Endocrinology最新文献

12-Lipoxygenase inhibition improves glycemia and obesity-associated inflammation in male human gene replacement mice. 12-脂氧合酶抑制改善男性人类基因替代小鼠的血糖和肥胖相关炎症。

IF 3.8 3区医学

Endocrinology Pub Date : 2025-04-05 DOI: 10.1210/endocr/bqaf069

Kerim B Kaylan, Titli Nargis, Kayla Figatner, Jiayi E Wang, Sarida Pratuangtham, Advaita Chakraborty, Isabel Casimiro, Jerry L Nadler, Matthew B Boxer, David J Maloney, Ryan M Anderson, Raghavendra G Mirmira, Sarah A Tersey

{"title":"12-Lipoxygenase inhibition improves glycemia and obesity-associated inflammation in male human gene replacement mice.","authors":"Kerim B Kaylan, Titli Nargis, Kayla Figatner, Jiayi E Wang, Sarida Pratuangtham, Advaita Chakraborty, Isabel Casimiro, Jerry L Nadler, Matthew B Boxer, David J Maloney, Ryan M Anderson, Raghavendra G Mirmira, Sarah A Tersey","doi":"10.1210/endocr/bqaf069","DOIUrl":"https://doi.org/10.1210/endocr/bqaf069","url":null,"abstract":"Obesity-associated inflammation is characterized by macrophage infiltration into peripheral tissues, contributing to the progression of prediabetes and type 2 diabetes (T2D). 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and promotes the migration of macrophages, yet its role in obesity-associated inflammation remains incompletely understood. Furthermore, differences between mouse and human orthologs of 12-LOX have limited efforts to study existing pharmacologic inhibitors of 12-LOX. In this study, we utilized a human gene replacement mouse model in which the gene encoding mouse 12-LOX (Alox15) is replaced by the human ALOX12 gene. As a model of obesity and dysglycemia, we administered male mice a high-fat diet. We subsequently investigated the effects of VLX-1005, a potent and selective small molecule inhibitor of human 12-LOX. Oral administration of VLX-1005 resulted in improved glucose homeostasis, decreased β cell dedifferentiation, and reduced macrophage infiltration in islets and adipose tissue. Analysis of the stromal vascular fraction from adipose tissue showed a reduction in myeloid cells and cytokine expression with VLX-1005 treatment, indicating decreased adipose tissue inflammation. In a distinct mouse model in which Alox15 was selectively deleted in myeloid cells, we observed decreased β cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and T2D.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comment on 'Atlas of Fshr expression from novel reporter mice'. 对“新型报告小鼠Fshr表达图谱”的评论。

IF 3.8 3区医学

Endocrinology Pub Date : 2025-04-03 DOI: 10.1210/endocr/bqaf066

Livio Casarini, Nafis Rahman, Eric Reiter, Pascale Crépieux, Adolfo Rivero-Müller, Kim C Jonas, T Rajendra Kumar, Alfredo Ulloa-Aguirre, Stephen Franks, Daniel J Bernard, Stine Gry Kristensen, John S Davis, George R Bousfield, James A Dias, Claus Y Andersen, David J Handelsman, Ilpo T Huhtaniemi, Manuela Simoni

引用次数: 0

Weight gain with advancing age is controlled by the muscarinic acetylcholine receptor M4 in male mice. 雄性小鼠老年增重受毒蕈碱乙酰胆碱受体M4控制。

IF 3.8 3区医学

Endocrinology Pub Date : 2025-04-03 DOI: 10.1210/endocr/bqaf064

Toshio Takahashi, Yuta Takase, Akira Shiraishi, Shin Matsubara, Takehiro Watanabe, Shinji Kirimoto, Tohru Yamagaki, Masatake Osawa

{"title":"Weight gain with advancing age is controlled by the muscarinic acetylcholine receptor M4 in male mice.","authors":"Toshio Takahashi, Yuta Takase, Akira Shiraishi, Shin Matsubara, Takehiro Watanabe, Shinji Kirimoto, Tohru Yamagaki, Masatake Osawa","doi":"10.1210/endocr/bqaf064","DOIUrl":"https://doi.org/10.1210/endocr/bqaf064","url":null,"abstract":"Obesity is characterized by the excessive accumulation of adipose tissue, and it is a serious global health issue. Understanding the pathology of obesity is crucial for developing effective interventions. In this study, we investigated the role of muscarinic acetylcholine receptor M4 (mAChR-M4) in the regulation of obesity in Chrm4-knockout (M4-KO) mice. Male M4-KO mice showed higher weight gain and accumulation of white adipose tissue (WAT) with advancing age when compared to the wild-type mice. The M4-KO mice also showed increased leptin expression at both the transcription and translation levels. RNA sequencing and quantitative reverse transcription polymerase chain reaction analyses of subcutaneous adipose tissues revealed that the expression of WAT marker genes was significantly enhanced in the M4-KO mice. In contrast, the expression levels of brown adipose tissue/beige adipose tissue markers were strongly decreased in the M4-KO mice. To identify the Chrm4-expressing cell types, we generated Chrm4-mScarlet reporter mice and examined the localization of the mScarlet fluorescent signals in subcutaneous tissues. Fluorescent signals were prominently detected in WAT and mesenchymal stem cells. Additionally, we also found that choline acetyltransferase was expressed in macrophages, suggesting their involvement in acetylcholine (ACh) secretion. Corroborating this notion, we were able to quantitatively measure the ACh in subcutaneous tissues by liquid chromatography tandem mass spectrometry. Collectively, our findings suggest that endogenous ACh released from macrophages maintains the homeostasis of adipose cell growth and differentiation via mAChR-M4 in male mice. This study provides new insights into the molecular mechanisms underlying obesity and potential targets for therapeutic interventions.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transgenerational Effects of the Obesogen Tributyltin on Metabolic Health in Mice: Interactions with a Western Diet. 肥胖原三丁基廷对小鼠代谢健康的跨代影响：与西方饮食的相互作用。

IF 3.8 3区医学

Endocrinology Pub Date : 2025-04-03 DOI: 10.1210/endocr/bqaf063

Richard C Chang, Yikai Huang, Kaitlin To, Ryan Scott Whitlock, Katelyn Uyen Nguyen, Michelle Clara Joemon, Miranda Lopez, Kritin Guy Deeprompt, Toshi Shioda, Bruce Blumberg

{"title":"Transgenerational Effects of the Obesogen Tributyltin on Metabolic Health in Mice: Interactions with a Western Diet.","authors":"Richard C Chang, Yikai Huang, Kaitlin To, Ryan Scott Whitlock, Katelyn Uyen Nguyen, Michelle Clara Joemon, Miranda Lopez, Kritin Guy Deeprompt, Toshi Shioda, Bruce Blumberg","doi":"10.1210/endocr/bqaf063","DOIUrl":"https://doi.org/10.1210/endocr/bqaf063","url":null,"abstract":"Obesity is a global health crisis, with increasing evidence linking environmental factors such as exposure to endocrine-disrupting chemicals (EDCs) to its development. This study examines the transgenerational effects of exposure to the model obesogen, tributyltin (TBT), on obesity and metabolic health, specifically focusing on how these effects interact with a diet modeling the 50th percentile of US dietary consumption (the Total Western Diet, TWD). Pregnant F0 dams were exposed to TBT, and their offspring were subjected at adulthood to different diets, including a high-fat diet and TWD, across multiple subsequent generations (F1-F3). We found that TBT exposure predisposed male offspring to increased fat accumulation, insulin resistance, and metabolic dysfunction, effects that were exacerbated by the TWD. Notably, male offspring displayed elevated leptin levels, hepatic fibrosis, and inflammatory responses under TWD exposure, suggesting an additive or synergistic relationship between obesogen exposure and dietary fat intake. These transgenerational effects were largely absent in female offspring, underscoring sex-specific vulnerabilities to environmental and dietary factors. Our results demonstrated that the combination of prenatal TBT exposure and TWD amplifies metabolic disturbances across generations, highlighting the need to consider both environmental chemicals and dietary patterns in addressing the obesity pandemic. This study underscores the critical role of early-life EDC exposures and dietary factors in shaping long-term metabolic health and the potential for transgenerational programming of susceptibility to obesity and metabolic disorders.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lipotoxicity Induces Beta Cell Small Extracellular Vesicle-mediated β-cell Dysfunction in Male Mice. 脂肪毒性诱导β细胞细胞外小泡介导的雄性小鼠β细胞功能障碍。

IF 3.8 3区医学

Endocrinology Pub Date : 2025-04-03 DOI: 10.1210/endocr/bqaf067

Abhishek Roy, Alexandra Hoff, Tracy K Her, Gallage Ariyaratne, Roberto-León Gutiérrez, M H D Noor Tahawi, Kamalnath Sankaran Rajagopalan, Matthew R Brown, Kazuno Omori, Sean Lewis-Brinkman, Thanh Nguyen, Alondra Soto-González, Quinn P Peterson, Aleksey V Matveyenko, Naureen Javeed

{"title":"Lipotoxicity Induces Beta Cell Small Extracellular Vesicle-mediated β-cell Dysfunction in Male Mice.","authors":"Abhishek Roy, Alexandra Hoff, Tracy K Her, Gallage Ariyaratne, Roberto-León Gutiérrez, M H D Noor Tahawi, Kamalnath Sankaran Rajagopalan, Matthew R Brown, Kazuno Omori, Sean Lewis-Brinkman, Thanh Nguyen, Alondra Soto-González, Quinn P Peterson, Aleksey V Matveyenko, Naureen Javeed","doi":"10.1210/endocr/bqaf067","DOIUrl":"https://doi.org/10.1210/endocr/bqaf067","url":null,"abstract":"Chronically elevated circulating excess free fatty acids (i.e. lipotoxicity) is a pathological process implicated in several metabolic disorders, including obesity-driven Type 2 diabetes (T2D). Lipotoxicity exerts detrimental effects on pancreatic islet β-cells by reducing glucose-stimulated insulin secretion (GSIS), altering β-cell transcriptional identity, and promoting apoptosis. While β-cell-derived small extracellular vesicles (sEV) have been shown to contribute to β-cell failure in T2D, their specific role in lipotoxicity-mediated β-cell failure remains to be elucidated. In this work, we demonstrate that lipotoxicity enhances the release of sEVs from β-cells, which exhibit altered proteomic and lipidomic profiles. These PAL EV induce β-cell dysfunction in healthy mouse and human islets and trigger significant islet transcriptional changes, including the upregulation of genes associated with the TGFβ/Smad3 pathway, as noted by RNA sequencing. Importantly, pharmacological inhibition of the TGFβI/II receptor improved PAL EV-induced β-cell dysfunction, underscoring their involvement in activating the TGFβ/Smad3 pathway during this process. We have comprehensively characterized lipotoxic β-cell sEVs and implicated their role in inducing β-cell functional failure in T2D. These findings highlight potential avenues for therapeutic interventions targeting sEV-mediated pathways to preserve β-cell health in metabolic disorders.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Early embryo development: What does daddy do? 早期胚胎发育：爸爸做什么？

IF 3.8 3区医学

Endocrinology Pub Date : 2025-04-03 DOI: 10.1210/endocr/bqaf065

Rossella Cannarella, Roberto Curto, Rosita A Condorelli, Sandro La Vignera, Aldo E Calogero

{"title":"Early embryo development: What does daddy do?","authors":"Rossella Cannarella, Roberto Curto, Rosita A Condorelli, Sandro La Vignera, Aldo E Calogero","doi":"10.1210/endocr/bqaf065","DOIUrl":"https://doi.org/10.1210/endocr/bqaf065","url":null,"abstract":"Infertility represents a major global health challenge, with male infertility accounting for a significant proportion of cases, yet its underlying causes remain elusive in many instances. Traditionally, spermatozoa were viewed merely as DNA carriers, with little consideration given to their role beyond fertilization. Recent research, however, is challenging this view, revealing that spermatozoa are far more than passive delivery vehicles. They carry a complex array of molecules, particularly RNAs, which actively influence fertilization, early embryo development, and the transmission of paternal traits. These sperm-carried RNAs, including mRNAs, small RNAs, and non-coding RNAs, regulate gene expression in both spermatozoa and embryo, with profound implications for offspring development. Additionally, environmental factors, such as lifestyle choices and exposure to toxins, have been shown to affect sperm RNA composition, highlighting the dynamic interplay between genetics and the environment in shaping fertility. This emerging and evolving understanding of sperm function challenges traditional reproductive biology and offers new insights into male infertility, particularly in cases that remain unexplained by current diagnostic methods. While the exact molecular mechanisms underlying these processes are still being investigated, this paradigm shift opens the door to innovative diagnostic tools and therapeutic strategies for treating male infertility. By uncovering the critical role of sperm RNAs, these findings not only enhance our understanding of reproductive biology but also hold the promise to improve assisted reproductive technologies and outcomes for infertile couples.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GH-releasing hormone neurons regulate the hypothalamic-pituitary-somatotropic axis via short-loop negative feedback. gh释放激素神经元通过短环负反馈调节下丘脑-垂体-体促轴。

IF 3.8 3区医学

Endocrinology Pub Date : 2025-04-02 DOI: 10.1210/endocr/bqaf062

Daniela O Gusmao, Maria E de Sousa, Ligia M M de Sousa, Josiane N Silva, Renata Frazao, Edward O List, John J Kopchick, Jose Donato

{"title":"GH-releasing hormone neurons regulate the hypothalamic-pituitary-somatotropic axis via short-loop negative feedback.","authors":"Daniela O Gusmao, Maria E de Sousa, Ligia M M de Sousa, Josiane N Silva, Renata Frazao, Edward O List, John J Kopchick, Jose Donato","doi":"10.1210/endocr/bqaf062","DOIUrl":"https://doi.org/10.1210/endocr/bqaf062","url":null,"abstract":"Growth hormone (GH)-releasing hormone (GHRH) neurons are master regulators of GH secretion. However, the role of these cells in controlling pituitary GH secretion through short-loop negative feedback has not yet been fully clarified. Thus, GHRH-specific GH receptor (GHR) knockout (GHRHΔGHR) mice were generated, and possible consequences on GH secretion and body growth were determined. Approximately 60% of arcuate nucleus GHRH neurons exhibited GH-induced STAT5 phosphorylation, a marker of GHR-expressing cells. This response was practically eliminated in GHRHΔGHR mice. GHR ablation in GHRH-expressing cells increased body weight, lean mass, and naso-anal length in male and female mice without affecting fat mass. The higher body growth of GHRHΔGHR mice was associated with increases in GH secretion, mainly via higher pulsatile GH secretion and GH pulse amplitude. GHRHΔGHR female mice also showed increased GH pulse frequency and basal (non-pulsatile) secretion compared to control females. Liver Igf1 expression was increased only in GHRHΔGHR male mice. Mice carrying ablation of the insulin-like growth factor-1 (IGF-1) receptor (IGF1R) or both GHR and IGF1R in GHRH-expressing cells were generated. The increases in body growth and serum IGF-1 levels were significantly higher in GHRHΔGHR/IGF1R mice compared to GHRHΔGHR mice but similar to that observed in GHRHΔIGF1R mice. Electrophysiological experiments showed no acute changes in the activity of GHRH neurons after GH or IGF-1 exposure. In conclusion, GH feeds back on GHRH cells to control the hypothalamic-pituitary-somatotropic axis. However, IGF1R signaling prevails over GHR as the primary signal sensed by GHRH neurons to regulate GH secretion.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fifty Years of Support From the NIDDK for a Pioneer in Thyroid Research. NIDDK五十年来对甲状腺研究先驱的支持。

IF 3.8 3区医学

Endocrinology Pub Date : 2025-04-02 DOI: 10.1210/endocr/bqaf060

Antonio C Bianco

引用次数: 0

Primordial follicle survival and changes in ovarian vasculature may be independently regulated during chemotherapy. 原始卵泡存活和卵巢脉管系统的变化可能在化疗期间独立调节。

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-26 DOI: 10.1210/endocr/bqaf059

Wonmi So, Rosemary Dong, Donghee Lee, Amirhossein Abazarikia, Bryan T Hackfort, Andrea S Cupp, So-Youn Kim

{"title":"Primordial follicle survival and changes in ovarian vasculature may be independently regulated during chemotherapy.","authors":"Wonmi So, Rosemary Dong, Donghee Lee, Amirhossein Abazarikia, Bryan T Hackfort, Andrea S Cupp, So-Youn Kim","doi":"10.1210/endocr/bqaf059","DOIUrl":"10.1210/endocr/bqaf059","url":null,"abstract":"Chemotherapeutic agents induce irreversible gonadotoxic side effects, resulting in endocrine dysfunction and infertility in female cancer survivors. In the current study, we investigated strategies to protect ovarian function from chemotherapy-induced toxicity by evaluating the effects of cisplatin, doxorubicin, or cyclophosphamide on ovarian vasculature and primordial follicle survival. This investigation was conducted using adult CD-1, postnatal 5-7 CD-1, and oocyte-specific Trp63 conditional knockout (Trp63 cKO) mice that demonstrated primordial follicle survived following chemotherapy. In control ovaries, vasculature typically surrounds primordial and primary follicles, is in the theca layer as secondary follicles develop, and is distributed among stromal cells. Our findings revealed that the expression pattern of CD31/PECAM-1 (platelet endothelial adhesion molecule-1) was significantly altered in ovaries treated with chemotherapeutic agents compared to controls. The data demonstrate that these agents not only caused the loss of ovarian follicles but also damaged ovarian vasculature. Using Trp63 cKO mice and CK2II, an inhibitor of checkpoint kinase 2, we demonstrated that vascular damage can occur independently of primordial follicle loss, and VEGFA165 was unable to prevent either outcomes. This indicates that the mechanisms governing the death of primordial follicles and vascular damage may not directly affect each other. Long-term ex vivo culture and in vivo experiments demonstrated the ability of ovarian vasculature to recover from cisplatin-induced damage. In conclusion, our study suggests that the ovarian follicle survival and vascular integrity may be independently regulated as independent processes, governed by distinct signaling pathway or mechanisms.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Leptin Receptor Mutation Which Impairs Fertility in Ewes Causes Delayed Puberty in Male and Female Mice. 一种瘦素受体突变会损害母羊的生育能力，导致雄性和雌性老鼠的青春期延迟。

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-24 DOI: 10.1210/endocr/bqaf058

Rebecca A Lord, Megan A Inglis, Jennifer L Juengel, Greg M Anderson

{"title":"A Leptin Receptor Mutation Which Impairs Fertility in Ewes Causes Delayed Puberty in Male and Female Mice.","authors":"Rebecca A Lord, Megan A Inglis, Jennifer L Juengel, Greg M Anderson","doi":"10.1210/endocr/bqaf058","DOIUrl":"10.1210/endocr/bqaf058","url":null,"abstract":"Reproductive function is tightly linked to nutritional status due to its high energetic demands. Leptin, a key adipose tissue-derived hormone signalling energy reserves to the brain, integrates metabolic status with the hypothalamic-pituitary-gonadal axis to ensure reproductive function is maintained or suppressed appropriately. Mutations in leptin or its receptor (LepR) are known to cause infertility and obesity in mice. In Davisdale ewes, 2 naturally occurring LepR mutations (R62C and P1019S) were associated with delayed puberty and subfertility, but their effects in males or in other species remain to be determined. This study examined the impact of analogous LepR mutations (A63C and P1018S) in mice using CRISPR-Cas9 gene editing. Puberty onset, adult fertility, and metabolic phenotypes were assessed in wild-type, heterozygous, and homozygous mutant mice. The A63C mutation, located in the extracellular domain of the receptor, resulted in increased body weight and adiposity in females, along with delays in puberty onset in both sexes. Despite these delays, adult reproductive function was maintained. Immunohistochemical analysis revealed no detectable reductions in leptin-induced pSTAT3, pERK1/2, or pmTOR signalling in the hypothalamic arcuate nucleus in either mutant line, indicating these pathways remain largely intact. These findings demonstrate the conserved importance of this region of the leptin receptor for puberty onset and adiposity across species, but also the resilience of leptin signalling in preserving reproductive function despite genetic variation.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0