Pub Date : 2026-01-01Epub Date: 2025-11-05DOI: 10.1016/j.metabol.2025.156431
Eun-Seon Yoo , Jieun Yu , Moonsun Sa , C. Justin Lee , Jong-Woo Sohn
<div><h3>Objectives</h3><div>The serotonin 2C receptor (<em>Htr2c</em>) 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 <em>Htr2c</em> stimulation. To develop a safe and effective anti-obesity medication targeting <em>Htr2c</em>, we need to better understand how <em>Htr2c</em> agonists suppress appetite. In this study, we focused on the effects of <em>Htr2c</em> agonists on corticotropin-releasing hormone (CRH) neurons to identify the contribution of humoral components to the suppression of fasting-induced food intake.</div></div><div><h3>Methods</h3><div>We used the <em>Crh</em>-ires-cre mice to fluorescently label CRH neurons for whole-cell patch-clamp recordings (<em>Crh</em>-ires-cre::tdTomato mice) and to delete <em>Htr2c</em> selectively in CRH neurons by breeding with <em>Htr2c</em><sup>flox/Y</sup> mice (<em>Crh</em>-ires-cre::<em>Htr2c</em><sup>flox/Y</sup> mice). We also injected <em>Htr2c</em>-targeting short hairpin RNA (shRNA) into the paraventricular nucleus of the hypothalamus (PVH) of <em>Crh</em>-ires-cre mice to knock down <em>Htr2c</em> selectively in CRH neurons within the PVH (CRH<sup>PVH</sup> neurons). Using these model mice, we tested the effects of WAY161503, a selective <em>Htr2c</em> agonist, on CRH neuronal activity <em>ex vivo</em> as well as fasting-induced food intake and plasma corticosterone (CORT) levels <em>in vivo</em>.</div></div><div><h3>Results</h3><div>WAY161503 inhibited the activity of CRH<sup>PVH</sup> neurons. The appetite-suppressing effects of WAY161503 were significantly attenuated when <em>Htr2c</em> was deleted selectively in CRH<sup>PVH</sup> neurons. On the other hand, WAY161503 promoted the reduction of plasma CORT levels during fasting-induced refeeding <em>via Htr2c</em> expressed by CRH<sup>PVH</sup> neurons. Importantly, when mice were pretreated with RU486, a glucocorticoid receptor antagonist that blocks CORT action, WAY161503 suppressed food intake whether CRH<sup>PVH</sup> neurons expressed functional <em>Htr2c</em> or not. Finally, we characterized the expression of single-minded 1 (<em>Sim1</em>) messenger RNA (mRNA), <em>Crh</em> mRNA, and <em>Htr2c</em> mRNA in PVH neurons, which may help to explain the effects of <em>Htr2c</em> stimulation on fasting-induced refeeding.</div></div><div><h3>Conclusions</h3><div>Our results demonstrate that <em>Htr2c</em> expression in the CRH<sup>PVH</sup> 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 <em>Htr2c</em> stimulation during fasting-induced refeeding. To our knowledge, this study is the first to highlight the necessity of coordination between n
{"title":"Serotonin 2C receptors inhibit hypothalamic CRH neurons to suppress appetite","authors":"Eun-Seon Yoo , Jieun Yu , Moonsun Sa , C. Justin Lee , Jong-Woo Sohn","doi":"10.1016/j.metabol.2025.156431","DOIUrl":"10.1016/j.metabol.2025.156431","url":null,"abstract":"<div><h3>Objectives</h3><div>The serotonin 2C receptor (<em>Htr2c</em>) 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 <em>Htr2c</em> stimulation. To develop a safe and effective anti-obesity medication targeting <em>Htr2c</em>, we need to better understand how <em>Htr2c</em> agonists suppress appetite. In this study, we focused on the effects of <em>Htr2c</em> agonists on corticotropin-releasing hormone (CRH) neurons to identify the contribution of humoral components to the suppression of fasting-induced food intake.</div></div><div><h3>Methods</h3><div>We used the <em>Crh</em>-ires-cre mice to fluorescently label CRH neurons for whole-cell patch-clamp recordings (<em>Crh</em>-ires-cre::tdTomato mice) and to delete <em>Htr2c</em> selectively in CRH neurons by breeding with <em>Htr2c</em><sup>flox/Y</sup> mice (<em>Crh</em>-ires-cre::<em>Htr2c</em><sup>flox/Y</sup> mice). We also injected <em>Htr2c</em>-targeting short hairpin RNA (shRNA) into the paraventricular nucleus of the hypothalamus (PVH) of <em>Crh</em>-ires-cre mice to knock down <em>Htr2c</em> selectively in CRH neurons within the PVH (CRH<sup>PVH</sup> neurons). Using these model mice, we tested the effects of WAY161503, a selective <em>Htr2c</em> agonist, on CRH neuronal activity <em>ex vivo</em> as well as fasting-induced food intake and plasma corticosterone (CORT) levels <em>in vivo</em>.</div></div><div><h3>Results</h3><div>WAY161503 inhibited the activity of CRH<sup>PVH</sup> neurons. The appetite-suppressing effects of WAY161503 were significantly attenuated when <em>Htr2c</em> was deleted selectively in CRH<sup>PVH</sup> neurons. On the other hand, WAY161503 promoted the reduction of plasma CORT levels during fasting-induced refeeding <em>via Htr2c</em> expressed by CRH<sup>PVH</sup> neurons. Importantly, when mice were pretreated with RU486, a glucocorticoid receptor antagonist that blocks CORT action, WAY161503 suppressed food intake whether CRH<sup>PVH</sup> neurons expressed functional <em>Htr2c</em> or not. Finally, we characterized the expression of single-minded 1 (<em>Sim1</em>) messenger RNA (mRNA), <em>Crh</em> mRNA, and <em>Htr2c</em> mRNA in PVH neurons, which may help to explain the effects of <em>Htr2c</em> stimulation on fasting-induced refeeding.</div></div><div><h3>Conclusions</h3><div>Our results demonstrate that <em>Htr2c</em> expression in the CRH<sup>PVH</sup> 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 <em>Htr2c</em> 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}
Pub Date : 2025-12-01Epub Date: 2025-07-30DOI: 10.1016/j.metabol.2025.156360
Pierre-Anne R. Laird , Rebecca M. Wall , Siobhan M. Craige
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.
{"title":"The intersection of exercise, nitric oxide, and metabolism: Unraveling the role of eNOS in skeletal muscle and beyond","authors":"Pierre-Anne R. Laird , Rebecca M. Wall , 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}
Pub Date : 2025-12-01Epub Date: 2025-09-16DOI: 10.1016/j.metabol.2025.156390
Shuman Ran , Siqi Wang , Qi Jin , Genzheng Liu , Xiaobin Xue , Peng Qu , Liang Peng , Hua Meng
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.
{"title":"Emerging role of E4BP4/NFIL3 in metabolic homeostasis","authors":"Shuman Ran , Siqi Wang , Qi Jin , Genzheng Liu , Xiaobin Xue , Peng Qu , Liang Peng , 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}
Pub Date : 2025-12-01Epub Date: 2025-09-13DOI: 10.1016/j.metabol.2025.156391
Anna Giannakogeorgou , Sabine Kahl , Cesare Granata , Geronimo Heilmann , Lucia Mastrototaro , Bedair Dewidar , Pavel Bobrov , Irene Esposito , Aslihan Yavas , Sandra Trenkamp , Frank A. Granderath , Matthias Schlensak , Christos S. Mantzoros , Michael Roden , Patrick Schrauwen
Background and purpose
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.
Methods
Humans without (n = 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.
Results
Serum GDF15 correlated negatively with M-value (r = −0.35, p = 0.017) and NEFA suppression (r = −0.29, p = 0.046), but not with hepatic mitochondrial respiration across the whole cohort. However, correlations were found upon stratification into groups based on the presence (n = 37, age: 41 ± 2y, BMI: 49 ± 1 kg/m2) or absence of hepatic fibrosis (n = 23, 44 ± 2 years, BMI: 49 ± 1 kg/m2). In persons without fibrosis, GDF15 correlated positively with fatty acid oxidation-linked (FP; r = 0.35, p = 0.035) and maximal coupled (FNSP; r = 0.42, p = 0.010) mitochondrial respiration. Conversely, GDF15 correlated negatively with hepatic FNP in persons with fibrosis (r = −0.48, p = 0.022).
Conclusions
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.
{"title":"Relationship of GDF15 with hepatic mitochondrial respiration is depending on the presence of fibrosis in obese individuals","authors":"Anna Giannakogeorgou , Sabine Kahl , Cesare Granata , Geronimo Heilmann , Lucia Mastrototaro , Bedair Dewidar , Pavel Bobrov , Irene Esposito , Aslihan Yavas , Sandra Trenkamp , Frank A. Granderath , Matthias Schlensak , Christos S. Mantzoros , Michael Roden , 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/m<sup>2</sup>) or absence of hepatic fibrosis (<em>n</em> = 23, 44 ± 2 years, BMI: 49 ± 1 kg/m<sup>2</sup>). In persons without fibrosis, GDF15 correlated positively with fatty acid oxidation-linked (F<sub>P</sub>; <em>r</em> = 0.35, <em>p</em> = 0.035) and maximal coupled (FNS<sub>P</sub>; <em>r</em> = 0.42, <em>p</em> = 0.010) mitochondrial respiration. Conversely, GDF15 correlated negatively with hepatic FN<sub>P</sub> 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}
Pub Date : 2025-12-01Epub Date: 2025-09-09DOI: 10.1016/j.metabol.2025.156387
Deng Fu Guo , Zili Luo , Alexis Olson , Donald A. Morgan , Elizabeth A. Newell , Kamal Rahmouni
Aims
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.
Methods and results
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.
Conclusions
These findings identify neuronal SerpinA3N as a key regulator of energy balance, leptin and insulin sensitivity, and autonomic function.
{"title":"SerpinA3N in leptin-sensitive neurons is required for energy and glucose homeostasis and autonomic regulation","authors":"Deng Fu Guo , Zili Luo , Alexis Olson , Donald A. Morgan , Elizabeth A. Newell , 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}
Pub Date : 2025-12-01Epub Date: 2025-08-28DOI: 10.1016/j.metabol.2025.156375
Dengxiong Li , Jie Wang , Ruicheng Wu , Qingxin Yu , Fanglin Shao , Dilinaer Wusiman , Zhipeng Wang , Zhouting Tuo , Luxia Ye , Yiqing Guo , Koo Han Yoo , Zhihong Liu , William C. Cho , Dechao Feng
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.
嵌合抗原受体（CAR）细胞疗法已经成为一种突破性的癌症治疗方法，为难治性肿瘤患者提供了新的希望。尽管取得了成功，但CAR细胞疗法的治疗效果经常受到肿瘤微环境（TME）内代谢因素的破坏，这些代谢因素阻碍了CAR细胞的功能并导致治疗耐药性。目前的文献并没有充分探讨这些代谢过程是如何导致CAR细胞治疗失败的，特别是在实体肿瘤的背景下，TME提出了独特的挑战。解决这一差距对于提高CAR细胞疗法在更广泛的癌症中的有效性至关重要。在这里，我们回顾了影响CAR细胞治疗结果的代谢机制的最新研究，从临床前研究到临床应用。我们对来自PubMed和Web of Science的研究进行了综合分析，重点关注各种代谢过程（如缺氧、免疫细胞因子信号传导、糖酵解、腺嘌呤代谢、细胞衰老、乳酸增加和胆固醇代谢）如何影响CAR细胞功能，包括细胞毒性、增殖、干细胞和活化。此外，我们还研究了CAR细胞与TME的其他成分（如肿瘤细胞、基质细胞和细胞外基质）之间的相互作用如何导致免疫抑制环境，从而降低CAR细胞的功效。我们还讨论了克服这些代谢障碍的潜在策略，包括开发具有增强代谢调节、基因表达调节的CAR细胞，以及将CAR细胞治疗与现有药物治疗相结合。我们的研究结果强调了代谢在血液和实体肿瘤中形成CAR细胞疗法抗肿瘤疗效的关键作用。通过靶向TME内的代谢途径，有可能增强CAR细胞的浸润、功能和持久性，从而克服耐药性并改善治疗结果。这种方法不仅解决了当前CAR细胞疗法的一个关键限制，而且为未来更有效的癌症治疗铺平了道路。
{"title":"Modulating metabolism to improve the therapeutic outcomes of CAR cell therapies: From bench to bedside","authors":"Dengxiong Li , Jie Wang , Ruicheng Wu , Qingxin Yu , Fanglin Shao , Dilinaer Wusiman , Zhipeng Wang , Zhouting Tuo , Luxia Ye , Yiqing Guo , Koo Han Yoo , Zhihong Liu , William C. Cho , 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}
Pub Date : 2025-12-01Epub Date: 2025-09-15DOI: 10.1016/j.metabol.2025.156393
Thiago dos Reis Araujo , Joel Alves da Silva Junior , Bruna Lourençoni Alves , Dimitrius Santiago Passos Simões Fróes Guimarães , Lohanna Monali Barreto , Mariana Roberta Rodrigues Muniz , Jennifer Rieusset , Everardo Magalhães Carneiro
Aims/hypothesis
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).
Methods
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.
Results
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.
Conclusions/interpretation
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.
{"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 , Joel Alves da Silva Junior , Bruna Lourençoni Alves , Dimitrius Santiago Passos Simões Fróes Guimarães , Lohanna Monali Barreto , Mariana Roberta Rodrigues Muniz , Jennifer Rieusset , 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}
Pub Date : 2025-12-01Epub Date: 2025-09-15DOI: 10.1016/j.metabol.2025.156392
Jinni Yang , Xue Yang , Yuan Zheng , Anhui Wang , Ziwen Kong , Qinwen Xiao , Yuan Tian , Haijuan Dong , Zunjian Zhang , Min Wang , Rui Song
Background and aims
Insulin resistance is a key driver of metabolic disorders, yet its molecular mechanisms remain elusive. This study identifies 27-hydroxycholesterol (27HC), a cholesterol-derived metabolite, and investigates its role in insulin resistance.
Methods
Targeted metabolomics quantified absolute and relative levels of 27HC (27HC/cholesterol ratio) in patients, mice, and hepatocytes. Insulin resistant mouse models were established to characterize spatiotemporal dynamics of 27HC and related enzymes. Functional analyses assessed 27HC's effect on insulin signaling across multiple hepatocyte types. Transcriptomic analysis identified key effector pathways. Plasma membrane cholesterol accessibility was evaluated using biosensors and validated by cholesterol rescue. Membrane protein extraction, immunofluorescence, and flow cytometry were employed to assess the impact of 27HC on insulin receptor (IR) distribution and binding capacity.
Results
Elevated 27HC levels were observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), obese and type 2 diabetic mice (T2DM), and PA-treated HepG2 and primary hepatocytes, correlating with impaired insulin sensitivity. CYP27A1 was identified as the key enzyme regulating liver 27HC levels. In vitro studies demonstrated that 27HC disrupts insulin signaling in HepG2, AML12, and primary hepatocytes, whereas CYP27A1 knockdown restored IR responsiveness. 27HC suppresses SREBP2-dependent cholesterol biosynthesis, depleting accessible cholesterol in the plasma membrane, triggering IR mislocalization and signal attenuation. Liver-specific CYP27A1 silencing in mice fed a high-fat diet improved systemic insulin sensitivity and restored metabolic homeostasis.
Conclusion
Our findings establish 27HC as a key effector linking cholesterol metabolism to insulin resistance and propose CYP27A1 inhibition as a potential therapeutic strategy for insulin resistance.
{"title":"27-Hydroxycholesterol exacerbates hepatic insulin resistance via plasma membrane cholesterol remodeling","authors":"Jinni Yang , Xue Yang , Yuan Zheng , Anhui Wang , Ziwen Kong , Qinwen Xiao , Yuan Tian , Haijuan Dong , Zunjian Zhang , Min Wang , Rui Song","doi":"10.1016/j.metabol.2025.156392","DOIUrl":"10.1016/j.metabol.2025.156392","url":null,"abstract":"<div><h3>Background and aims</h3><div>Insulin resistance is a key driver of metabolic disorders, yet its molecular mechanisms remain elusive. This study identifies 27-hydroxycholesterol (27HC), a cholesterol-derived metabolite, and investigates its role in insulin resistance.</div></div><div><h3>Methods</h3><div>Targeted metabolomics quantified absolute and relative levels of 27HC (27HC/cholesterol ratio) in patients, mice, and hepatocytes. Insulin resistant mouse models were established to characterize spatiotemporal dynamics of 27HC and related enzymes. Functional analyses assessed 27HC's effect on insulin signaling across multiple hepatocyte types. Transcriptomic analysis identified key effector pathways. Plasma membrane cholesterol accessibility was evaluated using biosensors and validated by cholesterol rescue. Membrane protein extraction, immunofluorescence, and flow cytometry were employed to assess the impact of 27HC on insulin receptor (IR) distribution and binding capacity.</div></div><div><h3>Results</h3><div>Elevated 27HC levels were observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), obese and type 2 diabetic mice (T2DM), and PA-treated HepG2 and primary hepatocytes, correlating with impaired insulin sensitivity. CYP27A1 was identified as the key enzyme regulating liver 27HC levels. In vitro studies demonstrated that 27HC disrupts insulin signaling in HepG2, AML12, and primary hepatocytes, whereas CYP27A1 knockdown restored IR responsiveness. 27HC suppresses SREBP2-dependent cholesterol biosynthesis, depleting accessible cholesterol in the plasma membrane, triggering IR mislocalization and signal attenuation. Liver-specific CYP27A1 silencing in mice fed a high-fat diet improved systemic insulin sensitivity and restored metabolic homeostasis.</div></div><div><h3>Conclusion</h3><div>Our findings establish 27HC as a key effector linking cholesterol metabolism to insulin resistance and propose CYP27A1 inhibition as a potential therapeutic strategy for insulin resistance.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"173 ","pages":"Article 156392"},"PeriodicalIF":11.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081130","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}
Pub Date : 2025-11-01Epub Date: 2025-08-07DOI: 10.1016/j.metabol.2025.156374
Daoqi Shen , Liyu Lin , Yiqi Su , Ying Huang , Yaqiong Wang , Jiarui Xu , Wuhua Jiang , Zhen Zhang , Xiaoqiang Ding , Xialian Xu
Background
The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is characterized by persistent renal fibrosis, in which abnormal lipid metabolism plays a crucial role. Syndecan-1 (SDC-1) has been implicated in various tissue remodeling processes; however, its role in lipid metabolism and fibrosis during the progression from AKI to CKD is not well understood.
Methods
This study used a murine model of unilateral ischemia-reperfusion-induced AKI-to-CKD progression for in vivo analysis and employed transforming growth factor-beta (TGF-β)-induced fibrosis in Human Kidney-2 cells and primary mouse tubular epithelial cells for in vitro studies. The tubule-specific knockout and overexpression of SDC-1 mice were utilized to investigate kidney fibrosis and lipid metabolism.
Results
Following unilateral ischemia-reperfusion and TGF-β stimulation, SDC-1 expression was significantly reduced, exacerbating renal fibrosis. Notably, SDC-1 deficiency led to lipid accumulation in the kidneys, while its overexpression alleviated lipid overload and improved metabolic parameters. Furthermore, SDC-1 played a crucial role in regulating fatty acid-binding protein 7 (FABP7), and its absence resulted in increased FABP7 levels. Inhibition of FABP7 not only reduced fibrosis but also restored carnitine palmitoyltransferase 1α expression, which suggests that the SDC-1/FABP7 axis is critical for maintaining lipid homeostasis and mitigating fibrosis in the kidney.
Conclusion
These findings underscore the importance of SDC-1 in lipid metabolism and suggest that targeting lipid metabolic pathways may represent therapeutic strategies that can slow the progression of AKI to CKD.
{"title":"Syndecan-1 regulates lipid metabolism and mitigates fibrosis during the transition from acute kidney injury to chronic kidney disease","authors":"Daoqi Shen , Liyu Lin , Yiqi Su , Ying Huang , Yaqiong Wang , Jiarui Xu , Wuhua Jiang , Zhen Zhang , Xiaoqiang Ding , Xialian Xu","doi":"10.1016/j.metabol.2025.156374","DOIUrl":"10.1016/j.metabol.2025.156374","url":null,"abstract":"<div><h3>Background</h3><div>The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is characterized by persistent renal fibrosis, in which abnormal lipid metabolism plays a crucial role. Syndecan-1 (SDC-1) has been implicated in various tissue remodeling processes; however, its role in lipid metabolism and fibrosis during the progression from AKI to CKD is not well understood.</div></div><div><h3>Methods</h3><div>This study used a murine model of unilateral ischemia-reperfusion-induced AKI-to-CKD progression for in vivo analysis and employed transforming growth factor-beta (TGF-β)-induced fibrosis in Human Kidney-2 cells and primary mouse tubular epithelial cells for in vitro studies. The tubule-specific knockout and overexpression of SDC-1 mice were utilized to investigate kidney fibrosis and lipid metabolism.</div></div><div><h3>Results</h3><div>Following unilateral ischemia-reperfusion and TGF-β stimulation, SDC-1 expression was significantly reduced, exacerbating renal fibrosis. Notably, SDC-1 deficiency led to lipid accumulation in the kidneys, while its overexpression alleviated lipid overload and improved metabolic parameters. Furthermore, SDC-1 played a crucial role in regulating fatty acid-binding protein 7 (FABP7), and its absence resulted in increased FABP7 levels. Inhibition of FABP7 not only reduced fibrosis but also restored carnitine palmitoyltransferase 1α expression, which suggests that the SDC-1/FABP7 axis is critical for maintaining lipid homeostasis and mitigating fibrosis in the kidney.</div></div><div><h3>Conclusion</h3><div>These findings underscore the importance of SDC-1 in lipid metabolism and suggest that targeting lipid metabolic pathways may represent therapeutic strategies that can slow the progression of AKI to CKD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"172 ","pages":"Article 156374"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812129","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}
Pub Date : 2025-11-01Epub Date: 2025-07-24DOI: 10.1016/j.metabol.2025.156356
Yanyan Cao , Yan Wang , Na Zhao , Ziyue Yuan , Lan Zhang , Peng Jin
Mitochondrial sirtuins, including SIRT3, SIRT4, and SIRT5, play pivotal roles in maintaining mitochondrial homeostasis by regulating oxidative phosphorylation, energy metabolism, and redox balance. Dysregulation of these enzymes is closely associated with the pathogenesis of aging-related diseases such as neurodegenerative diseases, metabolic diseases, and cardiovascular diseases. SIRT3 has been the most extensively studied, demonstrating protective effects against oxidative stress and metabolic dysregulation. In contrast, while SIRT4 and SIRT5 are less characterized, they are critical for the regulation of insulin sensitivity, nitrogen metabolism, and mitochondrial function. This review focuses on the involvement of mitochondrial sirtuins in modulating cellular metabolism, redox balance, and mitochondrial homeostasis, highlighting their roles in the development and progression of aging-related diseases. Furthermore, we provide an overview of small-molecule modulators targeting mitochondrial sirtuins, which aim to restore cellular function, attenuate aging processes, and offer novel therapeutic strategies for treating aging-related diseases.
{"title":"Unraveling the roles of mitochondrial sirtuins in aging-related diseases: From mechanistic insights to therapeutic strategies","authors":"Yanyan Cao , Yan Wang , Na Zhao , Ziyue Yuan , Lan Zhang , Peng Jin","doi":"10.1016/j.metabol.2025.156356","DOIUrl":"10.1016/j.metabol.2025.156356","url":null,"abstract":"<div><div>Mitochondrial sirtuins, including SIRT3, SIRT4, and SIRT5, play pivotal roles in maintaining mitochondrial homeostasis by regulating oxidative phosphorylation, energy metabolism, and redox balance. Dysregulation of these enzymes is closely associated with the pathogenesis of aging-related diseases such as neurodegenerative diseases, metabolic diseases, and cardiovascular diseases. SIRT3 has been the most extensively studied, demonstrating protective effects against oxidative stress and metabolic dysregulation. In contrast, while SIRT4 and SIRT5 are less characterized, they are critical for the regulation of insulin sensitivity, nitrogen metabolism, and mitochondrial function. This review focuses on the involvement of mitochondrial sirtuins in modulating cellular metabolism, redox balance, and mitochondrial homeostasis, highlighting their roles in the development and progression of aging-related diseases. Furthermore, we provide an overview of small-molecule modulators targeting mitochondrial sirtuins, which aim to restore cellular function, attenuate aging processes, and offer novel therapeutic strategies for treating aging-related diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"172 ","pages":"Article 156356"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718172","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}
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