta-cell function.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156393"},"PeriodicalIF":11.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081075","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}