Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Physician-Scientist Development
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • In-Press Preview
    • Resource and Technical Advances
    • Clinical Research and Public Health
    • Research Letters
    • Editorials
    • Perspectives
    • Physician-Scientist Development
    • Reviews
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Resource and Technical Advances
  • Clinical Research and Public Health
  • Research Letters
  • Editorials
  • Perspectives
  • Physician-Scientist Development
  • Reviews
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact

Endocrinology

  • 267 Articles
  • 0 Posts
  • ← Previous
  • 1
  • 2
  • 3
  • …
  • 26
  • 27
  • Next →
Epigenetic Programming of Estrogen Receptor in Adipocytes by High Fat Diet Regulates Obesity-Induced Inflammation
Rui Wu, … , Bingzhong Xue, Hang Shi
Rui Wu, … , Bingzhong Xue, Hang Shi
Published August 26, 2025
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.173423.
View: Text | PDF

Epigenetic Programming of Estrogen Receptor in Adipocytes by High Fat Diet Regulates Obesity-Induced Inflammation

  • Text
  • PDF
Abstract

Adipose inflammation plays a key role in obesity-induced metabolic abnormalities. Epigenetic regulation, including DNA methylation, is a molecular link between environmental factors and complex diseases. Here we found that high fat diet (HFD) feeding induced a dynamic change of DNA methylome in mouse white adipose tissue (WAT) analyzed by reduced representative bisulfite sequencing. Interestingly, DNA methylation at the promoter of estrogen receptor α (Esr1) was significantly increased by HFD, concomitant with a down-regulation of Esr1 expression. HFD feeding in mice increased the expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a, and binding of DNMT1 and DNMT3a to Esr1 promoter in WAT. Mice with adipocyte-specific Dnmt1 deficiency displayed increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity upon HFD challenge; while mice with adipocyte-specific Dnmt3a deficiency showed a mild metabolic phenotype. Using a modified CRISPR/RNA-guided system to specifically target DNA methylation at the Esr1 promoter in WAT, we found that reducing DNA methylation at Esr1 promoter increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity in HFD-challenged mice. Our study demonstrated that DNA methylation at Esr1 promoter played an important role in regulating adipose inflammation, which may contribute to obesity-induced insulin resistance.

Authors

Rui Wu, Fenfen Li, Shirong Wang, Jia Jing, Xin Cui, Yifei Huang, Xucheng Zhang, Jose A. Carrillo, Zufeng Ding, Jiuzhou Song, Liqing Yu, Huidong Shi, Bingzhong Xue, Hang Shi

×

PTH Counteracts Hippo Signaling via Src-dependent YAP Stabilization to Enhance Bone Marrow Stromal Cell Differentiation
Sara Monaci, … , Francesca Gori, Roland Baron
Sara Monaci, … , Francesca Gori, Roland Baron
Published July 22, 2025
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.191245.
View: Text | PDF

PTH Counteracts Hippo Signaling via Src-dependent YAP Stabilization to Enhance Bone Marrow Stromal Cell Differentiation

  • Text
  • PDF
Abstract

Parathyroid hormone (PTH) regulates serum calcium and phosphate through its actions in bone and the kidney and is used to increase bone in osteoporosis treatment. In bone, PTH targets osteoblasts and osteocytes to regulate bone remodeling but also bone marrow stromal cells (BMSCs), regulating their differentiation in the osteoblast and/or the adipocyte lineages. PTH exerts its action through the PTH/PTH-related peptide (PTHrP) receptor (PTH1R), a G protein-coupled receptor (GPCR), activating adenylyl cyclase and phospholipase C (PLC). Although the effects of cAMP and PKA are well characterized, little is known about the effects of PLC activation or on the cross-talk between PTH signaling and other pathways. Here, bulk RNA-seq of PTH-treated murine BMSC line (W-20) revealed significant changes in the Hippo pathway. PTH stabilized YAP, a key target of Hippo, by decreasing YAP/LATS1 interaction, YAPS127 phosphorylation and YAP ubiquitination, leading to YAP nuclear translocation and expression of YAP target genes. Similar events occurred in osteocyte cell lines. This occurred via an increase in Src kinase activity: we identified YAPY428 as a key tyrosine residue phosphorylated by Src in response to PTH. Preventing YAP428 phosphorylation led to YAP instability, blocking both osteogenic and adipogenic differentiation of W-20 cells. These results demonstrate active crosstalk between the PTH/PTHrP and the Hippo signaling pathways and reveal that PTH signaling utilizes the PLC-Ca2+-Src tyrosine kinase signaling cascade to influence YAP stability, antagonizing Hippo signaling and favoring stromal cell differentiation. Thus, PTH signaling counteracts the effects of Hippo signaling in BMSCs to favor their differentiation.

Authors

Sara Monaci, Mengrui Wu, Hiroyuki Okada, Kedkanya Mesil, Byeong-Rak Keum, Maisa Monseff Rodrigues da Silva, Clifford J. Rosen, Francesca Gori, Roland Baron

×

Type 2 diabetes alters quiescent pancreatic stellate cells to tumor-prone state
Yutaro Hara, … , Shinya Ueno, Kenichi Hakamada
Yutaro Hara, … , Shinya Ueno, Kenichi Hakamada
Published June 23, 2025
Citation Information: JCI Insight. 2025;10(12):e187424. https://doi.org/10.1172/jci.insight.187424.
View: Text | PDF
Article has an altmetric score of 2

Type 2 diabetes alters quiescent pancreatic stellate cells to tumor-prone state

  • Text
  • PDF
Abstract

Pancreatic stellate cells (PSCs) are the origin of cancer-associated fibroblasts. Type 2 diabetes mellitus (T2D) may promote pancreatic ductal adenocarcinoma (PDAC), eliciting changes in the quiescent PSC (qPSC) population from the precancerous stage. However, the details are unknown. We evaluated the subpopulations of qPSCs and the impact of T2D. PSCs isolated from 8-week-old C57BL/6J mice and diabetic db/db mice were analyzed by single-cell RNA-seq. Sorted qPSCs and PDAC cells were transplanted into allogenic mice. The isolated qPSCs were broadly classified into mesothelial cell and pancreatic fibroblast (Paf) populations by single-cell RNA-seq. Pafs were subclassified into inflammatory Pafs, myofibroblastic Pafs (myPafs) and a small population named tumor immunity- and angiogenesis-promoting Pafs (tapPafs), expressing Cxcl13. In the subcutaneous transplantation model, the tumors transplanted with myPafs were significantly larger than the tumors transplanted with tapPafs. An increase in myPafs and a decrease in tapPafs were observed from the precancerous stage in human T2D, indicating the effects of tumor progression. This study revealed the subpopulation changes in qPSCs in T2D. A therapy that increases the number of tapPafs could be a therapeutic option for patients with PDAC and T2D and even those in a precancerous stage of T2D.

Authors

Yutaro Hara, Hiroki Mizukami, Takahiro Yamada, Shuji Shimoyama, Keisuke Yamazaki, Takanori Sasaki, Zhenchao Wang, Hanae Kushibiki, Masaki Ryuzaki, Saori Ogasawara, Hiroaki Tamba, Akiko Itaya, Norihisa Kimura, Keinosuke Ishido, Shinya Ueno, Kenichi Hakamada

×

Role of progesterone action in inguinal hernia formation via skeletal muscle fibrosis and atrophy
Tianming You, … , Hong Zhao, Serdar E. Bulun
Tianming You, … , Hong Zhao, Serdar E. Bulun
Published June 12, 2025
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.193208.
View: Text | PDF
Article has an altmetric score of 1

Role of progesterone action in inguinal hernia formation via skeletal muscle fibrosis and atrophy

  • Text
  • PDF
Abstract

More than one in four men will undergo surgery for inguinal hernia, which is commonly associated with fibrotic degeneration of the lower abdominal muscle (LAM) in the groin region. Utilizing a male mouse model expressing the human aromatase gene (Aromhum), previous studies showed that locally produced estradiol acting via estrogen receptor alpha in LAM fibroblasts leads to fibrosis, myofiber atrophy, and hernia development. Here, we found that upregulation of progesterone receptor (PGR) in a LAM fibroblast population mediates this estrogenic effect. A PGR-selective progesterone antagonist in Aromhum mice decreased LAM fibrosis and atrophy, preventing hernia formation and stopping progression of existing hernias. Addition of progesterone to estradiol treatment was essential for early-onset development of LAM fibrosis and large hernias in wild type mice, which was averted by a progesterone antagonist. Single-nuclei multiomics sequencing of herniated LAM revealed a unique population of Pgr-expressing fibroblasts that promotes fibrosis and myofiber atrophy through transforming growth factor beta-2 signaling. Multiomics findings were validated in vivo in herniated LAM tissues of both mice and adult men. Our findings suggest an important and rare pathologic role of progesterone signaling in males and provide evidence for progesterone antagonists as a non-surgical alternative for inguinal hernia management.

Authors

Tianming You, Mehrdad Zandigohar, Tanvi Potluri, Natalie Piehl, John S. Coon V, Elizabeth Baker, Maya Kafali, Yang Dai, Jonah J. Stulberg, David J. Escobar, Richard L. Lieber, Hong Zhao, Serdar E. Bulun

×

Neonatal diabetes–associated missense PDX1 variant disrupts chromatin association and protein-protein interaction
Xiaodun Yang, … , Fabrizio Barbetti, Doris A. Stoffers
Xiaodun Yang, … , Fabrizio Barbetti, Doris A. Stoffers
Published June 9, 2025
Citation Information: JCI Insight. 2025;10(11):e189343. https://doi.org/10.1172/jci.insight.189343.
View: Text | PDF
Article has an altmetric score of 2

Neonatal diabetes–associated missense PDX1 variant disrupts chromatin association and protein-protein interaction

  • Text
  • PDF
Abstract

PDX1 mutations are associated with multiple forms of diabetes, including syndromic, neonatal, mature onset diabetes of the young (MODY), and type 2 diabetes. Two PDX1 missense mutations (Thr151Met and Asn196Thr) were identified in a pediatric female patient that cause permanent neonatal diabetes, pancreas hypoplasia, and a malformed gallbladder. We found that the mouse Pdx1 Asn197Thr variant (homologous to human PDX1 Asn196Thr), but not Pdx1 Thr152Met (homologous to human PDX1 Thr151Met), altered its nuclear localization and disrupted the PDX1-ONECUT1 interaction. Neither variant substantially affected PDX1 protein stability, but both reduced PDX1 binding to the Pdx1 gene promoter. Importantly, the Pdx1 Asn197Thr variant caused pancreas agenesis and reduced enteroendocrine cells in the duodenum in genetically engineered mice, due at least in part to reduced Pdx1 promoter binding and disrupted PDX1-ONECUT1 interaction.

Authors

Xiaodun Yang, Angela Zanfardino, Riccardo Schiaffini, Jeff Ishibashi, Bareket Daniel, Matthew W. Haemmerle, Novella Rapini, Alessia Piscopo, Emanuele Miraglia del Giudice, Maria Cristina Digilio, Raffaele Iorio, Mafalda Mucciolo, Stefano Cianfarani, Dario Iafusco, Fabrizio Barbetti, Doris A. Stoffers

×

Colonic inflammation triggers β cell proliferation during obesity development via a liver-to-pancreas interorgan mechanism
Haremaru Kubo, … , Keizo Kaneko, Hideki Katagiri
Haremaru Kubo, … , Keizo Kaneko, Hideki Katagiri
Published May 8, 2025
Citation Information: JCI Insight. 2025;10(9):e183864. https://doi.org/10.1172/jci.insight.183864.
View: Text | PDF
Article has an altmetric score of 78

Colonic inflammation triggers β cell proliferation during obesity development via a liver-to-pancreas interorgan mechanism

  • Text
  • PDF
Abstract

Under insulin-resistant conditions, such as obesity, pancreatic β cells adaptively proliferate and secrete more insulin to prevent blood glucose elevation. We previously reported hepatic ERK activation during obesity development to stimulate a neuronal relay system, consisting of afferent splanchnic nerves from the liver and efferent vagal nerves to the pancreas, thereby triggering adaptive β cell proliferation. However, the mechanism linking obesity with the interorgan system originating in hepatic ERK activation remains unclear. Herein, we clarified that colonic inflammation promotes β cell proliferation through this interorgan system from the liver to the pancreas. First, dextran sodium sulfate (DSS) treatment induced colonic inflammation and hepatic ERK activation as well as β cell proliferation, all of which were suppressed by blockades of the neuronal relay system by several approaches. In addition, treatment with anti–lymphocyte Peyer’s patch adhesion molecule-1 (anti-LPAM1) antibody suppressed β cell proliferation induced by DSS treatment. Importantly, high-fat diet (HFD) feeding also elicited colonic inflammation, and its inhibition by anti-LPAM1 antibody administration suppressed hepatic ERK activation and β cell proliferation induced by HFD. Thus, colonic inflammation triggers adaptive β cell proliferation via the interorgan mechanism originating in hepatic ERK activation. The present study revealed a potentially novel role of the gastrointestinal tract in the maintenance of β cell regulation.

Authors

Haremaru Kubo, Junta Imai, Tomohito Izumi, Masato Kohata, Yohei Kawana, Akira Endo, Hiroto Sugawara, Junro Seike, Takahiro Horiuchi, Hiroshi Komamura, Toshihiro Sato, Shinichiro Hosaka, Yoichiro Asai, Shinjiro Kodama, Kei Takahashi, Keizo Kaneko, Hideki Katagiri

×

Glycine receptor activation promotes pancreatic islet cell proliferation via the PI3K/mTORC1/p70S6K pathway
Ziyi Zhang, … , Feihan F. Dai, Michael B. Wheeler
Ziyi Zhang, … , Feihan F. Dai, Michael B. Wheeler
Published April 22, 2025
Citation Information: JCI Insight. 2025;10(8):e178754. https://doi.org/10.1172/jci.insight.178754.
View: Text | PDF
Article has an altmetric score of 8

Glycine receptor activation promotes pancreatic islet cell proliferation via the PI3K/mTORC1/p70S6K pathway

  • Text
  • PDF
Abstract

Glycine and β-alanine activate glycine receptors (GlyRs), with glycine known to enhance insulin secretion from pancreatic islet β cells, primarily through GlyR activation. However, the effects of GlyR activation on β cell proliferation have not been examined. Here, we aim to investigate the potential proliferative effects of glycine and β-alanine on islets. In vitro experiments on mouse and human islets revealed that glycine and β-alanine, via GlyR activation, stimulated the proliferation of β cells and α cells, without affecting insulin or glucagon secretion. Further analysis indicated the involvement of the PI3K/mTORC1/p70S6K signaling pathway in this process. Inhibition of GlyRs and PI3K/mTORC1/p70S6K signaling attenuated proliferative effects of glycine and β-alanine. In vivo and ex vivo studies supported these findings, showing increased β and α cell mass after 12 weeks of oral administration of glycine and β-alanine, with no changes in insulin secretion or glucose homeostasis under normal conditions. However, during an acute insulin resistance induced by insulin receptor antagonist S961, glycine and β-alanine enhanced insulin secretion and reduced blood glucose levels by increasing β cell secretory capacity. These findings demonstrate glycine and β-alanine in vivo and in vitro promote islet cell proliferation via GlyR activation and the PI3K/mTORC1/p70S6K pathway, potentially providing a target to enhance islet capacity.

Authors

Ziyi Zhang, Wenyue W. Ye, Anthony L. Piro, Dian-Shi Wang, Ashley Untereiner, Sulayman A. Lyons, Alpana Bhattacharjee, Ishnoor Singh, Jacqueline L. Beaudry, Beverley A. Orser, Feihan F. Dai, Michael B. Wheeler

×

C-terminal FGF-23 production coupling with aldosterone via FAM20C and predicting cardiovascular events in primary aldosteronism
Vin-Cent Wu, … , Hung-Hsiang Liou, Jeff S. Chueh
Vin-Cent Wu, … , Hung-Hsiang Liou, Jeff S. Chueh
Published February 24, 2025
Citation Information: JCI Insight. 2025;10(4):e166461. https://doi.org/10.1172/jci.insight.166461.
View: Text | PDF

C-terminal FGF-23 production coupling with aldosterone via FAM20C and predicting cardiovascular events in primary aldosteronism

  • Text
  • PDF
Abstract

This study examined the involvement of fibroblast growth factor-23 (FGF-23) in primary aldosteronism (PA), a condition characterized by elevated aldosterone levels and hypertension. We recruited patients with unilateral PA (uPA) and observed increased levels of C-terminal FGF-23 (cFGF-23) and C-terminal to intact FGF-23 (iFGF-23) in patients with uPA compared with essential hypertension control participants. Elevated preoperative cFGF-23 levels were associated with adverse outcomes, including mortality and cardiovascular or kidney events. Plasma cFGF-23 levels demonstrated a nonlinear rise with aldosterone, but iFGF-23 levels were not correlated with plasma aldosterone concentration. Higher cFGF-23 levels independently predicted hypertension remission after adrenalectomy for patients with uPA. Patients with uPA, who exhibited elevated cFGF-23 levels, had decreased levels after adrenalectomy. In cell cultures, aldosterone enhanced cleavage of iFGF-23, leading to increased levels of cFGF-23 fragments, an effect mitigated by silencing of family with sequence similarity 20, member C (FAM20C). However, the enhancement of cFGF-23 levels remained unaffected by the furin inhibitor. The study suggests that aldosterone influences FGF-23 phosphorylation by interacting with FAM20C, with docking experiments indicating aldosterone’s binding to FAM20C. This work highlights that patients with uPA with elevated cFGF-23 levels are associated with cardiovascular risks, and adrenalectomy reduces cFGF-23. Aldosterone likely promotes cFGF-23 production through FAM20C-mediated phosphorylation of iFGF-23.

Authors

Vin-Cent Wu, Kang-Yung Peng, Tsu-I Chen, Chiao-Yin Sun, Hung-Wei Liao, Chieh-Kai Chan, Yen-Hung Lin, Hung-Hsiang Liou, Jeff S. Chueh

×

Adiponectin signaling regulates urinary bladder function by blunting smooth muscle purinergic contractility
Zhaobo Luo, … , Seth L. Alper, Weiqun Yu
Zhaobo Luo, … , Seth L. Alper, Weiqun Yu
Published February 24, 2025
Citation Information: JCI Insight. 2025;10(4):e188780. https://doi.org/10.1172/jci.insight.188780.
View: Text | PDF

Adiponectin signaling regulates urinary bladder function by blunting smooth muscle purinergic contractility

  • Text
  • PDF
Abstract

Lower urinary tract symptoms (LUTS) affect approximately 50% of the population over 40 years of age and are strongly associated with obesity and metabolic syndrome. Adipose tissue plays a key role in obesity/metabolic syndrome by releasing adipokines that regulate systemic energy/lipid metabolism, insulin resistance, and inflammation. Adiponectin (ADPN), the most abundant adipokine, modulates energy/metabolism homeostasis through its insulin-sensitizing and antiinflammatory effects. Human plasma ADPN levels are inversely associated with obesity and diabetes. To the best of our knowledge, the role of adipokines such as ADPN in the LUTS associated with obesity/metabolic syndrome remains unknown. We have tested such a possible role in a global ADPN-knockout (Adpn–/–) mouse model. Adpn–/– mice exhibited increased voiding frequency, small voids, and reduced bladder smooth muscle (BSM) contractility, with absence of purinergic contraction. Molecular examination indicated significantly altered metabolic and purinergic pathways. The ADPN receptor agonist AdipoRon was found to abolish acute BSM contraction. Intriguingly, both AMPK activators and inhibitors also abolished BSM purinergic contraction. These data indicate the important contribution of what we believe is a novel ADPN signaling pathway to the regulation of BSM contractility. Dysregulation of this ADPN signaling pathway might be an important mechanism leading to LUTS associated with obesity/metabolic syndrome.

Authors

Zhaobo Luo, Ali Wu, Simon Robson, Seth L. Alper, Weiqun Yu

×

Genotype-phenotype correlation in multiple endocrine neoplasia type 1
Charlita C. Worthy, … , Jenny E. Blau, Smita Jha
Charlita C. Worthy, … , Jenny E. Blau, Smita Jha
Published February 13, 2025
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.176993.
View: Text | PDF

Genotype-phenotype correlation in multiple endocrine neoplasia type 1

  • Text
  • PDF
Abstract

BACKGROUND. 80% of patients with multiple endocrine neoplasia type 1 (MEN1) develop duodenopancreatic neuroendocrine tumors (dpNETs), of whom, 15% to 25% die of metastasis. There is a need to identify biomarkers to predict aggressive disease. MEN1 genotype affords an attractive possibility as a biomarker as it remains constant during lifetime. Currently, patients are clinically diagnosed with MEN1 by the presence of ≥ 2 primary endocrine tumors (pituitary, parathyroid and pancreas) or ≥ 1 primary endocrine tumor(s) with a positive family history. 10-30% of patients diagnosed clinically with MEN1 have no pathogenic germline MEN1 variants. METHODS. Retrospective study of 162 index patients or probands with genotype-positive and 47 with genotype-negative MEN1 enrolled from 1977–2022. RESULTS. Compared to patients with genotype-negative disease, patients with genotype-positive disease were younger at diagnosis and had an increased frequency of recurrent parathyroid tumors, dpNETs and angiofibromas or collagenomas. We propose a novel weighted scoring system to diagnose genotype-positive MEN1 based on clinical characteristics. No evidence of MEN1 mosaicism was seen in 30 tumors from 17 patients with genotype-negative MEN1. Patients with germline MEN1 variants in exons 2 and 3 have a reduced risk of distant metastases. CONCLUSIONS. The clinical course of genotype-negative MEN1 is distinct from genotype-positive disease raising uncertainty about the benefits of lifetime surveillance inpatients with genotype-negative disease. MEN1 mosaicism is rare. TRIAL REGISTRATION. ClinicalTrials.gov NCT04969926. FUNDING. Intramural Research Program of NIDDK (ZIA DK043006-46).

Authors

Charlita C. Worthy, Rana Tora, Chandra N. Uttarkar, James M. Welch, Lynn Bliss, Craig Cochran, Anisha Ninan, Sheila Kumar, Stephen Wank, Sungyoung Auh, Lee S. Weinstein, William F. Simonds, Sunita K. Agarwal, Jenny E. Blau, Smita Jha

×
  • ← Previous
  • 1
  • 2
  • 3
  • …
  • 26
  • 27
  • Next →

No posts were found with this tag.

Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts

Posted by 2 X users
Referenced by 2 Bluesky users
2 readers on Mendeley
See more details
Posted by 1 X users
Referenced by 1 Bluesky users
See more details
Picked up by 9 news outlets
Blogged by 1
Posted by 12 X users
On 2 Facebook pages
Referenced by 3 Bluesky users
See more details
Posted by 3 X users
2 readers on Mendeley
See more details
Blogged by 1
Referenced by 1 Bluesky users
3 readers on Mendeley
See more details