Type 3 iodothyronine deiodinase (Dio3) converts triiodothyronine (T3) to diiodothyronine, thereby reducing intracellular T3 levels. In this study, we investigated the potential roles of Dio3 in the differentiation of human pancreatic β cells, using β cells derived from human induced pluripotent stem cells (hiPSCs).
Main methods
hiPSCs were differentiated to β cells in a stepwise manner over 29 days. The differentiation medium was supplemented with B27, which contains T3 but not T4, instead of serum. The T3 levels in the differentiated cells were determined based on the amount of T3 supplied to the medium and the activity of Dio3 within the cells. Iopanoic acid (IOP) was used as the Dio3 inhibitor.
Key findings
Dio3 expression is substantially altered during differentiation. IOP treatment reduced Dio3 activity on day 4 and increased T3 levels in the medium on day 29. To investigate the involvement of Dio3 during differentiation, we used IOP, in which cells differentiated in the presence of IOP (+IOP) were compared to those differentiated without IOP (−IOP). On day 29, the proportion of β cells expressing C-peptide, NKX6 homeobox 1, and both markers was considerably higher in the presence than in the absence of IOP. Furthermore, on day 29, the insulin content of differentiated + IOP cells was considerably higher than that of differentiated −IOP cells.
Conclusions
An increase in intracellular T3 content promoted via the inhibition of Dio3 activity by IOP from day 0–29 enhances the differentiation of hiPSCs to β cells.
{"title":"Expression of genes involved in thyroid hormone action in human induced pluripotent stem cells during differentiation to insulin-producing cells: Effects of iopanoic acid on differentiation","authors":"Azusa Maruoka , Azuma Kimura , Fumiyuki Hattori , Hirofumi Hitomi , Kenji Osafune , Ichiro Shiojima , Nagaoki Toyoda","doi":"10.1016/j.mce.2025.112490","DOIUrl":"10.1016/j.mce.2025.112490","url":null,"abstract":"<div><h3>Aims</h3><div>Type 3 iodothyronine deiodinase (Dio3) converts triiodothyronine (T3) to diiodothyronine, thereby reducing intracellular T3 levels. In this study, we investigated the potential roles of Dio3 in the differentiation of human pancreatic β cells, using β cells derived from human induced pluripotent stem cells (hiPSCs).</div></div><div><h3>Main methods</h3><div>hiPSCs were differentiated to β cells in a stepwise manner over 29 days. The differentiation medium was supplemented with B27, which contains T3 but not T4, instead of serum. The T3 levels in the differentiated cells were determined based on the amount of T3 supplied to the medium and the activity of Dio3 within the cells. Iopanoic acid (IOP) was used as the Dio3 inhibitor.</div></div><div><h3>Key findings</h3><div>Dio3 expression is substantially altered during differentiation. IOP treatment reduced Dio3 activity on day 4 and increased T3 levels in the medium on day 29. To investigate the involvement of Dio3 during differentiation, we used IOP, in which cells differentiated in the presence of IOP (+IOP) were compared to those differentiated without IOP (−IOP). On day 29, the proportion of β cells expressing C-peptide, NKX6 homeobox 1, and both markers was considerably higher in the presence than in the absence of IOP. Furthermore, on day 29, the insulin content of differentiated + IOP cells was considerably higher than that of differentiated −IOP cells.</div></div><div><h3>Conclusions</h3><div>An increase in intracellular T3 content promoted via the inhibition of Dio3 activity by IOP from day 0–29 enhances the differentiation of hiPSCs to β cells.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"599 ","pages":"Article 112490"},"PeriodicalIF":3.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-03DOI: 10.1016/j.mce.2025.112485
Yuejun Ju , Runze Wu , Guanyi Wang , Ting Shen , Ji Hu , Yinghong Kong
Vitronectin, a protein derived the human placenta, has been identified as an inducer of insulin resistance in trophoblast cells in gestational diabetes mellitus (GDM). As a secreted protein, vitronectin may have systemic effects on dysregulated glucose metabolism in GDM. To address this speculation, we generated a GDM mouse model using high-fat diet-induced obese mice. Consistent with findings in placentas of GDM patients, GDM mouse placentas showed higher vitronectin expression, accompanied by increased serum vitronectin levels. Reduced insulin signaling transduction was observed in both the placentas and livers of GDM mice, along with enhanced hepatic gluconeogenesis. To further explore the role of vitronectin in hepatic gluconeogenesis, we constructed an adeno-associated virus expressing Vtn (AAV-VTN), which was administered to mice via tail vein injection. In AAV-VTN-treated mice, glucose production from exogenous pyruvate increased, and the expression of gluconeogenic genes in the liver was upregulated, indicating that hepatic gluconeogenesis was stimulated by vitronectin. Mechanistically, vitronectin binds to its receptor CD51/61, activating the cAMP/PKA/CREB axis in hepatocytes, thereby promoting hepatic gluconeogenesis. In summary, our findings suggest that placenta-derived vitronectin plays a critical role in inducing insulin resistance in the liver in GDM. Moreover, vitronectin stimulates hepatic gluconeogenesis through activation of the cAMP/PKA/CREB axis. These results point to vitronectin as a potential therapeutic target for managing hyperglycemia in GDM.
{"title":"Vitronectin stimulates hepatic gluconeogenesis by activating the cAMP/PKA/CREB axis in the liver","authors":"Yuejun Ju , Runze Wu , Guanyi Wang , Ting Shen , Ji Hu , Yinghong Kong","doi":"10.1016/j.mce.2025.112485","DOIUrl":"10.1016/j.mce.2025.112485","url":null,"abstract":"<div><div>Vitronectin, a protein derived the human placenta, has been identified as an inducer of insulin resistance in trophoblast cells in gestational diabetes mellitus (GDM). As a secreted protein, vitronectin may have systemic effects on dysregulated glucose metabolism in GDM. To address this speculation, we generated a GDM mouse model using high-fat diet-induced obese mice. Consistent with findings in placentas of GDM patients, GDM mouse placentas showed higher vitronectin expression, accompanied by increased serum vitronectin levels. Reduced insulin signaling transduction was observed in both the placentas and livers of GDM mice, along with enhanced hepatic gluconeogenesis. To further explore the role of vitronectin in hepatic gluconeogenesis, we constructed an adeno-associated virus expressing <em>Vtn</em> (AAV-VTN), which was administered to mice via tail vein injection. In AAV-VTN-treated mice, glucose production from exogenous pyruvate increased, and the expression of gluconeogenic genes in the liver was upregulated, indicating that hepatic gluconeogenesis was stimulated by vitronectin. Mechanistically, vitronectin binds to its receptor CD51/61, activating the cAMP/PKA/CREB axis in hepatocytes, thereby promoting hepatic gluconeogenesis. In summary, our findings suggest that placenta-derived vitronectin plays a critical role in inducing insulin resistance in the liver in GDM. Moreover, vitronectin stimulates hepatic gluconeogenesis through activation of the cAMP/PKA/CREB axis. These results point to vitronectin as a potential therapeutic target for managing hyperglycemia in GDM.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"599 ","pages":"Article 112485"},"PeriodicalIF":3.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255843","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}
Pub Date : 2025-02-03DOI: 10.1016/j.mce.2025.112487
Aalya Hamouda , Stephanie Sirmakesyan , Aya Hajj , Philippe G. Cammisotto , H. Uri Saragovi , Lysanne Campeau
In urine samples from an aging female cohort with overactive bladder syndrome (OAB), the proteolytic activity of matrix metalloproteinase-9 (MMP-9), an enzyme which degrades mature NGF, was elevated and associated with low levels of nerve growth factor (NGF). Given that a substantial portion of urine constituents originate from bladder cellular processes, we examined the synthesis of NGF and MMP-9 in rat urothelial (UROs) and smooth muscle (SMCs) cells in culture. NGF and proNGF were found expressed and released by both cell types while UROs were the major source of secreted MMP-9. THX-B, a highly specific p75NTR antagonist, decreased the expression of MMP-9 resulting in increased mature NGF levels in culture medium of UROs while displaying minor effects on SMCs. Likewise, CRISPR-cas9 genomic deletion of MMP-9 potently increased mature NGF levels in both cell types. On the other hand, THX-B decreased the synthesis and release of α2 Macroglobulin (α2M), a protein that stabilizes proNGF in UROs but increased it in SMCs. THX-B also increased the activity of enzymes furin and matrix metalloproteinase-7 (MMP-7), that convert proNGF to mature NGF in UROs, yielding a net increase in mature NGF and a decrease of proNGF. We conclude that p75NTR is involved in the control of proNGF and mature NGF secretion from bladder cells through modulation of proteolytic activities. Since neurotrophins and binding to their receptors are relevant to pathologies, inhibition of p75NTR by THX-B may be exploited in a therapeutic strategy.
{"title":"p75NTR antagonist THX-B increases mature nerve growth factor secretion by bladder cells through decreased activity of matrix metalloproteinase-9","authors":"Aalya Hamouda , Stephanie Sirmakesyan , Aya Hajj , Philippe G. Cammisotto , H. Uri Saragovi , Lysanne Campeau","doi":"10.1016/j.mce.2025.112487","DOIUrl":"10.1016/j.mce.2025.112487","url":null,"abstract":"<div><div>In urine samples from an aging female cohort with overactive bladder syndrome (OAB), the proteolytic activity of matrix metalloproteinase-9 (MMP-9), an enzyme which degrades mature NGF, was elevated and associated with low levels of nerve growth factor (NGF). Given that a substantial portion of urine constituents originate from bladder cellular processes, we examined the synthesis of NGF and MMP-9 in rat urothelial (UROs) and smooth muscle (SMCs) cells in culture. NGF and proNGF were found expressed and released by both cell types while UROs were the major source of secreted MMP-9. THX-B, a highly specific p75<sup>NTR</sup> antagonist, decreased the expression of MMP-9 resulting in increased mature NGF levels in culture medium of UROs while displaying minor effects on SMCs. Likewise, CRISPR-cas9 genomic deletion of MMP-9 potently increased mature NGF levels in both cell types. On the other hand, THX-B decreased the synthesis and release of α2 Macroglobulin (α2M), a protein that stabilizes proNGF in UROs but increased it in SMCs. THX-B also increased the activity of enzymes furin and matrix metalloproteinase-7 (MMP-7), that convert proNGF to mature NGF in UROs, yielding a net increase in mature NGF and a decrease of proNGF. We conclude that p75<sup>NTR</sup> is involved in the control of proNGF and mature NGF secretion from bladder cells through modulation of proteolytic activities. Since neurotrophins and binding to their receptors are relevant to pathologies, inhibition of p75<sup>NTR</sup> by THX-B may be exploited in a therapeutic strategy.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"599 ","pages":"Article 112487"},"PeriodicalIF":3.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255826","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}
Pub Date : 2025-02-01DOI: 10.1016/j.mce.2024.112441
Yilin He , Wenpeng Song , Yinxin Deng , Xiao Lin , Zhenhua Gao , Pan Ma
As a GLP-1 receptor agonist widely used in treating type 2 diabetes, liraglutide shows potential applications in bone tissue engineering. This study investigated liraglutide's direct effects on rat bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation and its regulatory mechanism through macrophage polarization. Results showed that liraglutide significantly enhanced BMSC migration and osteogenic differentiation. Additionally, liraglutide markedly inhibited M1 macrophage polarization induced by LPS and IFN-γ, reducing inflammatory factors CXCL9 and TNF-α secretion, possibly by partially reversing M1 macrophage regulatory signals (AMPK and NF-κB pathways). Compared to M1 macrophage-conditioned medium (M1-CM), conditioned medium from liraglutide-treated macrophages showed stronger promotion of BMSC osteogenic differentiation, though this effect was reversed by CXCL9 addition. The study demonstrates that liraglutide enhances BMSC osteogenic capacity both directly and by inhibiting M1 macrophage polarization and CXCL9 secretion, offering a new therapeutic option for severe bone defects with inflammatory responses.
{"title":"Liraglutide promotes osteogenic differentiation of mesenchymal stem cells by inhibiting M1 macrophage polarization and CXCL9 release in vitro","authors":"Yilin He , Wenpeng Song , Yinxin Deng , Xiao Lin , Zhenhua Gao , Pan Ma","doi":"10.1016/j.mce.2024.112441","DOIUrl":"10.1016/j.mce.2024.112441","url":null,"abstract":"<div><div>As a GLP-1 receptor agonist widely used in treating type 2 diabetes, liraglutide shows potential applications in bone tissue engineering. This study investigated liraglutide's direct effects on rat bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation and its regulatory mechanism through macrophage polarization. Results showed that liraglutide significantly enhanced BMSC migration and osteogenic differentiation. Additionally, liraglutide markedly inhibited M1 macrophage polarization induced by LPS and IFN-γ, reducing inflammatory factors CXCL9 and TNF-α secretion, possibly by partially reversing M1 macrophage regulatory signals (AMPK and NF-κB pathways). Compared to M1 macrophage-conditioned medium (M1-CM), conditioned medium from liraglutide-treated macrophages showed stronger promotion of BMSC osteogenic differentiation, though this effect was reversed by CXCL9 addition. The study demonstrates that liraglutide enhances BMSC osteogenic capacity both directly and by inhibiting M1 macrophage polarization and CXCL9 secretion, offering a new therapeutic option for severe bone defects with inflammatory responses.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"597 ","pages":"Article 112441"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872520","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}
Pub Date : 2025-02-01DOI: 10.1016/j.mce.2024.112447
Na Liu , Jing YangOu , Chenxuan Wei, Guojing Li, Ruoer Yu, Yu Lin, Hong Xu
Endometriosis, a gynecological disorder marked by pelvic pain and infertility, has its pathogenesis and pathophysiology significantly influenced by epigenetics, as these factors have been well characterized. However, the role of RNA-mediated epigenetic regulation in endometriosis remains to be elucidated. In our study, we found that N4-acetylcytidine (ac4C) RNA modification and N-acetyltransferase 10 (NAT10) were significantly upregulated in endometrial lesions compared to eutopic endometrium. Knockdown of NAT10 suppressed endometrial epithelial cell proliferation, epithelial-to-mesenchymal transition (EMT), and cell cycle processes in vitro. RNA-seq and acRIP-seq analyses revealed that the knockdown of NAT10 impaired cell proliferation and the TGF-beta signaling pathway. We further identified that ac4C RNA modification enhanced TGFB1 mRNA stability and expression levels, and inhibition of NAT10 activity by Remodelin effectively suppressed the growth of ectopic lesions in an endometriosis mouse model. Collectively, our findings reveal that increased NAT10-mediated ac4C modification enhances TGFB1 mRNA stability, thereby promoting the development of endometriosis. This discovery lays the molecular foundation for future therapeutic approaches targeting endometriosis.
{"title":"NAT10 drives endometriosis progression through acetylation and stabilization of TGFB1 mRNA","authors":"Na Liu , Jing YangOu , Chenxuan Wei, Guojing Li, Ruoer Yu, Yu Lin, Hong Xu","doi":"10.1016/j.mce.2024.112447","DOIUrl":"10.1016/j.mce.2024.112447","url":null,"abstract":"<div><div>Endometriosis, a gynecological disorder marked by pelvic pain and infertility, has its pathogenesis and pathophysiology significantly influenced by epigenetics, as these factors have been well characterized. However, the role of RNA-mediated epigenetic regulation in endometriosis remains to be elucidated. In our study, we found that N4-acetylcytidine (ac<sup>4</sup>C) RNA modification and N-acetyltransferase 10 (NAT10) were significantly upregulated in endometrial lesions compared to eutopic endometrium. Knockdown of NAT10 suppressed endometrial epithelial cell proliferation, epithelial-to-mesenchymal transition (EMT), and cell cycle processes in vitro. RNA-seq and acRIP-seq analyses revealed that the knockdown of NAT10 impaired cell proliferation and the TGF-beta signaling pathway. We further identified that ac<sup>4</sup>C RNA modification enhanced TGFB1 mRNA stability and expression levels, and inhibition of NAT10 activity by Remodelin effectively suppressed the growth of ectopic lesions in an endometriosis mouse model. Collectively, our findings reveal that increased NAT10-mediated ac<sup>4</sup>C modification enhances TGFB1 mRNA stability, thereby promoting the development of endometriosis. This discovery lays the molecular foundation for future therapeutic approaches targeting endometriosis.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"597 ","pages":"Article 112447"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896076","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}
Pub Date : 2025-02-01DOI: 10.1016/j.mce.2024.112439
Seong Mi Ji , Hana Yoo , Jea Il Kim , Mi Jin Choi , Hyae Gyeong Cheon
Previous studies have shown that melatonin induces adipocyte browning in vivo. However, the underlying mechanisms of melatonin action at the cellular level remain elusive. In this study, we investigated the mechanisms underlying melatonin-induced browning in 3T3-L1 adipocytes and RAW 264.7 macrophages. Melatonin caused the transdifferentiation of fully differentiated white adipocytes into beige adipocytes, which involves the activation of melatonin receptor 1, followed by increased phosphorylation of p38 MAPK and Akt. Both luzindole (LZ), a non-selective melatonin receptor antagonist, and selective melatonin receptor 1 knockdown attenuated the browning effects of melatonin. Melatonin also induced M2 polarization in RAW 264.7, involving the melatonin receptor 1-Src-STAT3/STAT6 phosphorylation signaling cascade. Melatonin-treated M2-conditioned medium (CM) contained increased levels of catecholamine (CA) and induced beige adipocytes when treated with differentiated 3T3-L1 white adipocytes. In vivo oral administration of melatonin to high-fat diet (HFD)-induced obese (DIO) mice reduced body weight, accompanied by increased expression of uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in subcutaneous adipose tissues. Moreover, arginase-1 (Arg1) and mannose receptor C type-1 (MRC1) levels were markedly higher in the melatonin-treated groups, suggesting that melatonin induces adipose browning and M2 polarization in vivo. Collectively, melatonin-induced adipocyte browning appeared to be reflected by the sum of melatonin receptor 1-activated direct browning effects and indirect M2 polarization-mediated effects.
{"title":"Melatonin induces white-to-beige adipocyte transdifferentiation through melatonin receptor 1-mediated direct browning and indirect M2 polarization","authors":"Seong Mi Ji , Hana Yoo , Jea Il Kim , Mi Jin Choi , Hyae Gyeong Cheon","doi":"10.1016/j.mce.2024.112439","DOIUrl":"10.1016/j.mce.2024.112439","url":null,"abstract":"<div><div>Previous studies have shown that melatonin induces adipocyte browning <em>in vivo</em>. However, the underlying mechanisms of melatonin action at the cellular level remain elusive. In this study, we investigated the mechanisms underlying melatonin-induced browning in 3T3-L1 adipocytes and RAW 264.7 macrophages. Melatonin caused the transdifferentiation of fully differentiated white adipocytes into beige adipocytes, which involves the activation of melatonin receptor 1, followed by increased phosphorylation of p38 MAPK and Akt. Both luzindole (LZ), a non-selective melatonin receptor antagonist, and selective melatonin receptor 1 knockdown attenuated the browning effects of melatonin. Melatonin also induced M2 polarization in RAW 264.7, involving the melatonin receptor 1-Src-STAT3/STAT6 phosphorylation signaling cascade. Melatonin-treated M2-conditioned medium (CM) contained increased levels of catecholamine (CA) and induced beige adipocytes when treated with differentiated 3T3-L1 white adipocytes. <em>In vivo</em> oral administration of melatonin to high-fat diet (HFD)-induced obese (DIO) mice reduced body weight, accompanied by increased expression of uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in subcutaneous adipose tissues. Moreover, arginase-1 (Arg1) and mannose receptor C type-1 (MRC1) levels were markedly higher in the melatonin-treated groups, suggesting that melatonin induces adipose browning and M2 polarization <em>in vivo</em>. Collectively, melatonin-induced adipocyte browning appeared to be reflected by the sum of melatonin receptor 1-activated direct browning effects and indirect M2 polarization-mediated effects.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"597 ","pages":"Article 112439"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801752","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}
Pub Date : 2025-02-01DOI: 10.1016/j.mce.2025.112484
Isabelle Tenori Ribeiro , Matheus Naia Fioretto , Sérgio Alexandre Alcantara dos Santos , Marcus Vinicius Niz Alvarez , Luiz Marcos Frediani Portela , Renato Mattos , Hecttor Baptista Sebastian , Pedro Menchini Vitali , Fábio Rodrigues Ferreira Seiva , Luís Fernando Barbisan , Clélia Akiko Hiruma Lima , Débora Cristina Damasceno , Elena Zambrano , Luis Antonio Justulin
This study investigated the late effects of maternal protein restriction (MPR) and early postnatal sugar consumption on liver health in male Sprague-Dawley rat offspring, focusing on changes observed throughout the aging process. The animals were divided into the following groups: Control (CTR): Male offspring whose dams consumed a normal protein diet (NPD, 17% protein) and water ad libitum during gestation and lactation, and then fed a NPD and water until PND 540; Control + Sugar (CTR + SUG): The same treatment as CTR, but consuming a sugar solution (10% diluted in water) from postnatal day (PND) 21–90, and then fed a NPD and water until PND 540; Gestational and Lactational Low Protein (GLLP): Male offspring whose dams consumed a low-protein diet (LPD, 6% protein) during gestation and lactation and, then fed a NPD and water ad libitum until PND 540; Gestational and Lactational Low Protein + Sugar (GLLP + SUG): male offspring whose dams consumed a LPD during gestation and lactation, and then fed a NPD and a sugar solution (10% diluted in water) ad libitum from PND 21 to 90. On PND 540, the animals were anesthetized, weighed, and euthanized, and their livers were collected for morphological and molecular analyses. The GLLP and GLLP + SUG groups showed lower body weight and lower retroperitoneal fat weight compared to the CTR and CTR + SUG groups. Morphological analysis revealed inflammatory foci in the liver from the CTR + SUG, GLLP, and GLLP + SUG groups, compared to the CTR group. Hepatic activities of CAT, SOD, and GSH-Px were increased in the GLLP + SUG group and decreased in the GLLP group, compared to the CTR group. Immunohistochemistry showed a significant increase in occupied area per foci de hepatocytes positive for GSTpi (placental form) in the CTR + SUG, GLLP, and GLLP + SUG groups, compared to the CTR group. Proteomic analysis of the groups revealed significant changes in hepatic metabolic and inflammatory pathways. In the CTR + SUG group, upregulated pathways associated with non-alcoholic fatty liver disease (NAFLD) and downregulated pathways related to autophagy were observed. In the GLLP and GLLP + SUG groups, there was a significant impact on metabolic pathways, including glucose metabolism, gluconeogenesis, glycogenesis, and cellular stress responses. An upregulation of pathways associated with chemokine- and cytokine-mediated inflammatory processes was also identified, indicating activation of the immune system in the liver during aging. Therefore, MPR, with or without postnatal sugar consumption, resulted in hepatic changes in metabolism and the antioxidant defense in old male offspring.
{"title":"Maternal protein restriction and postnatal sugar consumption increases inflammatory response and deregulates metabolic pathways in the liver of male offspring rats with aging","authors":"Isabelle Tenori Ribeiro , Matheus Naia Fioretto , Sérgio Alexandre Alcantara dos Santos , Marcus Vinicius Niz Alvarez , Luiz Marcos Frediani Portela , Renato Mattos , Hecttor Baptista Sebastian , Pedro Menchini Vitali , Fábio Rodrigues Ferreira Seiva , Luís Fernando Barbisan , Clélia Akiko Hiruma Lima , Débora Cristina Damasceno , Elena Zambrano , Luis Antonio Justulin","doi":"10.1016/j.mce.2025.112484","DOIUrl":"10.1016/j.mce.2025.112484","url":null,"abstract":"<div><div>This study investigated the late effects of maternal protein restriction (MPR) and early postnatal sugar consumption on liver health in male Sprague-Dawley rat offspring, focusing on changes observed throughout the aging process. The animals were divided into the following groups: Control (CTR): Male offspring whose dams consumed a normal protein diet (NPD, 17% protein) and water <em>ad libitum</em> during gestation and lactation, and then fed a NPD and water until PND 540; Control + Sugar (CTR + SUG): The same treatment as CTR, but consuming a sugar solution (10% diluted in water) from postnatal day (PND) 21–90, and then fed a NPD and water until PND 540; Gestational and Lactational Low Protein (GLLP): Male offspring whose dams consumed a low-protein diet (LPD, 6% protein) during gestation and lactation and, then fed a NPD and water <em>ad libitum</em> until PND 540; Gestational and Lactational Low Protein + Sugar (GLLP + SUG): male offspring whose dams consumed a LPD during gestation and lactation, and then fed a NPD and a sugar solution (10% diluted in water) <em>ad libitum</em> from PND 21 to 90. On PND 540, the animals were anesthetized, weighed, and euthanized, and their livers were collected for morphological and molecular analyses. The GLLP and GLLP + SUG groups showed lower body weight and lower retroperitoneal fat weight compared to the CTR and CTR + SUG groups. Morphological analysis revealed inflammatory foci in the liver from the CTR + SUG, GLLP, and GLLP + SUG groups, compared to the CTR group. Hepatic activities of CAT, SOD, and GSH-Px were increased in the GLLP + SUG group and decreased in the GLLP group, compared to the CTR group. Immunohistochemistry showed a significant increase in occupied area per foci de hepatocytes positive for GSTpi (placental form) in the CTR + SUG, GLLP, and GLLP + SUG groups, compared to the CTR group. Proteomic analysis of the groups revealed significant changes in hepatic metabolic and inflammatory pathways. In the CTR + SUG group, upregulated pathways associated with non-alcoholic fatty liver disease (NAFLD) and downregulated pathways related to autophagy were observed. In the GLLP and GLLP + SUG groups, there was a significant impact on metabolic pathways, including glucose metabolism, gluconeogenesis, glycogenesis, and cellular stress responses. An upregulation of pathways associated with chemokine- and cytokine-mediated inflammatory processes was also identified, indicating activation of the immune system in the liver during aging. Therefore, MPR, with or without postnatal sugar consumption, resulted in hepatic changes in metabolism and the antioxidant defense in old male offspring.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"599 ","pages":"Article 112484"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123380","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}
Pub Date : 2025-02-01DOI: 10.1016/j.mce.2024.112438
Victoria Aiassa , María del Rosario Ferreira , Paola Ingaramo , María Eugenia D'Alessandro
We have previously demonstrated that dietary Salvia hispanica L. (chia) seed, rich in α-linolenic acid (ALA), was able to reduce visceral adiposity and improves insulin sensitivity in a rodent experimental model of adiposity induced by the administration of a sucrose-rich diet (SRD). The evidence suggests that the pathological expansion of visceral adipose tissue (VAT) is accompanied by changes in the extracellular matrix (ECM) components, which can lead to fibrosis, and/or a greater expression of pro-inflammatory adipokines. The aim of the present work was to evaluate the effect of chia seed administration upon key components and modulators of ECM remodeling and inflammation in different white adipose tissues (WAT) (epididymal-eWAT- and retroperitoneal-rWAT-) in a SRD-induced adiposity rodent model. The results showed that chia seed reduced the increased hydroxyproline levels observed in SRD-fed group and this was accompanied by changes in the activity/expression of matrix metalloproteinases MMP-2 and MMP-9. No changes were observed in transforming growth factor β (TGF-β) expression levels. In addition, this nutritional intervention was able to reduce the levels of PAI-1 and MCP-1, and to increase the levels of adiponectin in both VAT. An increase in the ratio of n-3/n-6 polyunsaturated fatty acids in the membrane phospholipids of both VAT was also observed. The present study demonstrated that chia seed have anti-fibrotic and anti-inflammatory actions in the VAT which could play a key role in the amelioration of visceral adiposity and whole-body insulin insensitivity developed in SRD-fed rats.
{"title":"Salvia hispanica L. (chia) seed have beneficial effects upon visceral adipose tissues extracellular matrix disorders and inflammation developed in a sucrose-rich diet-induced adiposity rodent model","authors":"Victoria Aiassa , María del Rosario Ferreira , Paola Ingaramo , María Eugenia D'Alessandro","doi":"10.1016/j.mce.2024.112438","DOIUrl":"10.1016/j.mce.2024.112438","url":null,"abstract":"<div><div>We have previously demonstrated that dietary <em>Salvia hispanica</em> L. (chia) seed, rich in α-linolenic acid (ALA), was able to reduce visceral adiposity and improves insulin sensitivity in a rodent experimental model of adiposity induced by the administration of a sucrose-rich diet (SRD). The evidence suggests that the pathological expansion of visceral adipose tissue (VAT) is accompanied by changes in the extracellular matrix (ECM) components, which can lead to fibrosis, and/or a greater expression of pro-inflammatory adipokines. The aim of the present work was to evaluate the effect of chia seed administration upon key components and modulators of ECM remodeling and inflammation in different white adipose tissues (WAT) (epididymal-eWAT- and retroperitoneal-rWAT-) in a SRD-induced adiposity rodent model. The results showed that chia seed reduced the increased hydroxyproline levels observed in SRD-fed group and this was accompanied by changes in the activity/expression of matrix metalloproteinases MMP-2 and MMP-9. No changes were observed in transforming growth factor β (TGF-β) expression levels. In addition, this nutritional intervention was able to reduce the levels of PAI-1 and MCP-1, and to increase the levels of adiponectin in both VAT. An increase in the ratio of n-3/n-6 polyunsaturated fatty acids in the membrane phospholipids of both VAT was also observed. The present study demonstrated that chia seed have anti-fibrotic and anti-inflammatory actions in the VAT which could play a key role in the amelioration of visceral adiposity and whole-body insulin insensitivity developed in SRD-fed rats.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"597 ","pages":"Article 112438"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785305","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}
Excessive consumption of saturated fatty acids creates a debilitating cellular environment that hinders the normal function and survival of osteoblasts, contributing to bone metabolic disorders such as osteoporosis. The FDA-approved polypeptide PTH 1–34 is a well-established therapy for post-menopausal osteoporosis, yet its protective effects in a palmitic acid (PA)-rich hyperlipidemic environment are not well understood. This study investigates the impact of PTH 1–34 on PA-induced cellular responses in osteoblasts. Experiments were conducted on mouse and human-derived osteoblasts as well as C57BL/6J male mice. PA was found to suppress osteoblast differentiation, increase apoptosis, and disrupt autophagy, and thereby impair cellular health. Conversely, PTH 1–34 enhanced cellular health by counteracting these effects. At the molecular level, PTH 1–34 exerted its bioactivity by modulating PTH signaling components such as cAMP and CREB. Impaired osteogenic differentiation was restored by modulating bone-anabolic genes. PTH 1–34 also improved mitochondrial health by preserving mitochondrial membrane potential and maintaining the Bax/Bcl2 ratio, thereby improving cellular viability. Additionally, PTH 1–34 regulated autophagic processes, as evidenced by balanced p62 and LC3 levels, further validated using the autophagy inhibitor Bafilomycin A1. In vivo studies in C57BL/6J male mice corroborated these findings. PTH 1–34 reversed the PA action by maintaining osteoblast number and function. This study establishes the protective role of PTH 1–34 in safeguarding osteoblasts from lipotoxicity caused by excessive PA accumulation, highlighting its potential repurposing for patients with lipid-induced skeletal dysfunctions. The new data underscores the therapeutic versatility of the FDA-approved polypeptide PTH 1–34 in managing lipid-related bone health issues.
{"title":"FDA-approved polypeptide PTH 1–34 impedes palmitic acid-mediated osteoblasts dysfunction by promoting its differentiation and thereby improving skeletal health","authors":"Anirban Sardar , Divya Rai , Ashish Kumar Tripathi , Kunal Chutani , Shradha Sinha , Geeta Dhaniya , Ritu Trivedi","doi":"10.1016/j.mce.2024.112445","DOIUrl":"10.1016/j.mce.2024.112445","url":null,"abstract":"<div><div>Excessive consumption of saturated fatty acids creates a debilitating cellular environment that hinders the normal function and survival of osteoblasts, contributing to bone metabolic disorders such as osteoporosis. The FDA-approved polypeptide PTH 1–34 is a well-established therapy for post-menopausal osteoporosis, yet its protective effects in a palmitic acid (PA)-rich hyperlipidemic environment are not well understood. This study investigates the impact of PTH 1–34 on PA-induced cellular responses in osteoblasts. Experiments were conducted on mouse and human-derived osteoblasts as well as C57BL/6J male mice. PA was found to suppress osteoblast differentiation, increase apoptosis, and disrupt autophagy, and thereby impair cellular health. Conversely, PTH 1–34 enhanced cellular health by counteracting these effects. At the molecular level, PTH 1–34 exerted its bioactivity by modulating PTH signaling components such as cAMP and CREB. Impaired osteogenic differentiation was restored by modulating bone-anabolic genes. PTH 1–34 also improved mitochondrial health by preserving mitochondrial membrane potential and maintaining the Bax/Bcl2 ratio, thereby improving cellular viability. Additionally, PTH 1–34 regulated autophagic processes, as evidenced by balanced p62 and LC3 levels, further validated using the autophagy inhibitor Bafilomycin A1. <em>In vivo</em> studies in C57BL/6J male mice corroborated these findings. PTH 1–34 reversed the PA action by maintaining osteoblast number and function. This study establishes the protective role of PTH 1–34 in safeguarding osteoblasts from lipotoxicity caused by excessive PA accumulation, highlighting its potential repurposing for patients with lipid-induced skeletal dysfunctions. The new data underscores the therapeutic versatility of the FDA-approved polypeptide PTH 1–34 in managing lipid-related bone health issues.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"597 ","pages":"Article 112445"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886054","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}
Pub Date : 2025-02-01DOI: 10.1016/j.mce.2024.112440
Jiali Luo , Jian Zhang , Yu Zhang , Meihui Li , Lin Yu , Di Song , Zhaogui Sun
Research question
Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme specifically highly expressed in the brain and gonads. Inhibition of UCHL1 hydrolase activity impairs oocyte maturation. Uchl1 knockout mice exhibit reproductive dysfunction, but the underlying pathogenesis remains unclear.
Design
Uchl1 knockout mice were used to explore the role of UCHL1 in oocyte maturation and follicle development. Oocyte development potential and mitochondrial membrane potential were also assessed to determine UCHL1 function on early embryo development. Transcriptome and proteomic analyses were conducted to elucidate molecular changes associated with Uchl1 knockout.
Results
Uchl1−/− mice exhibited ovarian dysfunction and infertility, with decreased serum estrogen, reduced antral follicle number, and diminished oocyte developmental potential compared to wild types. Histological examination revealed compromised follicle development and disrupted granulosa cell function in Uchl1−/− ovaries. In vitro, Uchl1−/− follicles had impaired preantral follicle development and poor FSH response. Loss of UCHL1 not only leads to mitochondrial dysfunction in oocytes, but also negatively affected estrogen biosynthesis with downregulation of steroidogenic acute regulatory protein (STAR) and estrogen receptor alpha (ER-α) in granulosa cells. Additionally, downregulated expression of connexin 37 (CX37), which is known to impair gap junction intercellular communication between oocyte and granulosa cells, transmitted the Uchl1 gene damage from oocyte to granulosa cells, which in turn affected functions of follicles and even the whole ovary.
Conclusions
Loss of UCHL1 leads to significant disruptions in follicular development and oocyte quality, resulting in infertility. UCHL1 in oocytes influences not only the quality and quantity of the oocytes themselves, but also the follicles and the ovaries as a whole. This disruption ultimately manifests in symptoms similar to diminished ovarian reserve (DOR).
{"title":"Genetic loss of Uchl1 leads to female infertility by affecting oocyte quality and follicular development","authors":"Jiali Luo , Jian Zhang , Yu Zhang , Meihui Li , Lin Yu , Di Song , Zhaogui Sun","doi":"10.1016/j.mce.2024.112440","DOIUrl":"10.1016/j.mce.2024.112440","url":null,"abstract":"<div><h3>Research question</h3><div>Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme specifically highly expressed in the brain and gonads. Inhibition of UCHL1 hydrolase activity impairs oocyte maturation. <em>Uchl1 knockout</em> mice exhibit reproductive dysfunction, but the underlying pathogenesis remains unclear.</div></div><div><h3>Design</h3><div><em>Uchl1 knockout</em> mice were used to explore the role of UCHL1 in oocyte maturation and follicle development. Oocyte development potential and mitochondrial membrane potential were also assessed to determine UCHL1 function on early embryo development. Transcriptome and proteomic analyses were conducted to elucidate molecular changes associated with <em>Uchl1 knockout</em>.</div></div><div><h3>Results</h3><div><em>Uchl1</em><sup><em>−/−</em></sup> mice exhibited ovarian dysfunction and infertility, with decreased serum estrogen, reduced antral follicle number, and diminished oocyte developmental potential compared to wild types. Histological examination revealed compromised follicle development and disrupted granulosa cell function in <em>Uchl1</em><sup><em>−/−</em></sup> ovaries. In vitro, <em>Uchl1</em><sup>−/−</sup> follicles had impaired preantral follicle development and poor FSH response. Loss of UCHL1 not only leads to mitochondrial dysfunction in oocytes, but also negatively affected estrogen biosynthesis with downregulation of steroidogenic acute regulatory protein (STAR) and estrogen receptor alpha (ER-α) in granulosa cells. Additionally, downregulated expression of connexin 37 (CX37), which is known to impair gap junction intercellular communication between oocyte and granulosa cells, transmitted the <em>Uchl1</em> gene damage from oocyte to granulosa cells, which in turn affected functions of follicles and even the whole ovary.</div></div><div><h3>Conclusions</h3><div>Loss of UCHL1 leads to significant disruptions in follicular development and oocyte quality, resulting in infertility. UCHL1 in oocytes influences not only the quality and quantity of the oocytes themselves, but also the follicles and the ovaries as a whole. This disruption ultimately manifests in symptoms similar to diminished ovarian reserve (DOR).</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"597 ","pages":"Article 112440"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818408","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}
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