American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Modulation of peripheral energy metabolism through central leucine administration in rainbow trout (<i>Oncorhynchus mykiss</i>).","authors":"Sara Comesaña, Gabriel Pérez-Tierra, Jessica Calo, Cristina Velasco, Marta Conde-Sieira, José L Soengas","doi":"10.1152/ajpendo.00066.2025","DOIUrl":"10.1152/ajpendo.00066.2025","url":null,"abstract":"<p><p>We aimed to evaluate the role of central leucine administration in the modulation of peripheral energy metabolism in fish. For this, rainbow trout (<i>Oncorhynchus mykiss</i>) were administered via intracerebroventricular 1 μL·100 g^-1 body mass of saline solution alone (Control) or containing 10 μg·μL^-1 of leucine. Samples of plasma, liver, adipose tissue, white muscle, and red muscle were collected 1- and 3-h postinjection. Firstly, metabolite levels were assessed in plasma and liver and a decrease in liver triglyceride at 1 h and an increase in plasma fatty acid at 3 h were observed. Metabolites levels were also assessed in white muscle, revealing decreased levels of α-amino acids and glycogen at 1 h. In addition, liver enzymatic activity and mRNA levels related to glucose, fatty acid, and amino acid metabolism showed no relevant changes. Then, energy metabolism in adipose tissue and muscle was assessed by examining the mRNA abundance of genes related to metabolism and oxidative capacity, thermogenesis, mitochondrial dynamics (mitochondrial fusion and fission), and other metabolic regulatory factors. Mitochondrial fusion was significantly influenced at 1-h postinjection in white muscle (upregulation of <i>mfn1</i>, <i>mfn2</i>, <i>tfam</i>, and <i>opa1</i>) and to a lesser extent in red muscle (upregulation of <i>tfam</i>). These findings differ from studies in mammals with leucine and in fish with other nutrients, in which liver metabolism is modulated. This also highlights the importance of leucine and its relationship with muscle and mitochondrial dynamics in controlling energy homeostasis in fish.<b>NEW & NOTEWORTHY</b> We studied how central leucine administration affects peripheral energy metabolism in rainbow trout. No significant changes were found in liver metabolism, differing from mammalian comparable studies and from changes in hypothalamic energy status elicited by other nutrients in fish. Mitochondrial fusion was notably influenced in white muscle and to a lesser extent in red muscle. These findings highlight the unique role of leucine in the maintenance of energy homeostasis in fish.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E314-E323"},"PeriodicalIF":3.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615832","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}

{"title":"Nonequilibrium thermodynamic analysis of human bioenergetics in obesity: implications of the second law.","authors":"Nawfal Istfan","doi":"10.1152/ajpendo.00487.2024","DOIUrl":"10.1152/ajpendo.00487.2024","url":null,"abstract":"<p><p>The fundamental principle of energy balance, a statement of the first law of thermodynamics, overlooks the second law, resulting in gaps in our knowledge of body weight regulation and obesity. This study develops research tools to implement nonequilibrium thermodynamics in human subjects based on a mitochondrial energy conversion model. A key advancement measures ATP phosphorylation through its relationship to the mitochondrial redox couple, beta-hydroxybutyrate, and acetoacetate. Applying this methodology in humans, utilizing data from a recent study, provides a comprehensive understanding of the impact of the second law. The results demonstrate that oxidative phosphorylation efficiency is approximately 57%, with minor but significant variations among individuals. Four out of 24 healthy subjects exhibited a sufficiently higher efficiency of oxidative phosphorylation and lower free energy dissipation compared to the remaining subjects. Feeding is associated with lower efficiency, a higher rate of free energy dissipation, and a slight reduction in coupling. The amount of energy utilized for useful work represents only one-third of resting energy expenditure. These findings are integrated with the current principle of energy balance to adhere to the constraints of the first and second laws. Based on theoretical modeling, it is demonstrated that interindividual differences and variations in mitochondrial efficiency and energy dissipation during specific metabolic conditions can lead to discrepancies between total energy balance and the balance of the fraction of energy used for useful work. Consequently, the constraints imposed by the second law should be incorporated into the current understanding of energy balance and obesity.<b>NEW & NOTEWORTHY</b> This article introduces the second law of thermodynamics as an integral component of the study of human energy metabolism. The concepts of efficiency and energy dissipation are unified with the current understanding of energy balance in human subjects. It is important to note that the energy utilized in biological processes constitutes only a fraction of the total energy metabolism. Measurement of this fraction relative to total energy expenditure elucidates the body's mechanisms for adapting to fuel scarcity and abundance, as exemplified by weight gain and weight loss.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E191-E209"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309363","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}

{"title":"Genealogical Rabson-Mendenhall syndrome caused by <i>INSR</i> gene mutation.","authors":"Xuewen Yuan, Ziyang Zhu, Chao Liang","doi":"10.1152/ajpendo.00285.2024","DOIUrl":"10.1152/ajpendo.00285.2024","url":null,"abstract":"<p><p>Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder caused by mutations in the insulin receptor gene (<i>INSR</i>), leading to severe insulin resistance. Clinical manifestations of RMS include hypertrichosis and acanthosis nigricans. A 3-yr-old male patient presented with darkened skin on the neck, without any apparent precipitating factors, and did not exhibit symptoms of polyuria or polydipsia. Both the patient and his older sister displayed signs of hypertrichosis and acanthosis nigricans. Laboratory investigations revealed significantly elevated levels of insulin and C-peptide. Genetic testing identified two mutations in the <i>INSR</i> gene: c.3614C>T in exon 20 and c.3670G>A in exon 21, with the latter being a novel mutation previously unreported in RMS. His sister also exhibited similar clinical features and harbored the same mutations. Consequently, both siblings were diagnosed with RMS. The novel mutation c.3670G>A in exon 21, inherited from the father, is likely to impair insulin receptor function by disrupting tyrosine kinase activity, thereby contributing to the pathogenesis of genealogical RMS.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E227-E232"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273981","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}

{"title":"Ketone metabolites in metabolic dysfunction-associated steatotic liver disease progression: optimizing keto-therapeutic strategies.","authors":"Taylor J Kelty, Alexa A Krause, R Scott Rector","doi":"10.1152/ajpendo.00178.2025","DOIUrl":"10.1152/ajpendo.00178.2025","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) ranges from simple steatosis to hepatocellular injury, inflammation, and fibrosis, ultimately leading to end-stage liver disease. Despite its rising prevalence, treatment options remain limited, highlighting the need for novel therapeutic strategies. In recent years, ketone metabolism has emerged as a key modulator of hepatic metabolic health. Hepatic ketogenesis provides a mechanism for fatty acid mobilization. Endogenously synthesized ketone metabolites can then provide energy for hepatic nonparenchymal cells and extrahepatic tissues. Ketones also function as signaling molecules that can reduce key pathological drivers of MASLD progression. Impaired ketogenesis is observed in MASLD, contributing to metabolic inflexibility and liver dysfunction. Conversely, ketogenic interventions, including exogenous ketone supplementation and ketogenic diets, have been shown to be hepatoprotective, attenuating steatosis, inflammation, and fibrosis. Ketogenic enzyme loss- and gain-of-function studies have highlighted the roles of ketogenesis, ketolysis, and ketone metabolite conversion in MASLD, providing insights to refine keto-therapeutic strategies for disease management. This review seeks to offer a thorough examination of ketone metabolism in MASLD, exploring the mechanistic roles of ketone metabolites in disease progression, and highlighting gaps in the current literature to optimize keto-therapeutics and combat MASLD progression.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E290-E301"},"PeriodicalIF":3.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582830","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}

{"title":"Corrigendum for Li et al., volume 308, 2014, p. E257-E269.","authors":"","doi":"10.1152/ajpendo.00348.2014_COR","DOIUrl":"10.1152/ajpendo.00348.2014_COR","url":null,"abstract":"","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"329 2","pages":"E312-E313"},"PeriodicalIF":3.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726521","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}

{"title":"Breaking the vicious cycle: bitter compounds targeting metabolic defects and inflammation in Alzheimer's disease.","authors":"Hao Wu, Ling He, Li Dai","doi":"10.1152/ajpendo.00166.2025","DOIUrl":"10.1152/ajpendo.00166.2025","url":null,"abstract":"<p><p>Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive decline, poses an increasing global health burden among aging populations. Despite decades of research, its pathogenesis remains incompletely understood, and effective therapies are urgently needed. Growing evidence links AD progression to inflammation and type 2 diabetes mellitus (T2DM), with hyperglycemia, insulin resistance, and chronic inflammation synergistically driving neuronal dysfunction. These factors perpetuate a pathogenic \"metabolic-inflammatory cycle\": inflammatory cytokines disrupt insulin signaling, exacerbating insulin resistance, which further amplifies neuroinflammation. Whereas anti-inflammatory and antidiabetic drugs show limited clinical efficacy in AD, bitter compounds, natural and synthetic agents with pleiotropic bioactivities, offer a novel therapeutic avenue. Notably, bitter compounds such as the alkaloid berberine, the flavonoid naringenin, and synthetic bitter compounds such as denatonium benzoate and metformin exhibit dual anti-inflammatory and metabolic regulatory effects. Preclinical studies have demonstrated their ability to suppress neuroinflammation, restore insulin sensitivity, and mitigate amyloid/tau pathology, potentially disrupting the metabolic-inflammatory cycle. Emerging insights also highlight their modulation of the gut-brain axis, linking intestinal homeostasis to neuroprotection. This mini-review synthesizes current evidence on the interplay of T2DM and inflammation in AD, emphasizing how bitter compounds target immunometabolic cross talk. This review also briefly discusses the metabolic and anti-inflammatory properties of bitter compounds via the gut-brain axis, alongside their potential for combination with current anti-AD drugs, suggesting multidisciplinary collaboration. Further mechanistic studies and clinical validation are warranted to translate bitter compound-based therapies into practice, addressing unmet needs in AD management.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E266-E275"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582831","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}

{"title":"Behavior-driven monitoring of thermogenesis in mice using a thermal gradient ring.","authors":"Paulo De Melo, Nayara Pereira, Rafaela Braun Araujo, William T Festuccia, Thiago Mattar Cunha, Luiz Osório Leiria","doi":"10.1152/ajpendo.00133.2025","DOIUrl":"10.1152/ajpendo.00133.2025","url":null,"abstract":"<p><p>Accurately assessing whole body heat production requires reliable thermometry methods. In mice, common approaches include rectal temperature (RT) measurement, infrared (IR) thermography, and implanted probes. However, factors such as stress, handling, surgery, and variability limit their applicability for evaluating thermogenesis. The Thermal Gradient Ring (TGR), widely used in neuropathic pain and ion channel studies, consists of a circular structure with 12 temperature zones and an integrated camera for real-time behavior monitoring. This system allows for precise analysis of independent behavioral measures, including preferred temperature (PT), distance accumulation in the zones, locomotion pattern, and zone occupancy over time, thereby offering an indirect readout of thermoregulatory state. In this study, we evaluated TGR as a noninvasive tool to detect thermoregulatory behavior adaptations, quantifying zone occupancy time, mobility patterns across temperature gradients, and preferred temperature. Using models with both elevated (β-adrenergic stimulation and high-fat diet feeding) and reduced core body temperature [brown adipose tissue (BAT) lipectomy, uncoupling protein 1 (UCP1) deficiency, and cold exposure], we found that the TGR system reliably detects context-specific thermoregulatory behaviors that contribute to energy homeostasis, while simultaneously serving as a quantitative tool for evaluating thermogenic status. These findings suggest that TGR is a valuable tool for metabolic research, offering a reliable additional assessment for thermogenesis in mice.<b>NEW & NOTEWORTHY</b> The integration between adaptive thermogenesis and behavioral strategies governing metabolic state regulation in mice remains poorly characterized. Using a TGR system, we developed and validated a novel methodology for noninvasive, unbiased, and continuous monitoring of behavior-driven thermogenic capacity. Using loss- and gain-of-function models of BAT thermogenesis, we identified distinct behavioral strategies, mice dynamically adjusted locomotor activity and thermal zone occupancy to modulate heat production, directly reflecting their real-time monitoring of metabolic status.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E241-E253"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526034","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}

{"title":"Topical application of menthol enhances brown adipose tissue thermogenesis and fat oxidation in humans.","authors":"Hitoshi Wakabayashi, Tomomi Fujimoto, Aiko Miura, Juno Kita, Mami Matsushita, Toshimitsu Kameya, Takafumi Maeda, Masayuki Saito","doi":"10.1152/ajpendo.00243.2025","DOIUrl":"10.1152/ajpendo.00243.2025","url":null,"abstract":"<p><p>This study examined the relationship between human brown adipose tissue (BAT) activity and thermogenesis in response to topical menthol application, which activates the transient receptor potential melastatin-8 in individuals with various BAT activity. Thirteen healthy male participants were separated into high (<i>n</i> = 6) and low (<i>n</i> = 7) BAT groups based on BAT activity (SUV_max). They were placed in a supine position at 27°C for 120 min with 4% l-menthol or a control solution applied to their abdomen and lower limbs. Expired gas was measured to calculate energy expenditure (EE) and substrate oxidation. Menthol application increased EE at 60-120 min, with no effect in the controls. Changes in EE adjusted for free fat mass (ΔEE/FFM) were significantly higher following menthol treatment compared with the control application at 60-120 min in the high BAT group (<i>P</i> < 0.05), but not in the low BAT group. A significant positive correlation was observed between SUV_max and EE/FFM averaged over 60-120 min with menthol treatment (<i>r</i> = 0.57, <i>P</i> < 0.05), but not in the controls. Fat oxidation averaged over 60-120 min was significantly greater with menthol in the high BAT group (<i>P</i> < 0.05) compared with the low BAT group. Rectal temperature at 120 min was significantly higher with menthol treatment in the high BAT groups (<i>P</i> < 0.05); however, menthol showed a minor effect on vasomotor responses, with no effect from BAT activity. Taken together, topical menthol application enhances thermogenesis and fat oxidation, which depends, in part, on BAT activity.<b>NEW & NOTEWORTHY</b> This study examined the relationship between human brown adipose tissue (BAT) activity and thermogenesis in response to topical menthol application, which activates transient receptor potential melastatin-8. A significant positive correlation was observed between BAT activity and energy expenditure. Fat oxidation was significantly greater with menthol application in the individuals with high BAT activity. Taken together, topical menthol application enhances thermogenesis and fat oxidation, which depends, in part, on BAT activity in humans.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E302-E311"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599124","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}

{"title":"Resistance training volume dictates distinct redox molecular signature in white adipose tissue: a high-sensitivity proteomics study.","authors":"Ivo Vieira de Sousa Neto, Isabelle Souza Luz, Adelino Sanchez Ramos da Silva, Wendy Assis Silveira, Muhammad Tahir, Fabiane Hiratsuka Veiga de Souza, Paulo Eduardo Narcizo de Souza, Ramires Alsamir Tibana, Bernardo Petriz, Thiago Dos Santos Rosa, Jonato Prestes, Arkadiusz Nawrocki, Martin Røssel Larsen, Wagner Fontes, Rita de Cassia Marqueti","doi":"10.1152/ajpendo.00231.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00231.2025","url":null,"abstract":"<p><p>Although white adipose tissue (WAT) serves as a dynamic storage organ that regulates overall metabolism, the molecular impacts of resistance training (RT) on WAT are still not fully understood. Considering that training variables influence RT outcomes, understanding the relationship between exercise volume and WAT remodeling is crucial for elucidating adaptive mechanisms. The hypothesis posits that a higher volume of RT, specifically 8 weeks of climbing a vertical ladder for 8 sets (RT-8), will lead to more significant positive adaptations in WAT remodeling than a lower volume of 4 sets (RT-4). The investigation combined histological, molecular (proteomic), and biochemical analyses (EPR, zymography and ELISA) with bioinformatics tools. By high-throughput mass spectrometry-based proteomics, we quantified 4434 proteins in WAT of male rats and revealed that the RT-8 group displayed increased protein abundance associated with lipid transport, fatty acid unsaturation, and lipolysis compared to RT-4. Additionally, compared to sedentary controls, RT-8 showed enhanced antioxidant capacity through phase II antioxidant enzymes (thioredoxins, peroxiredoxins, glutathione transferases, and ferritin). In contrast, the RT-4 group did not significantly alter the redox proteome, but selectively upregulated first-line antioxidant defense via the α-Klotho/SOD/catalase axis. RT-4 was also associated with a reduction in ROS production (superoxide ion and hydrogen peroxide), matrix metalloproteinase-2 (MMP-2) activity and adipocyte cross-sectional area to a similar extent as RT-8, without disrupting redox balance, ubiquitin ligase complex activity, or inflammatory pathways. Our findings contribute to the growing body of literature suggesting that RT volume is a key determinant of the WAT proteomic signature, with training volume eliciting distinct molecular adaptations.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764372","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}

{"title":"Exendin-4 induced retching-like behavior mediated by postsynaptic effect via AMPA receptors in the area postrema of mice.","authors":"Hanting Ding, Mengtian Wang, Jian Zhang, Chenchen Wan, Zhaohuan Huang, Ling Liu, Ji Liu","doi":"10.1152/ajpendo.00174.2025","DOIUrl":"10.1152/ajpendo.00174.2025","url":null,"abstract":"<p><p>Although glucagon-like peptide-1 (GLP-1) analogs have been clinically approved for type 2 diabetes mellitus (T2DM) and obesity treatment for an extended period, their associated adverse effects of nausea and vomiting remain unsolved. To elucidate the neural mechanisms underlying GLP-1-induced emesis, we investigated how GLP-1 signaling in the area postrema (AP) modulates retching-like behavior in mice. Our experiments demonstrated that intraperitoneal administration of the GLP-1 receptor agonist Exendin-4 (Exn4) induced dose-dependent retching-like behavior, which was replicated by direct Exn4 administration into the AP. Notably, while vagal afferent denervation failed to attenuate Exn4-induced retching-like behavior, genetic ablation of GLP-1 receptor (GLP-1R) expression in the AP completely abolished this response, establishing AP GLP-1R as the critical mediator of GLP-1-associated emesis. Further mechanistic studies revealed that Exn4 enhances AP GLP-1R neuronal activity through a postsynaptic pathway dependent on AMPA receptor signaling. These findings provide a neural circuit basis for GLP-1-induced emesis and identify a potential therapeutic target for mitigating this clinically significant side effect.<b>NEW & NOTEWORTHY</b> Here, we used a mouse-based paradigm to identify that the retching-like behavioral effects are caused by direct central GLP-1R neurons activation in the caudal brainstem, independent of the vagal afferent pathway. Importantly, the activation of AP^GLP-1R is mediated by postsynaptic AMPA receptors, which strengthen excitatory currents. Thus, we revealed the target and neural basis of GLP-1 analog-induced vomiting effect, which highlights a potential intervening site for clinical treatment.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E254-E265"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582832","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}