American journal of physiology. Endocrinology and metabolism最新文献

{"title":"HDAC1 deacetylates PGC-1α and its inhibition improves glucose homeostasis in diet-induced obese mice.","authors":"Chaim Atay Fainshtein, Or Maalumi, Keren-El De-Leon, Rachel Barkan-Michaeli, Kfir Sharabi","doi":"10.1152/ajpendo.00399.2024","DOIUrl":"10.1152/ajpendo.00399.2024","url":null,"abstract":"<p><p>Excessive hepatic glucose production (HGP) driven by increased gluconeogenesis is a hallmark of type 2 diabetes, making its inhibition a crucial strategy for reducing hyperglycemia. Central to HGP regulation is the transcriptional coactivator proliferator-activated receptor gamma coactivator 1α (PGC-1α), which promotes the expression of key gluconeogenic enzymes. The acetylation state of PGC-1α significantly influences its coactivating potential, with increased acetylation-whether induced genetically or chemically-shown to suppress its gluconeogenic activity and lower hyperglycemia. The delicate balance between specific acetyltransferases and deacetylases determines the acetylation status of PGC-1α and, consequently, its activity. Although the role of sirtuin deacetylases in PGC-1α acetylation has been extensively studied, zinc-dependent histone deacetylases (HDACs) have received less attention in this context. In this study, we demonstrate that HDAC1 strongly deacetylates PGC-1α, enhancing its ability to coactivate the transcription factor hepatic nuclear factor 4α. Furthermore, we show that depleting <i>Hdac1</i> in mouse primary hepatocytes and liver tissue reduces glucose production, consistent with decreased PGC-1α activity. Although the HDAC family has been investigated for their contributions to metabolic homeostasis, our findings reveal a specific mechanistic pathway by which HDAC1 modulates glucose homeostasis.<b>NEW & NOTEWORTHY</b> We identify HDAC1 as a regulator of PGC-1α acetylation and gluconeogenic activity in hepatocytes. Genetic depletion of HDAC1 increases PGC-1α acetylation in hepatocytes and reduces hepatic glucose production, revealing a previously unrecognized mechanism for glucose homeostasis. These findings highlight HDAC1 as a potential therapeutic target for type 2 diabetes.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E151-E159"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309361","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":"Promotion of obesity by fibroblast growth factor 21-oxytocin system dysfunction due to sugar-specific hyperphagia.","authors":"Hajime Mori, Kanako Inoue, Sho Matsui, Yasuo Oguri, Satoshi Tsuzuki, Tsutomu Sasaki","doi":"10.1152/ajpendo.00138.2025","DOIUrl":"10.1152/ajpendo.00138.2025","url":null,"abstract":"<p><p>Fibroblast growth factor (FGF) 21 activates oxytocin (OXT) neurons in the hypothalamus and suppresses simple sugar preference; however, alterations in the FGF21-OXT system in obesity remain unclear. In this study, we examined alterations in FGF21 secretion to systemic circulation and FGF21 sensitivity of OXT neurons in obesity, and the effects of FGF21-OXT dysfunction on feeding and body weight regulation. High-fat high-sucrose diet (HFHSD) feeding promoted hypersecretion of FGF21. The administration of recombinant FGF21 to normal diet-fed mice significantly activated OXT neurons in the paraventricular nucleus of the hypothalamus; this response was attenuated in HFHSD-fed mice. OXT neuron-specific FGF21 receptor-deficient (OXT<i>-Klb</i> cKO) mice were used as a model of FGF21-OXT dysfunction. The preference and appetite for sugar and fat were assessed using two-food choice test, two-bottle choice test, and lick microstructure analyses. The cKO mice showed an increased preference and appetite for FGF21-inducing simple sugars but not fat. These mice gained more weight when fed an HFHSD, which caused hyperphagia, but not when fed a high-fat diet. Therefore, obesity causes FGF21-OXT dysfunction, which promotes diet-induced obesity by increasing sugar appetite, suggesting that the dysfunction of the FGF21-OXT system plays a role in the vicious cycle of sugar-based diet-induced obesity in mice.<b>NEW & NOTEWORTHY</b> FGF21 activates OXT neurons and suppresses simple sugar preference, but the relationship between FGF21-OXT system and obesity is unknown. Here, we showed that obesity causes FGF21-OXT dysfunction and promotes sugar appetite and diet-induced obesity, suggesting that there is a vicious cycle of FGF21-OXT dysfunction and obesity in mice.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E18-E24"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186296","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":"Modeling hepatic glucose tracer kinetics from isotope dilution technique and deuterium metabolic imaging in postbariatric surgery and nonoperated individuals.","authors":"Alessandro Brunasso, Chiara Dalla Man, Simone Poli, Jeanine J Prompers, David Herzig, Roland Kreis, Lia Bally, Michele Schiavon","doi":"10.1152/ajpendo.00511.2024","DOIUrl":"10.1152/ajpendo.00511.2024","url":null,"abstract":"<p><p>Despite extensive research on liver metabolism, mathematical models describing hepatic glucose kinetics are currently limited due to the lack of organ-level data. Here, we propose a model of postprandial hepatic glucose kinetics exploiting liver deuterium metabolic imaging (DMI) data combined with plasma isotope dilution analysis in humans. We used data from 10 individuals who had previously undergone Roux-en-Y gastric bypass surgery (RYGB) and 10 healthy controls (HCs). The experimental setting included a labeled oral glucose tolerance test comprising 60 g of [6,6'-²H₂]-glucose in combination with liver DMI at 7 T. The hepatic glucose tracer signal was frequently quantified over 150 min, whereas peripheral plasma insulin and glucose tracer concentrations were measured in venous blood. The model was able to describe both liver and peripheral glucose tracer data well and provided estimates of postprandial glucose appearance and disposal in both the liver and the systemic circulation. The model predicted that almost all the ingested glucose had appeared in the liver in RYGB, but not in HC (89.0% vs. 64.0%, <i>P</i> = 0.008) after 150 min, whereas total hepatic disposal (RYGB = 26.4% vs. HC = 29.7%) and first-pass extraction (RYGB = 10.7% vs. HC = 11.4%) were similar between populations. The fraction of glucose eliminated in the periphery was greater in RYGB (49.9% vs. 25.3%, <i>P</i> = 0.003). Finally, no differences were observed in hepatic blood flow and GLUT2 transport rates. Although further studies are needed to validate and extend the model to include endogenous glucose production and disposal, it can be used to quantify parameters, and possibly reveal defects, of hepatic glucose handling.<b>NEW & NOTEWORTHY</b> The proposed hepatic model allows, for the first time, to describe postprandial liver glucose tracer kinetics in humans, allowing to estimate exogenous glucose appearance and disposal in the liver, as well as glucose transport and hepatic blood flow rate. The model may become a useful tool in clinical research by supporting the identification of metabolic defects at the hepatic level without requiring invasive procedures.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E102-E116"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141002","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 Henrique de Melo, Nayara Pereira, Rafaela Braun Araujo, William T Festuccia, Thiago Cunha, Luiz Osório Leiria","doi":"10.1152/ajpendo.00133.2025","DOIUrl":"https://doi.org/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 twelve 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 non-invasive 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 (BAT lipectomy, 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.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-30","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":"Sugar Type and Route of Delivery Influence Insulin and Glucose-Dependent Insulinotropic Polypeptide Responses in Rats.","authors":"A Valentina Nisi, Myrtha Ml Arnold, Ginger D Blonde, Lindsey Anne Schier, Graciela Sanchez-Watts, Alan G Watts, Wolfgang Langhans, Alan Craig Spector","doi":"10.1152/ajpendo.00460.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00460.2024","url":null,"abstract":"<p><p>To help resolve the characteristics of orally stimulated endocrine responses to sugar, we developed a novel rat preparation with surgically implanted intraoral (IO) and intragastric (IG) cannulas for stimulus delivery, along with jugular vein catheters for blood sampling, and tested the effects of 1-min and 10-min IO vs. IG infusions (1 mL/min) of 1.0M glucose on plasma levels of insulin, glucose-dependent insulinotropic polypeptide (GIP), and glucose. Oral glucose delivery (1-min and 10-min) caused a greater (p ≤ .05) early rise (1 min) in insulin levels than gastric glucose delivery, also reflected in the 3-min AUC. The 10-min, but not the 1-min, IO glucose infusion also caused a greater (p ≤ .05) increase in GIP levels than the IG infusions, as evidenced by the 3-min AUC. Oral delivery of 1.0M fructose produced marginally (but significantly) higher insulin and GIP levels than gastric fructose delivery, though the difference appeared much smaller than that observed for isomolar glucose, suggesting some degree of chemospecificity and the involvement of a T1R-independent mechanism. Our triple cannulation/catheterization rat preparation is well suited to assess endocrine responses to oral stimulation. By comparing the effects of stimulus infusion into the oral cavity (oral + post-oral stimulation) with the stimulus infusion directly into the stomach (only post-oral stimulation), we confirmed the primacy of glucose to orally trigger an increase in circulating insulin while controlling for changes in plasma glucose. This approach offers promise for reliably characterizing orally stimulated endocrine responses in rats and potentially in other animal models as well.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493414","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":"Metabolic Pathways and Male Fertility: Exploring the Role of Sertoli Cells in Energy Homeostasis and Spermatogenesis.","authors":"Zi-Feng Chen, Yi-Feng Shen, Da-Wei Gao, Deng-Feng Lin, Wen-Zhe Ma, De-Gui Chang","doi":"10.1152/ajpendo.00074.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00074.2025","url":null,"abstract":"<p><p>Globalization has driven a surge in noncommunicable diseases, including metabolic disorders, which are major global health challenges. These disorders, fueled by high-calorie diets, sedentary lifestyles, and gut microbiota imbalances, disrupt energy metabolism, gastrointestinal function, and vitamin and trace element homeostasis. Sertoli cells provide the metabolic and structural support essential for germ cell development within the seminiferous epithelium. This review examines how metabolic disorders affect male reproductive health, focusing on glucose, lipid, and vitamin metabolism, as well as the gut-testis axis, in relation to Sertoli cell function and the blood-testis barrier (BTB) integrity. Glucose metabolism in Sertoli cells provides lactate to germ cells, which is crucial for spermatogenesis. However, metabolic stressors, such as diabetes, impair glucose transport and lactate production, compromising energy supply. Lipid metabolism, including fatty acid oxidation and lipid droplet dynamics, is essential for energy homeostasis in Sertoli cells. Moreover, the gut microbiota further influences Sertoli cells and BTB integrity via metabolites, such as short-chain fatty acids, which enhance barrier function and reduce inflammation. Conversely, dysbiosis and microbially derived lipopolysaccharides induce oxidative stress and immune responses, leading to BTB disruption and infertility. Deficiencies or imbalances in the levels of these vitamins and trace elements can impair spermatogenesis. This review highlights the complex interplay between metabolic pathways and Sertoli cell function, their collective impact on male fertility, and provides a basis for developing targeted therapeutic strategies, including metabolic modulators, vitamin supplementation, and gut microbiota interventions, to mitigate the effects of metabolic disorders on spermatogenesis and fertility.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309362","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":"Non-equilibrium Thermodynamic Analysis of Human Bioenergetics in Obesity: Implications of the Second Law.","authors":"Nawfal Istfan","doi":"10.1152/ajpendo.00487.2024","DOIUrl":"https://doi.org/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 non-equilibrium 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 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 inter-individual 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.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-16","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":"FURIN R81C Variant: A Link to Type 2 Diabetes via Impaired Enzymatic Activity.","authors":"Ashraf Al Madhoun, Anwar Mohammad, Mohamed Abu-Farha, Prashantha Hebbar, Dania Haddad, Lavina Miranda, Arshad Channanath, Rasheeba Nizam, Malaika Bourashed, Rasheed Ahmad, Jehad Abubaker, Thangavel Alphonse Thanaraj, Fahd Al-Mulla","doi":"10.1152/ajpendo.00182.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00182.2024","url":null,"abstract":"<p><p>Furin, a proprotein convertase, regulates glucose homeostasis by processing the insulin receptor precursor. While the association of furin genetic variants with cardiac and neuronal diseases is well-established, studies investigating the association with type 2 diabetes (T2D) are scarce. This study aimed to examine the association of furin variants with T2D in an Arab cohort. Additionally, it sought to elucidate the functional impact of these diabetes-associated variants on furin stability and kinetic activity. Of the 15 rare missense variants in furin identified in global genomic studies, only one, rs148110342_C>T_(R81C), was found in our study cohort, with a minor allele frequency of 2.4%. Allele-based association testing, adjusted for age, sex, and body mass index, revealed significant associations between the rs148110342 and being T2D, and borderline associations with fasting plasma glucose, and HbA1c levels. Enzyme kinetic studies showed that the R81C variant has higher K_m values, indicating lower enzymatic activity compared to wild type furin. In silico structural modeling of the interactions between the R81C variant prodomain and the furin catalytic subunit revealed an increase in hydrogen bonding, which might explain the observed reduction in enzymatic activity. Furthermore, cell culture studies suggested that the R81C variant impairs furin's autocatalytic processing and its ability to cleave the precursor insulin receptor. A significant reduction in phosphorylation of ERK1/2 and AKT occurred in HEPG2 cells transfected with R81C variants, suggesting a downregulation of the IR signaling pathway. These findings suggest that the furin R81C variant can potentially impact insulin signaling and thereby contribute to T2D pathogenesis.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309360","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":"https://doi.org/10.1152/ajpendo.00285.2024","url":null,"abstract":"<p><p><b>Background:</b> Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder caused by mutations in the insulin receptor (INSR) gene, leading to severe insulin resistance. Clinical manifestations of RMS include hypertrichosis and acanthosis nigricans. <b>Case presentation:</b> A 3-year-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 he 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 INSR 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. <b>Conclusion:</b> 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":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-11","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":"Regulation of perinatal estrogen levels on primordial follicle formation and activation in mouse.","authors":"Rui Xu, Lu Yin, Yiqian Zhang, Yinxiang Niu, Sihai Lu, Yaju Tang, Sha Peng, Menghao Pan, Baohua Ma","doi":"10.1152/ajpendo.00026.2025","DOIUrl":"https://doi.org/10.1152/ajpendo.00026.2025","url":null,"abstract":"<p><p>Primordial follicle formation and activation are key for the reproductive ability of females. In mice, primordial follicles are formed and begin to activate during the perinatal period, when the levels of estrogen are fluctuating. Whether estrogen plays a role in primordial follicle formation and activation, and its mechanism are still not fully elucidated. In this study, estrogen remained at high levels before birth and declined after birth. When fetal mouse ovaries (E16.5) were cultured in vitro, higher levels (10 nM) of estrogen maintained the germ cell cysts, prevented primordial follicles from forming prematurely, and promoted the full differentiation of oocytes. Furthermore, it was found that estrogen-regulated JNK-signal pathway through both nuclear and membrane receptors, thereby inhibited the degradation of E-cadherin and maintained the germ cell cysts. After birth, ovarian estrogen concentration decreases and is accompanied by the activation of primordial follicles. Hence, the ovaries of newborn mice (P3) were treated with lower concentrations (0.1 nM) of estrogen to investigate the effect of estrogen on primordial follicle activation. The results demonstrated that estrogen regulated the protein expression of cAMP synthase adenylyl cyclase 3 (ADCY3) through the membrane receptor G-protein-coupled estrogen receptor (GPER), increased the level of cAMP in the ovary, and activated the cAMP-PKA signaling pathway to promote the activation of primordial follicles. This study revealed the regulatory role of perinatal estrogen levels on primordial follicle formation and activation before and after birth, which would help to better understand the potential physiological effect of estrogen in vivo.<b>NEW & NOTEWORTHY</b> In this study, the roles and underlying mechanisms of perinatal estrogen level changes in primordial follicle formation and activation in mice were elucidated. The elevated estrogen levels before birth inhibited the premature formation of primordial follicles and enhanced the quality of oocyte differentiation. Conversely, the reduced estrogen levels following birth promoted the activation of primordial follicles.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":"328 6","pages":"E772-E786"},"PeriodicalIF":4.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956570","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}