Bernardete F. Melo, Joana F. Sacramento, Julien Lavergne, Fátima O. Martins, Daniela Rosendo-Silva, Clara Panzolini, Cláudia S. Prego, Aidan Falvey, Elena Olea, Paulo Matafome, Asuncion Rocher, Jesus Prieto-Lloret, Miguel C. Correia, Phillipe Blancou, Silvia V. Conde
Background and Aims
The development of innovative strategies to treat diabesity and its comorbidities is of major societal importance. The carotid bodies (CB), classically defined as O2 sensors, are also metabolic sensors whose dysfunction contributes to the genesis and progression of metabolic disturbances. Here, we tested the hypothesis that the CBs are key players in the neural hypothalamic-sympathetic circuit controlling glucose and energy homeostasis. Moreover, we investigated if abolishment of CB activity has an anti-diabesity effect in Wistar rats and C75BL/6J mice, associated with increased visceral white and brown adipose tissue (AT) metabolism and the restoration of sympathetic activity within these tissues.
Results
We demonstrate that resection of the carotid sinus nerve, the CB-sensitive nerve, promotes weight loss and restores metabolic function in obese rats and mice by enhancing tyrosine hydroxylase expression at the paraventricular nucleus of the hypothalamus and its efferent sympathetic neurons to the AT. Moreover, we found that CSN resection increases sympathetic integration and catecholaminergic action in the AT in a manner that restores or even increases AT metabolism.
Conclusion
We provide groundbreaking and innovative data showing a new circuit involving the CB-hypothalamus-sympathetic efferents and the AT in controlling glucose and energy homeostasis and so a novel pathway for managing diabesity.
{"title":"Reversal of Diabesity Through Modulating Sympathetic Inputs to Adipose Tissue Following Carotid Body Resection","authors":"Bernardete F. Melo, Joana F. Sacramento, Julien Lavergne, Fátima O. Martins, Daniela Rosendo-Silva, Clara Panzolini, Cláudia S. Prego, Aidan Falvey, Elena Olea, Paulo Matafome, Asuncion Rocher, Jesus Prieto-Lloret, Miguel C. Correia, Phillipe Blancou, Silvia V. Conde","doi":"10.1111/apha.70074","DOIUrl":"https://doi.org/10.1111/apha.70074","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>The development of innovative strategies to treat diabesity and its comorbidities is of major societal importance. The carotid bodies (CB), classically defined as O<sub>2</sub> sensors, are also metabolic sensors whose dysfunction contributes to the genesis and progression of metabolic disturbances. Here, we tested the hypothesis that the CBs are key players in the neural hypothalamic-sympathetic circuit controlling glucose and energy homeostasis. Moreover, we investigated if abolishment of CB activity has an anti-diabesity effect in Wistar rats and C75BL/6J mice, associated with increased visceral white and brown adipose tissue (AT) metabolism and the restoration of sympathetic activity within these tissues.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We demonstrate that resection of the carotid sinus nerve, the CB-sensitive nerve, promotes weight loss and restores metabolic function in obese rats and mice by enhancing tyrosine hydroxylase expression at the paraventricular nucleus of the hypothalamus and its efferent sympathetic neurons to the AT. Moreover, we found that CSN resection increases sympathetic integration and catecholaminergic action in the AT in a manner that restores or even increases AT metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We provide groundbreaking and innovative data showing a new circuit involving the CB-hypothalamus-sympathetic efferents and the AT in controlling glucose and energy homeostasis and so a novel pathway for managing diabesity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Meng Chen, Li Zeng, Xiangbo Chen, Lan Chen, Di Gao, Zhe Yang, Zhongmin Tian
Aim
Circulating branched-chain amino acids (BCAAs) have been widely found to be associated with the risk of hypertension, but mechanisms remain unclear. In this study, we hypothesized that BCAAs could alleviate the development of salt-induced hypertension in Dahl salt-sensitive (SS) rats. The objective was to explore whether long-term high-salt diets (a major dietary risk for high blood pressure) alter BCAAs levels in SS rats and how dietary BCAAs influence salt-induced hypertension.
Methods
SS rats received an 11-week dietary intervention to investigate the effects of dietary BCAAs on SS hypertension. Metabolic changes were studied using GC–MS and LC–MS/MS, as well as selected enzyme activity measurements. Western blotting was used to measure the protein levels of p-BCKDHA/BCKDHA and AQP. HUVECs and HK-2 cells were treated with 2 mM BCAAs for 24 h before measuring metabolites and enzyme activities.
Results
An 11-week high-salt diet increased blood pressure in SS rats, which was accompanied by reduced circulating BCAAs levels. Dietary BCAAs attenuated salt-induced hypertension, restored circulating BCAAs levels, and enhanced BCAAs metabolic activity. It also decreased aquaporin-1 (AQP1) levels in the renal cortex, promoting water and sodium excretion and improving renal function in SS rats. Additionally, metabolomic analysis demonstrated that dietary BCAAs enhanced arginine-NO metabolism in the kidneys and thoracic aorta of SS rats, promoting NOS-mediated NO synthesis and improving vasodilation. The promotion of NO synthesis by BCAAs was confirmed at the cellular level.
Conclusions
Long-term BCAAs intake promoted water and sodium excretion, enhanced NO synthesis in kidneys and thoracic aortas, and lowered blood pressure in SS rats on a high-salt diet, suggesting BCAAs may improve SS hypertension rather than exacerbate it.
目的循环支链氨基酸（BCAAs）已被广泛发现与高血压风险相关，但其机制尚不清楚。在本研究中，我们假设支链氨基酸可以缓解Dahl盐敏感（SS）大鼠盐致高血压的发展。目的是探讨长期高盐饮食（高血压的主要饮食风险）是否会改变SS大鼠的支链氨基酸水平，以及膳食支链氨基酸如何影响盐诱导的高血压。方法对SS大鼠进行为期11周的饮食干预，观察BCAAs对SS高血压的影响。通过GC-MS和LC-MS /MS以及选定的酶活性测量来研究代谢变化。Western blotting检测p-BCKDHA/BCKDHA及AQP蛋白水平。用2 mM BCAAs处理HUVECs和HK-2细胞24 h，测定代谢产物和酶活性。结果11周的高盐饮食使SS大鼠血压升高，并伴有循环BCAAs水平降低。膳食BCAAs可减轻盐性高血压，恢复循环BCAAs水平，并增强BCAAs代谢活性。降低肾皮质水通道蛋白-1 （AQP1）水平，促进水钠排泄，改善SS大鼠肾功能。此外，代谢组学分析表明，膳食BCAAs可增强SS大鼠肾脏和胸主动脉的精氨酸-NO代谢，促进nos介导的NO合成，改善血管舒张。在细胞水平上证实了BCAAs对NO合成的促进作用。结论长期摄入BCAAs可促进高盐饮食SS大鼠的水钠排泄，增强肾脏和胸主动脉NO合成，降低血压，提示BCAAs可改善而非加重SS高血压。
{"title":"Effects of Dietary BCAAs Intake on the Blood Pressure in Dahl Salt-Sensitive Rats","authors":"Meng Chen, Li Zeng, Xiangbo Chen, Lan Chen, Di Gao, Zhe Yang, Zhongmin Tian","doi":"10.1111/apha.70070","DOIUrl":"https://doi.org/10.1111/apha.70070","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Circulating branched-chain amino acids (BCAAs) have been widely found to be associated with the risk of hypertension, but mechanisms remain unclear. In this study, we hypothesized that BCAAs could alleviate the development of salt-induced hypertension in Dahl salt-sensitive (SS) rats. The objective was to explore whether long-term high-salt diets (a major dietary risk for high blood pressure) alter BCAAs levels in SS rats and how dietary BCAAs influence salt-induced hypertension.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>SS rats received an 11-week dietary intervention to investigate the effects of dietary BCAAs on SS hypertension. Metabolic changes were studied using GC–MS and LC–MS/MS, as well as selected enzyme activity measurements. Western blotting was used to measure the protein levels of p-BCKDHA/BCKDHA and AQP. HUVECs and HK-2 cells were treated with 2 mM BCAAs for 24 h before measuring metabolites and enzyme activities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>An 11-week high-salt diet increased blood pressure in SS rats, which was accompanied by reduced circulating BCAAs levels. Dietary BCAAs attenuated salt-induced hypertension, restored circulating BCAAs levels, and enhanced BCAAs metabolic activity. It also decreased aquaporin-1 (AQP1) levels in the renal cortex, promoting water and sodium excretion and improving renal function in SS rats. Additionally, metabolomic analysis demonstrated that dietary BCAAs enhanced arginine-NO metabolism in the kidneys and thoracic aorta of SS rats, promoting NOS-mediated NO synthesis and improving vasodilation. The promotion of NO synthesis by BCAAs was confirmed at the cellular level.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Long-term BCAAs intake promoted water and sodium excretion, enhanced NO synthesis in kidneys and thoracic aortas, and lowered blood pressure in SS rats on a high-salt diet, suggesting BCAAs may improve SS hypertension rather than exacerbate it.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mitochondrial dysfunction is pivotal in both the development and progression of cardiovascular diseases (CVDs), though its exact mechanisms remain unclear. Cardiolipin (CL), a key mitochondrial phospholipid, is involved in various mitochondrial functions, including dynamics, membrane integrity, oxidative phosphorylation, mitochondrial DNA maintenance, and mitophagy. Due to enzyme limitations in the CL biosynthesis pathway, premature CL undergoes remodeling to acquire the proper acyl content for its function. Disruption in CL composition leads to mitochondrial dysfunction, contributing significantly to CVDs. The purpose of this review is to explore the role of CL remodeling in the mechanism of mitochondrial dysfunction that occurs in CVDs.
Methods
This review examines CL’s critical role in mitochondrial function, the consequences of CL deficiencies in CVDs, and the impact of mutations or deficiencies in CL remodeling enzymes-tafazzin (TAZ), Acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1), and Monolysocardiolipin acyltransferase (MLCLAT1)-on CL homeostasis, mitochondrial function, and CVDs pathogenesis. Emerging CL-targeted therapies are also reviewed.
Results
Proper CL function is crucial for mitochondrial health and cardioprotection. Pathological CL remodeling due to mutations or deficiencies in TAZ, ALCAT1, or MLCLAT1, drives mitochondrial dysfunction and accelerates CVDs progression. Based on these insights, current CL-based therapeutic strategies are also summarized, including precision medicine/gene therapy, targeted pharmacotherapy, and dietary interventions.
Conclusion
Targeting CL may represent a promising clinical therapeutic strategy for CVDs.
{"title":"Cardiolipin Remodeling in Cardiovascular Diseases: Implication for Mitochondrial Dysfunction","authors":"Huijie Zhang, Fengzhi Yu, Zhenjun Tian, Dandan Jia","doi":"10.1111/apha.70073","DOIUrl":"https://doi.org/10.1111/apha.70073","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Mitochondrial dysfunction is pivotal in both the development and progression of cardiovascular diseases (CVDs), though its exact mechanisms remain unclear. Cardiolipin (CL), a key mitochondrial phospholipid, is involved in various mitochondrial functions, including dynamics, membrane integrity, oxidative phosphorylation, mitochondrial DNA maintenance, and mitophagy. Due to enzyme limitations in the CL biosynthesis pathway, premature CL undergoes remodeling to acquire the proper acyl content for its function. Disruption in CL composition leads to mitochondrial dysfunction, contributing significantly to CVDs. The purpose of this review is to explore the role of CL remodeling in the mechanism of mitochondrial dysfunction that occurs in CVDs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This review examines CL’s critical role in mitochondrial function, the consequences of CL deficiencies in CVDs, and the impact of mutations or deficiencies in CL remodeling enzymes-tafazzin (TAZ), Acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1), and Monolysocardiolipin acyltransferase (MLCLAT1)-on CL homeostasis, mitochondrial function, and CVDs pathogenesis. Emerging CL-targeted therapies are also reviewed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Proper CL function is crucial for mitochondrial health and cardioprotection. Pathological CL remodeling due to mutations or deficiencies in TAZ, ALCAT1, or MLCLAT1, drives mitochondrial dysfunction and accelerates CVDs progression. Based on these insights, current CL-based therapeutic strategies are also summarized, including precision medicine/gene therapy, targeted pharmacotherapy, and dietary interventions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Targeting CL may represent a promising clinical therapeutic strategy for CVDs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Taste cells expressing GPR120 and connected chorda tympani nerve (CT) fibers are necessary for obtaining specific information on long-chain fatty acids (FA) in mice. However, the functions of GPR40, GPR120, and CD36 in the posterior part of the tongue remain unclear. Therefore, the present study has examined the neuron types coding for FA information in the glossopharyngeal (GL) nerve and their functions.
Methods
We performed single-fiber recordings in the GL nerve from GPR120-knockout (KO) and wild-type (WT) mice and behavioral preference tests based on five-minute intake using WT mice after the CT (and greater petrosal) nerves were sectioned bilaterally.
Results
Single fibers were classified into FA-(F), S-, M-, electrolyte-(E), Q-type, and N-best groups, based on their maximal responses to oleic acid (OA), sucrose, monopotassium glutamate, HCl, quinine hydrochloride, and NaCl. Among the GL fibers, 3.8% of GPR120-KO and 11.8% of WT mice were F-type. Furthermore, 81.8% or more of the S- and M-type fibers showed responses to FAs in both mouse genotypes. Residual responses to FAs were substantially suppressed by GPR40 and CD36 antagonists in GPR120-KO mice. Preference scores for OA decreased significantly with the addition of CD36 or GPR40 antagonists. Additionally, the preference scores for monopotassium glutamate and sucrose decreased when the mice were conditioned to avoid OA.
Conclusion
These results suggest that GPR120 contributes only to the existence of F-type fibers and that CD36 and GPR40 mediate the palatable umami or sweet taste of FAs via the activation of S- and M-type fibers in the GL nerve.
{"title":"Fatty Acid Taste Quality Information via GPR40 and CD36 in the Posterior Tongue of Mice","authors":"Yumiko Nagai, Kenichi Tokita, Keiko Yasumatsu","doi":"10.1111/apha.70071","DOIUrl":"https://doi.org/10.1111/apha.70071","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Taste cells expressing GPR120 and connected chorda tympani nerve (CT) fibers are necessary for obtaining specific information on long-chain fatty acids (FA) in mice. However, the functions of GPR40, GPR120, and CD36 in the posterior part of the tongue remain unclear. Therefore, the present study has examined the neuron types coding for FA information in the glossopharyngeal (GL) nerve and their functions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed single-fiber recordings in the GL nerve from GPR120-knockout (KO) and wild-type (WT) mice and behavioral preference tests based on five-minute intake using WT mice after the CT (and greater petrosal) nerves were sectioned bilaterally.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Single fibers were classified into FA-(F), S-, M-, electrolyte-(E), Q-type, and N-best groups, based on their maximal responses to oleic acid (OA), sucrose, monopotassium glutamate, HCl, quinine hydrochloride, and NaCl. Among the GL fibers, 3.8% of GPR120-KO and 11.8% of WT mice were F-type. Furthermore, 81.8% or more of the S- and M-type fibers showed responses to FAs in both mouse genotypes. Residual responses to FAs were substantially suppressed by GPR40 and CD36 antagonists in GPR120-KO mice. Preference scores for OA decreased significantly with the addition of CD36 or GPR40 antagonists. Additionally, the preference scores for monopotassium glutamate and sucrose decreased when the mice were conditioned to avoid OA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These results suggest that GPR120 contributes only to the existence of F-type fibers and that CD36 and GPR40 mediate the palatable umami or sweet taste of FAs via the activation of S- and M-type fibers in the GL nerve.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sanja Vojvodić, Giorgia Roticiani, Mario Vazdar, Elena E. Pohl
Background
Mitochondrial energy can be stored as ATP or released as heat by uncoupling protein 1 (UCP1) during non-shivering thermogenesis in brown adipose tissue. UCP1, located in the inner mitochondrial membrane, reduces the proton gradient in the presence of long-chain fatty acids (FA). FA act as weak, protein-independent uncouplers, with the transport of the FA anion across the membrane being the rate-limiting step. According to the fatty acid cycling hypothesis, UCP1 catalyzes this step through an as-yet-undefined mechanism.
Methods
We used computational and experimental techniques, including all-atom molecular dynamics (MD) simulations, membrane conductance measurements, and site-directed mutagenesis.
Results
We identified two novel pathways for fatty acid anion translocation (sliding) at the UCP1 protein–lipid interface, ending at key arginine residues R84 and R183 in a nucleotide-binding region. This region forms a stable complex with fatty acid anion, which is crucial for anion transport. Mutations of these two arginines reduced membrane conductance, consistent with the MD simulation prediction that the arachidonic acid anion slides between helices H2–H3 and H4–H5, terminating at R84 and R183. Protonation of the arachidonic acid anion predicts its release from the protein–lipid interface, allowing it to move to either cytosolic or matrix leaflets of the membrane.
Conclusion
We provide a novel, detailed mechanism by which UCP1 facilitates fatty acid anion transport, as part of the fatty acid cycling process originally proposed by Skulachev. The residues involved in this transport are conserved in other SLC25 proteins, suggesting the mechanism may extend beyond UCP1 to other members of the superfamily.
{"title":"Molecular Dynamics Simulations of a Putative Novel Mechanism for UCP1-Assisted FA Anion Transport","authors":"Sanja Vojvodić, Giorgia Roticiani, Mario Vazdar, Elena E. Pohl","doi":"10.1111/apha.70068","DOIUrl":"https://doi.org/10.1111/apha.70068","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mitochondrial energy can be stored as ATP or released as heat by uncoupling protein 1 (UCP1) during non-shivering thermogenesis in brown adipose tissue. UCP1, located in the inner mitochondrial membrane, reduces the proton gradient in the presence of long-chain fatty acids (FA). FA act as weak, protein-independent uncouplers, with the transport of the FA anion across the membrane being the rate-limiting step. According to the fatty acid cycling hypothesis, UCP1 catalyzes this step through an as-yet-undefined mechanism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used computational and experimental techniques, including all-atom molecular dynamics (MD) simulations, membrane conductance measurements, and site-directed mutagenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified two novel pathways for fatty acid anion translocation (sliding) at the UCP1 protein–lipid interface, ending at key arginine residues R84 and R183 in a nucleotide-binding region. This region forms a stable complex with fatty acid anion, which is crucial for anion transport. Mutations of these two arginines reduced membrane conductance, consistent with the MD simulation prediction that the arachidonic acid anion slides between helices H2–H3 and H4–H5, terminating at R84 and R183. Protonation of the arachidonic acid anion predicts its release from the protein–lipid interface, allowing it to move to either cytosolic or matrix leaflets of the membrane.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We provide a novel, detailed mechanism by which UCP1 facilitates fatty acid anion transport, as part of the fatty acid cycling process originally proposed by Skulachev. The residues involved in this transport are conserved in other SLC25 proteins, suggesting the mechanism may extend beyond UCP1 to other members of the superfamily.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi Ying, Zhiwei Qiu, Jihan Liu, Yazhu Quan, Yongpan An, Feng Lu, Keying Wang, Min Li, Hong Zhou, Baoxue Yang
Aim
The aim of this study was to determine whether water or solute transport plays a critical role in AQP3-mediated urine concentrating ability, using AQP3 knockout (AQP3-KO) mice and a novel mouse model in which the AQP3 gene coding region is replaced with AQP4 cDNA (AQP4-KI).
Methods
AQP3-KO and AQP4-KI mice were characterized using Western blot and immunofluorescence to confirm the absence of AQP3 and the in situ replacement of AQP4. Urinary output, osmolality and urea concentration were measured in mouse models under various conditions, including water deprivation, acute urea loading and high protein intake.
Results
AQP3-KO mice exhibited a significantly increased daily urine output (6 times that in wild-type mice) and reduced urinary osmolality (< 1000 mOsm/kg), with a marked inability to concentrate urea and osmolality in response to water deprivation, urea loading or high protein intake. In contrast, AQP4-KI mice showed restoration of urine output, urinary osmolality and urea concentration, approaching wild-type levels.
Conclusion
In situ replacement of AQP3 with AQP4 restores AQP3-mediated water permeability in the renal collecting duct, rescuing the nephrogenic diabetes insipidus (NDI) phenotype in AQP3-deficient mice. This study provides evidence that AQP3-mediated water permeability plays a crucial role in the renal urine concentrating mechanism.
{"title":"Aquaporin-4-Mediated Water Permeability Rescues Aquaporin-3 Deficiency Caused Nephrogenic Diabetes Insipidus","authors":"Yi Ying, Zhiwei Qiu, Jihan Liu, Yazhu Quan, Yongpan An, Feng Lu, Keying Wang, Min Li, Hong Zhou, Baoxue Yang","doi":"10.1111/apha.70072","DOIUrl":"https://doi.org/10.1111/apha.70072","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The aim of this study was to determine whether water or solute transport plays a critical role in AQP3-mediated urine concentrating ability, using AQP3 knockout (AQP3-KO) mice and a novel mouse model in which the AQP3 gene coding region is replaced with AQP4 cDNA (AQP4-KI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>AQP3-KO and AQP4-KI mice were characterized using Western blot and immunofluorescence to confirm the absence of AQP3 and the in situ replacement of AQP4. Urinary output, osmolality and urea concentration were measured in mouse models under various conditions, including water deprivation, acute urea loading and high protein intake.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>AQP3-KO mice exhibited a significantly increased daily urine output (6 times that in wild-type mice) and reduced urinary osmolality (< 1000 mOsm/kg), with a marked inability to concentrate urea and osmolality in response to water deprivation, urea loading or high protein intake. In contrast, AQP4-KI mice showed restoration of urine output, urinary osmolality and urea concentration, approaching wild-type levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In situ replacement of AQP3 with AQP4 restores AQP3-mediated water permeability in the renal collecting duct, rescuing the nephrogenic diabetes insipidus (NDI) phenotype in AQP3-deficient mice. This study provides evidence that AQP3-mediated water permeability plays a crucial role in the renal urine concentrating mechanism.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Steffen L. Hartmeyer, Nicholas E. Phillips, Friedrich C. Jassil, Céline Joris, Charna Dibner, Tinh-Hai Collet, Marilyne Andersen
Aim
As our understanding of light's impact on human health grows, studies examining light exposure and related health outcomes in everyday settings are increasingly important, particularly in high-risk groups like nightshift workers.
Methods
In this observational study, we monitored personal light exposure and physiological functions in a large cohort of healthcare nightshift workers using a spectrally resolved light dosimeter and wearable body temperature, actigraphy, and electrocardiography sensors.
Results
Our findings revealed a common occurrence of unfavorable light conditions during both shift types. During nightshift work, participants frequently experienced exposure to biologically potent cool-white LED lighting. On dayshifts, melanopic light levels often failed to meet recommended guidelines, with daylight as the primary source of bright light levels. Sleep duration, but not quality, significantly varied between shifts, with longer sleep before the first nightshift but shorter sleep on subsequent nights. Daytime and nighttime napping helped compensate for reduced sleep on nightshifts. Limited associations between light exposure and sleep were found, partially contradicting existing knowledge. Diurnal physiological and activity rhythms followed the change from day-active to night-active schedules; however, the change in physiological rhythms appeared partly dissociated from that of activity, suggesting a circadian modulation. Moreover, physiological functions exhibited bi-directional phase-shifts across consecutive nightshifts, which may have been mediated by differences in daytime light exposure before the first nightshift.
Conclusion
By employing a multi-wearable approach including recent sensors, we provide new insights into the lighting environments experienced by nightshift workers and the potential impact of nightshift work and light exposure on endogenous circadian rhythms.
{"title":"Multi-Wearable Approach for Monitoring Diurnal Light Exposure and Body Rhythms in Nightshift Workers","authors":"Steffen L. Hartmeyer, Nicholas E. Phillips, Friedrich C. Jassil, Céline Joris, Charna Dibner, Tinh-Hai Collet, Marilyne Andersen","doi":"10.1111/apha.70069","DOIUrl":"https://doi.org/10.1111/apha.70069","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>As our understanding of light's impact on human health grows, studies examining light exposure and related health outcomes in everyday settings are increasingly important, particularly in high-risk groups like nightshift workers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this observational study, we monitored personal light exposure and physiological functions in a large cohort of healthcare nightshift workers using a spectrally resolved light dosimeter and wearable body temperature, actigraphy, and electrocardiography sensors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our findings revealed a common occurrence of unfavorable light conditions during both shift types. During nightshift work, participants frequently experienced exposure to biologically potent cool-white LED lighting. On dayshifts, melanopic light levels often failed to meet recommended guidelines, with daylight as the primary source of bright light levels. Sleep duration, but not quality, significantly varied between shifts, with longer sleep before the first nightshift but shorter sleep on subsequent nights. Daytime and nighttime napping helped compensate for reduced sleep on nightshifts. Limited associations between light exposure and sleep were found, partially contradicting existing knowledge. Diurnal physiological and activity rhythms followed the change from day-active to night-active schedules; however, the change in physiological rhythms appeared partly dissociated from that of activity, suggesting a circadian modulation. Moreover, physiological functions exhibited bi-directional phase-shifts across consecutive nightshifts, which may have been mediated by differences in daytime light exposure before the first nightshift.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>By employing a multi-wearable approach including recent sensors, we provide new insights into the lighting environments experienced by nightshift workers and the potential impact of nightshift work and light exposure on endogenous circadian rhythms.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Duncan Mitchell, Shane K. Maloney, Edward P. Snelling, Robyn S. Hetem, Andrea Fuller
Most experts agree that the dominant mechanism through which body temperature is regulated, under a thermal challenge, environmental or metabolic, is negative feedback control. However, some consider negative feedback to be too sluggish to account for the rapid speed of response. The impression of sluggishness is based on an assumption that the body temperature that is regulated is a core temperature, whereas we concur with those who have concluded that what is regulated is an integrated temperature compiled from inputs from multiple body parts, including the skin. Negative feedback control is supplemented, though, by feedforward control, which is initiated by cues about the predicted magnitude and timing of the thermal challenge. Feedforward control is anticipatory because it can excite thermo-effectors in advance of the thermal challenge impacting on body temperature. Feedforward control is improved by learning but always is supervised by feedback control. There is disagreement about whether the pro-active excitation of thermo-effectors by temperature receptors in the skin occurs by fast feedback control or by feedforward control. We show that skin temperature receptors can provide physiologically meaningful negative feedback within seconds. Both the feedback and the feedforward regulation of integrated body temperature can be modulated by regulation of the temperature of body parts that have special thermoregulatory needs, notably the scrotum.
{"title":"Revisiting Concepts of Thermal Physiology: Understanding Feedback and Feedforward Control, and Local Temperature Regulation","authors":"Duncan Mitchell, Shane K. Maloney, Edward P. Snelling, Robyn S. Hetem, Andrea Fuller","doi":"10.1111/apha.70063","DOIUrl":"https://doi.org/10.1111/apha.70063","url":null,"abstract":"<p>Most experts agree that the dominant mechanism through which body temperature is regulated, under a thermal challenge, environmental or metabolic, is negative feedback control. However, some consider negative feedback to be too sluggish to account for the rapid speed of response. The impression of sluggishness is based on an assumption that the body temperature that is regulated is a core temperature, whereas we concur with those who have concluded that what is regulated is an integrated temperature compiled from inputs from multiple body parts, including the skin. Negative feedback control is supplemented, though, by feedforward control, which is initiated by cues about the predicted magnitude and timing of the thermal challenge. Feedforward control is anticipatory because it can excite thermo-effectors in advance of the thermal challenge impacting on body temperature. Feedforward control is improved by learning but always is supervised by feedback control. There is disagreement about whether the pro-active excitation of thermo-effectors by temperature receptors in the skin occurs by fast feedback control or by feedforward control. We show that skin temperature receptors can provide physiologically meaningful negative feedback within seconds. Both the feedback and the feedforward regulation of integrated body temperature can be modulated by regulation of the temperature of body parts that have special thermoregulatory needs, notably the scrotum.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70063","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144190664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mayra Colardo, Noemi Martella, Michela Varone, Daniele Pensabene, Giuseppina Caretti, Gianluca Bianchini, Andrea Aramini, Marco Segatto
Aim
Cancer cachexia is a severe metabolic disorder leading to skeletal muscle atrophy. Muscle wasting is a major clinical problem in cachectic patients, as it limits the efficacy of chemotherapeutic treatments and worsens quality of life. Nutritional support based on branched-chain amino acids (BCAA) has been shown to be a promising approach to counteract cachexia-induced muscle atrophy, but its efficacy is still debated. Furthermore, the putative role of di-alanine (Di-Ala) supplementation has yet to be evaluated. The present study therefore sought to assess whether BCAA supplementation, alone or in combination with a Di-Ala peptide, could attenuate muscle wasting in a preclinical model of cancer cachexia.
Methods
To this end, C26 tumor-bearing mice were administered BCAA supplementation, with or without Di-Ala. Body and muscle weights, as well as molecular, biochemical, and morphological analysis, were carried out to characterize prospective changes of markers involved in cachexia and muscle atrophy.
Results
The main findings revealed that BCAA supplementation effectively prevented body weight loss and muscle atrophy. Of note, Di-Ala significantly amplified the effects of BCAA. These phenomena were found to be mediated by the suppression of pathways involved in protein catabolism.
Conclusions
Collectively, these results highlight that innovative formulations containing Di-Ala, capable of increasing BCAA bioavailability, may be efficacious in counteracting muscle atrophy, especially during mild-to-moderate cancer cachexia.
{"title":"Branched-Chain Amino Acids and Di-Alanine Supplementation Attenuates Muscle Atrophy in a Murine Model of Cancer Cachexia","authors":"Mayra Colardo, Noemi Martella, Michela Varone, Daniele Pensabene, Giuseppina Caretti, Gianluca Bianchini, Andrea Aramini, Marco Segatto","doi":"10.1111/apha.70067","DOIUrl":"https://doi.org/10.1111/apha.70067","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Cancer cachexia is a severe metabolic disorder leading to skeletal muscle atrophy. Muscle wasting is a major clinical problem in cachectic patients, as it limits the efficacy of chemotherapeutic treatments and worsens quality of life. Nutritional support based on branched-chain amino acids (BCAA) has been shown to be a promising approach to counteract cachexia-induced muscle atrophy, but its efficacy is still debated. Furthermore, the putative role of di-alanine (Di-Ala) supplementation has yet to be evaluated. The present study therefore sought to assess whether BCAA supplementation, alone or in combination with a Di-Ala peptide, could attenuate muscle wasting in a preclinical model of cancer cachexia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To this end, C26 tumor-bearing mice were administered BCAA supplementation, with or without Di-Ala. Body and muscle weights, as well as molecular, biochemical, and morphological analysis, were carried out to characterize prospective changes of markers involved in cachexia and muscle atrophy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The main findings revealed that BCAA supplementation effectively prevented body weight loss and muscle atrophy. Of note, Di-Ala significantly amplified the effects of BCAA. These phenomena were found to be mediated by the suppression of pathways involved in protein catabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Collectively, these results highlight that innovative formulations containing Di-Ala, capable of increasing BCAA bioavailability, may be efficacious in counteracting muscle atrophy, especially during mild-to-moderate cancer cachexia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>In this issue of <i>Acta Physiologica</i>, Tatzl et al. [<span>1</span>] investigate the relevance of the <i>leucine-rich repeat transmembrane protein 4 like 1</i> (<i>lrrtm4l1</i>) gene, a zebrafish orthologue of the human <i>LRRTM4</i>, on behavioral, transcriptomic, and metabolomic readouts in mixed sex adult zebrafish (summarized in Figure 1). <i>LRRTM4</i> is one of four members of the <i>LRRTM</i> gene family, which code for synaptic cell adhesion molecules that promote excitatory synapse development, including synaptic insertion and stabilization of AMPA receptors. <i>LRRTM4</i> is associated with neurodevelopmental disorders, including autism spectrum disorder (ASD) and attempted suicide [<span>2</span>].</p><p>Using RNASeq, the authors identified 126 differentially expressed genes in the telencephalon of <i>lrrtm4l1</i> knockout (<i>lrrtm4l1</i><sup><i>−/−</i></sup>) fish. Among these, they highlight the upregulation of <i>rimkla</i> and <i>arhgap12</i>. The <i>rimkla</i> gene is linked to cognition and memory consolidation [<span>3</span>]. The mammalian orthologue of the <i>arhgap12b</i> gene (i.e., <i>ARHGAP12</i>) promotes endocytosis of postsynaptic AMPA receptors, opposing the effect of <i>LRRTM4</i> [<span>4</span>]. Notable downregulated genes include <i>tyrosine hydroxylase</i>, essential for catecholamine synthesis, and <i>plasmolipin</i>, encoding a major component of myelin sheaths; both genes have previously been linked to various disorders. Pathway analyses implicated semaphorin-plexin signaling, as well as fatty acid metabolism and degradation, as well as valine, leucine, and isoleucine degradation. Semaphorin-plexin signaling is involved in axon guidance and neuronal morphogenesis during neurodevelopment and might stabilize synaptic transmission both during development and adulthood [<span>5</span>].</p><p>Consistent with the differentially expressed genes, metabolomic changes in <i>lrrtm4l1</i><sup><i>−/−</i></sup> zebrafish revealed elevated levels of homovanillic acid, the end product of dopamine metabolism, and lower levels of adenosine. Additionally, <i>lrrtm4l1</i><sup><i>−/−</i></sup> zebrafish showed a trend toward higher serotonin and lower melatonin levels. Unbiased metabolite feature analysis revealed six significant features, including two upregulated features with fragmentation profiles similar to phospholipids and one downregulated feature that was similar to methyl vanillate.</p><p>To investigate the consequences of the observed transcriptomic and metabolic alterations, the authors performed several behavioral experiments in <i>lrrtm4l1</i><sup><i>−/−</i></sup> and wild-type zebrafish. In the open field test, <i>lrrtm4l1</i><sup><i>−/−</i></sup> fish displayed a lower total distance traveled and nominally increased immobile time. Additionally, their swimming movements appeared more erratic, and they displayed increased thigmotaxis, a potential indicator of increased anxiety-like behavior. The increased a
在这一期的《生理学报》中，Tatzl等人研究了富含亮氨酸的重复跨膜蛋白4 like 1 （lrrtm4l1）基因与人类LRRTM4的斑马鱼同源基因，与雌雄同体成年斑马鱼的行为、转录组学和代谢组学数据的相关性（总结见图1）。LRRTM4是LRRTM基因家族的四个成员之一，其编码突触细胞粘附分子，促进兴奋性突触的发育，包括突触插入和AMPA受体的稳定。LRRTM4与神经发育障碍有关，包括自闭症谱系障碍（ASD）和自杀未遂。使用RNASeq，作者在lrrtm4l1敲除（lrrtm4l1−/−）鱼的端脑中鉴定了126个差异表达基因。其中，他们强调了rimkla和arhgap12的上调。rimkla基因与认知和记忆巩固有关。arhgap12b基因的哺乳动物同源基因（即ARHGAP12）促进突触后AMPA受体的内吞作用，与LRRTM4[4]的作用相反。显著下调的基因包括酪氨酸羟化酶（儿茶酚胺合成所必需的）和浆磷脂（髓鞘的主要成分）；这两种基因之前都与各种疾病有关。通路分析涉及信号通路，以及脂肪酸代谢和降解，以及缬氨酸，亮氨酸和异亮氨酸降解。信号通路参与神经发育过程中轴突的引导和神经元的形态发生，并可能在发育和成年期稳定突触传递。与差异表达基因一致的是，lrrtm4l1−/−斑马鱼的代谢组学变化表明，多巴胺代谢的最终产物同质香草酸水平升高，腺苷水平降低。此外，lrrtm4l1−/−斑马鱼表现出更高的血清素和更低的褪黑素水平的趋势。无偏代谢物特征分析揭示了6个显著特征，包括两个与磷脂相似的片段化上调特征和一个与香草酸甲酯相似的下调特征。为了研究观察到的转录组学和代谢改变的后果，作者在lrrtm4l1−/−和野生型斑马鱼中进行了几项行为实验。在野外测试中，lrrtm4l1−/−鱼显示出较低的总移动距离，名义上增加了静止时间。此外，他们的游泳动作似乎更不稳定，他们表现出更大的移动性，这是焦虑样行为增加的潜在指标。在新型的水箱潜水测试中，增加的底部居住进一步支持了焦虑的增加，以及进入浅色/深色水箱的浅色区（浅色区反映出更容易焦虑的隔间）的频率减少，尽管在浅色和黑暗隔间中花费的时间在基因型之间没有差异。为了测试社会（新奇）偏好，作者使用了走廊社会互动测试，他们发现两种基因型之间没有差异。值得注意的是，尽管lrrtm4l1 - / -鱼的整体社交能力完好无损，但在镜像测试中，lrrtm4l1 - / -鱼比野生型鱼表现出更少的攻击性行为。与攻击减少一致，作者可以在斑马鱼社会决策网络（SDMN）中涉及的远端脑区发现高水平的lrrtm4l1表达。SDMN被包括攻击性在内的社会遭遇激活，可能以性别特定的方式激活。总之，转录组学和代谢测量将lrrtm4l1与脂肪酸代谢和某些氨基酸的降解以及神经发育和突触传递联系起来。观察到的行为表型表明lrrtm4l1在常见精神表型中的作用。未来的研究测量其他大脑区域的神经递质和基因表达，可以揭示其他区域儿茶酚胺能系统的潜在改变，例如间脑，多巴胺能神经元突出，酪氨酸羟化酶被发现下调，同型香草酸水平升高。此外，正如作者所建议的那样，考虑到相关的精神表型，即ASD和图雷特综合征，在男性中比在女性中更常见，性别差异测试可能会为lrrtm4l1的工作机制提供进一步的见解。此外，LRRTM4在女性中显示出比男性更高的自杀企图相关性[b]，并且攻击行为也可能在性别之间表现出差异[b]。在更广泛的背景下，本研究的发现进一步支持了兴奋性突触调节紊乱与lrrtm，特别是LRRTM4在精神疾病病理中的潜在关键作用的相关性。 事实上，兴奋性（谷氨酸能）信号对包括抑郁症、精神分裂症和包括ASD在内的神经发育障碍在内的几种精神疾病的病理生理起着至关重要的作用，并与这些疾病的治疗有关[7-9]。lrrtm通过与突触前伙伴、神经素和硫酸肝素蛋白聚糖结合，促进兴奋性突触的发育和可塑性。此外，它们有助于突触后AMPA受体的稳定和维持（见图1中的示意图）。一致地，缺乏LRRTM4已被证明可降低突触兴奋性和整体突触数量[10]。这可能解释了lrrtm与几种精神障碍的关联。此外，研究结果显示磷脂的上调和脂肪酸代谢的变化突出了脂质信号在精神疾病中的重要作用。据我们所知，这是第一个将lrrtm与脂质信号/代谢联系起来的研究。脂质、脂质信号传导和脂质代谢越来越被认为是脑内和细胞间信号传导的重要介质。在一系列精神障碍患者和临床前模型中发现了不同脂质种类和参与脂质代谢和信号传导的基因的变化。重要的是，脂质信号与炎症有关，而炎症本身又与精神疾病有关。事实上，炎症对心理健康的影响被认为是通过脂质代谢介导的，可能是通过损害兴奋性突触的信号传导和可塑性[7,11]。因此，LRRTM4可能是炎症和脂质信号传导对突触病理影响的重要介质。总之，这项研究为进一步探索LRRTM4作为神经精神干预的候选靶点提供了一个有说服力的论据，特别是在以改变攻击和焦虑为特征的疾病中，但也可能不止于此。Maja R. Adel：概念化，写作-原稿，写作-审查和编辑。弗洛里安·弗罗伊登伯格：概念化，写作-原稿，写作-审查和编辑，可视化。作者声明无利益冲突。
{"title":"Lack of Synaptic Adhesion Proteins Makes Zebrafish More Anxious and Less Aggressive","authors":"Maja R. Adel, Florian Freudenberg","doi":"10.1111/apha.70065","DOIUrl":"https://doi.org/10.1111/apha.70065","url":null,"abstract":"<p>In this issue of <i>Acta Physiologica</i>, Tatzl et al. [<span>1</span>] investigate the relevance of the <i>leucine-rich repeat transmembrane protein 4 like 1</i> (<i>lrrtm4l1</i>) gene, a zebrafish orthologue of the human <i>LRRTM4</i>, on behavioral, transcriptomic, and metabolomic readouts in mixed sex adult zebrafish (summarized in Figure 1). <i>LRRTM4</i> is one of four members of the <i>LRRTM</i> gene family, which code for synaptic cell adhesion molecules that promote excitatory synapse development, including synaptic insertion and stabilization of AMPA receptors. <i>LRRTM4</i> is associated with neurodevelopmental disorders, including autism spectrum disorder (ASD) and attempted suicide [<span>2</span>].</p><p>Using RNASeq, the authors identified 126 differentially expressed genes in the telencephalon of <i>lrrtm4l1</i> knockout (<i>lrrtm4l1</i><sup><i>−/−</i></sup>) fish. Among these, they highlight the upregulation of <i>rimkla</i> and <i>arhgap12</i>. The <i>rimkla</i> gene is linked to cognition and memory consolidation [<span>3</span>]. The mammalian orthologue of the <i>arhgap12b</i> gene (i.e., <i>ARHGAP12</i>) promotes endocytosis of postsynaptic AMPA receptors, opposing the effect of <i>LRRTM4</i> [<span>4</span>]. Notable downregulated genes include <i>tyrosine hydroxylase</i>, essential for catecholamine synthesis, and <i>plasmolipin</i>, encoding a major component of myelin sheaths; both genes have previously been linked to various disorders. Pathway analyses implicated semaphorin-plexin signaling, as well as fatty acid metabolism and degradation, as well as valine, leucine, and isoleucine degradation. Semaphorin-plexin signaling is involved in axon guidance and neuronal morphogenesis during neurodevelopment and might stabilize synaptic transmission both during development and adulthood [<span>5</span>].</p><p>Consistent with the differentially expressed genes, metabolomic changes in <i>lrrtm4l1</i><sup><i>−/−</i></sup> zebrafish revealed elevated levels of homovanillic acid, the end product of dopamine metabolism, and lower levels of adenosine. Additionally, <i>lrrtm4l1</i><sup><i>−/−</i></sup> zebrafish showed a trend toward higher serotonin and lower melatonin levels. Unbiased metabolite feature analysis revealed six significant features, including two upregulated features with fragmentation profiles similar to phospholipids and one downregulated feature that was similar to methyl vanillate.</p><p>To investigate the consequences of the observed transcriptomic and metabolic alterations, the authors performed several behavioral experiments in <i>lrrtm4l1</i><sup><i>−/−</i></sup> and wild-type zebrafish. In the open field test, <i>lrrtm4l1</i><sup><i>−/−</i></sup> fish displayed a lower total distance traveled and nominally increased immobile time. Additionally, their swimming movements appeared more erratic, and they displayed increased thigmotaxis, a potential indicator of increased anxiety-like behavior. The increased a","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 7","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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