Molecular and Cellular Endocrinology最新文献

{"title":"2-Hydroxyestradiol regulates extracellular matrix deposition through estrogen receptor beta activation in airway smooth muscle cells","authors":"Ashish Kumar ,&nbsp;Mohammad Irshad Reza ,&nbsp;Anurag Banerjee ,&nbsp;Nilesh Sudhakar Ambhore ,&nbsp;Premanand Balraj ,&nbsp;Buddhadev Layek ,&nbsp;Michael A. Thompson ,&nbsp;John R. Hawse ,&nbsp;Christina M. Pabelick ,&nbsp;Y.S. Prakash ,&nbsp;Venkatachalem Sathish","doi":"10.1016/j.mce.2026.112753","DOIUrl":"10.1016/j.mce.2026.112753","url":null,"abstract":"<div><div>Airway remodeling in asthma is characterized by increased extracellular matrix (ECM) production and deposition by airway smooth muscle (ASM) cells. Existing studies have shown contrasting effects of 17β-estradiol (E₂) in regulating ASM cellular remodeling via differential activation of estrogen receptors (ERs: α and β). Even though downstream metabolites of E₂ (2-hydroxyestradiol: 2-HE and 16-hydroxyestradiol: 16αHE₂) are gaining recognition for their biological roles in various cellular systems, their role in ASM remodeling remains largely unexplored. Here, we explore the effects of 2-HE and 16αHE₂, a highly potent metabolites, on ECM remodeling in ASM. ECM mRNA's/proteins expression and deposition were determined by Western blotting, qRT-PCR, and In-Cell Western analysis. Interaction of metabolites with ERs was performed using a docking study and their impact on regulation of an estrogen response element (ERE) was monitored via a luciferase reporter assay. Further, the ER-specific effect of metabolites was validated using shRNA-mediated ERα and ERβ knockdown ASM cells. 16αHE₂ exposure showed no notable changes in transforming growth factor-β (TGF-β)-induced ECM proteins expression and deposition, whereas 2-HE exposure blunted the TGF-β effects. Molecular docking unveiled the binding of 16αHE₂ with ERα, while 2-HE more strongly bound to ERβ, which was also confirmed by ERE-luciferase assay. In ERβ knockdown ASM cells, 2-HE inhibited the TGF-β-induced phosphorylation of SMAD2/3, AKT, and ERK1/2. However, 16αHE₂ failed to elicit any of these effects. Furthermore, 2-HE significantly decreased the TGF-β-induced transcriptional activities of AP-1 and NF-κB. Overall, our findings suggest 2-HE blunts TGF-β-induced ECM through ERβ; therefore, it may serve as a novel therapeutic target for airway remodeling and asthma.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"615 ","pages":"Article 112753"},"PeriodicalIF":3.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090432","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}

{"title":"Hyperglycemia differentially regulates osteoblast and osteoclast autophagy via AMPK/mTOR/p70 S6K signaling in diabetic osteoporosis","authors":"Bin Zhou ,&nbsp;Fen Feng ,&nbsp;Cila Zhou ,&nbsp;Kuang Yao ,&nbsp;Ping Huang","doi":"10.1016/j.mce.2026.112739","DOIUrl":"10.1016/j.mce.2026.112739","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (T2DM) often induces diabetic osteoporosis (DOP) with impaired bone remodeling, yet its underlying mechanism remains elusive. This study identified the differential regulatory role of the AMPK/mTOR/p70 S6K signaling axis in bone cell function. In vivo, diabetes reduced AMPK phosphorylation, enhanced mTOR/p70 S6K activation, and diminished autophagy in rat femoral tissue. In vitro, HG exerted cell-type-specific effects via the AMPK signaling pathway: in osteoblasts, HG inhibited AMPK phosphorylation, activated mTOR/p70 S6K, suppressed autophagy, and impaired mineralization as well as alkaline phosphatase (ALP) activity; conversely, in osteoclasts, HG enhanced autophagy through the inverse regulatory pathway and accelerated osteoclast differentiation and bone resorption. Collectively, these findings illustrate that hyperglycemia disrupts bone homeostasis via cell-type-specific regulation of AMPK, suggesting that AMPK-mediated autophagy serves as a potential critical therapeutic target for diabetes-related bone diseases.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"615 ","pages":"Article 112739"},"PeriodicalIF":3.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086432","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}

{"title":"Metabolite profiling of the effect of prenatal stimuli across postnatal treatments in the liver","authors":"Bruce R. Southey ,&nbsp;Andrea N. Gomez ,&nbsp;Gloria R. Sunderland ,&nbsp;Chance W. Riggins ,&nbsp;Maria B. Villamil ,&nbsp;Sandra L. Rodriguez-Zas","doi":"10.1016/j.mce.2026.112744","DOIUrl":"10.1016/j.mce.2026.112744","url":null,"abstract":"<div><div>Hepatic molecular mechanisms can be modulated by pro- and anti-inflammatory signals associated with infections and nutritional changes that can, in turn, affect the endocrine system. The sex-specific interplay between stimuli on hepatic pathways was studied using a biomedical model. The liver metabolome of pigs exposed to a prenatal immune activation from maternal infection was compared to that of matching female and male controls. Within prenatal treatment and sex group, the postnatal treatments were synthetic inflammatory factor, feeding deprivation (fasting), or saline. Liquid chromatography mass spectrometry enabled the detection of 2554 metabolites with significant (False Discovery Rate-adjusted p-value &lt;0.05) sex, prenatal, and postnatal treatment effects. The glycine, serine, and threonine metabolism, RNA metabolism, and neurotransmitter transporters pathways included metabolites with prenatal-by-postnatal treatment interaction effects, such as alanine, arginine, and ketobutyric acid. These disruptions can impact hepatic detoxification, protein synthesis, and methylation. The synergistic interaction for adenosylhomocysteine was characterized by higher levels in the postnatal fasted relative to the saline-treated group, whereas this trend was 4.5-fold higher in the prenatal immune-activated group compared to controls. The antagonistic interaction for chenodeoxycholyltaurine was characterized by higher levels in prenatal-activated relative to controls under saline conditions, whereas this trend declined 2.2-fold in the postnatal-stimulated groups. Sex-specific effects were observed for glutamic acid, with differences between prenatal groups 4.7 times higher in males than in females. These findings offer insights into the interplay between sex, prenatal, and postnatal stimuli across pathways that must be considered in the development of therapies to optimize liver function.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"615 ","pages":"Article 112744"},"PeriodicalIF":3.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090431","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}

{"title":"Plasma proteome mendelian randomization and network pharmacology reveal therapeutic targets for thyroid disorders","authors":"Chao Wang ,&nbsp;Yi Cai ,&nbsp;Xing Yang,&nbsp;Jie Jie","doi":"10.1016/j.mce.2026.112752","DOIUrl":"10.1016/j.mce.2026.112752","url":null,"abstract":"<div><h3>Introduction</h3><div>Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroid cancer, impose a substantial global health burden. Existing treatments face limitations due to adverse effects and incomplete efficacy, highlighting the need for innovative therapeutic strategies informed by genetic and molecular insights.</div></div><div><h3>Methods</h3><div>We integrated Mendelian randomization (MR) with network pharmacology to systematically prioritize druggable targets. Genetic correlations between different thyroid disorders were evaluated using linkage disequilibrium score regression analysis. Plasma protein quantitative trait loci from 4907 plasma proteins were leveraged as instrumental variables in MR analyses across two independent cohorts. Bayesian colocalization validated shared causal variants. Network pharmacology methods encompassed constructing protein-protein interaction networks, conducting functional enrichment analyses, and identifying potential therapeutic compounds via the DSigDB database. Docking and dynamics simulations assessed binding and stability, while PheWAS assessed off-target effects.</div></div><div><h3>Results</h3><div>The LDSC analysis identified notable genetic correlations of hypothyroidism with hyperthyroidism (Rg = 0.167, P = 0.017), as well as hyperthyroidism with thyroid cancer (Rg = 0.286, P = 0.033). MR and colocalization identified seven causal proteins: IL2RB, CDH1, FGF19 (hypothyroidism); PSAPL1 (hyperthyroidism); DCP1B, SPRN, RPS6KA6 (thyroid cancer). Drug prediction prioritized compounds such as BI-2536 (binding energy: −9.5 kcal/mol with RPS6KA6) and deoxycholic acid. PheWAS confirmed minimal pleiotropic risks.</div></div><div><h3>Conclusions</h3><div>By synergizing genetic epidemiology with network pharmacology, this study delineates shared genetic architecture among thyroid disorders and nominates seven high-confidence targets with therapeutic potential. The integrative framework advances precision medicine by bridging causal plasma protein identification, mechanistic pathway mapping, and drug repurposing, offering a blueprint for multi-omics-driven drug discovery in endocrine pathologies.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"615 ","pages":"Article 112752"},"PeriodicalIF":3.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090433","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}

{"title":"circPTPRM can encode a functional polypeptide circPTPRM-187aa to promote papillary thyroid carcinoma progression","authors":"Chengzhou Lv,&nbsp;Jiapeng Huang,&nbsp;Xiaoyu Ji,&nbsp;Wei Sun,&nbsp;Hao Zhang","doi":"10.1016/j.mce.2026.112734","DOIUrl":"10.1016/j.mce.2026.112734","url":null,"abstract":"<div><h3>Aims</h3><div>Papillary thyroid carcinoma (PTC) is the most common thyroid tumor, usually with a good prognosis, though some cases show early invasion, metastasis, and may become iodine-refractory. circRNAs can interact with miRNAs, bind proteins, regulate transcription, and encode polypeptides, but their translation function in thyroid cancer remains unexplored.</div></div><div><h3>Methods</h3><div>Quantitative real-time PCR (qRT-PCR), agarose gel electrophoresis, circRNA stability assessment, fluorescence in situ hybridization (FISH) were performed to explore the expression profile of circPTPRM in PTC tissues and adjacent non-cancerous thyroid tissues. We performed molecular biological and cell function experiments by constructing knockdown and various overexpression vectors. Effects of circPTPRM on PTC tumorigenesis were investigated through in vitro and in vivo experiments. The mechanism of circPTPRM-mediated tumor promotion was explored through immunofluorescence (IF), LC-MS/MS, immunoprecipitation (IP) and Co-immunoprecipitation (Co-IP), protein stability assessment, and ubiquitination assay.</div></div><div><h3>Results</h3><div>We confirmed that circPTPRM influenced PTC cell proliferation, migration, invasion through its translated polypeptides. In vivo experiments with nude mouse tumors also demonstrated that overexpression of circPTPRM contributed to the tumor's increased volume and weight. Subsequently, in the mechanistic analysis we found that circPTPRM-187aa polypeptide could bind IQGAP1 and induce TGF-β pathway activation by elevating RAC1 and CDC42.</div></div><div><h3>Conclusion</h3><div>CircPTPRM can encode circPTPRM-187aa polypeptide. circPTPRM-187aa, regulates the expression of IQGAP1 protein, and up-regulates RAC1 and CDC42 proteins in TGF-β signaling pathway, enhancing the PTC cells proliferation, migration, and invasion.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"614 ","pages":"Article 112734"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989955","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}

{"title":"Corrigendum to “The local corticotropin-releasing hormone receptor 2 signalling pathway partly mediates hypoxia-induced increases in lipolysis via the cAMP–protein kinase A signalling pathway in white adipose tissue” [Mol. Cellul. Endocrinol. 392/1–2 (2014) 106–114]","authors":"Yanlei Xiong ,&nbsp;Zhuan Qu ,&nbsp;Nan Chen ,&nbsp;Hui Gong ,&nbsp;Mintao Song ,&nbsp;Xuequn Chen ,&nbsp;Jizeng Du ,&nbsp;Chengli Xu","doi":"10.1016/j.mce.2025.112680","DOIUrl":"10.1016/j.mce.2025.112680","url":null,"abstract":"","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"614 ","pages":"Article 112680"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998637","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}

{"title":"Developmental exposure to a mixture of propiconazole and glyphosate induces histopathological lesions in the prostate of postpubertal rats","authors":"Ayelen L. Gomez ,&nbsp;Débora G. Reato ,&nbsp;Eduardo Masat ,&nbsp;Laura Kass ,&nbsp;Gabriela A. Altamirano","doi":"10.1016/j.mce.2026.112730","DOIUrl":"10.1016/j.mce.2026.112730","url":null,"abstract":"<div><div>Pesticide mixture exposure during critical developmental windows is a growing public health concern, given their potential additive or synergistic effects on the male reproductive system. This study aimed to evaluate whether developmental exposure to a mixture of propiconazole (PRO) and glyphosate (GLY) alters the postpubertal rat prostate. Pregnant rats were orally exposed to vehicle (saline) or a mixture of PRO and GLY (4 mg PRO/kg/day and 3.7 mg GLY/kg/day) from gestation day 9 until weaning. On postnatal day 60, male offspring were euthanized, and the prostate and serum samples were collected. PROGLY-exposed rats exhibited changes in the ventral and dorsolateral prostate histoarchitecture, including epithelial and stromal remodeling and increased incidence of prostate lesions. In the ventral prostate, although the relative glandular area remained unchanged, PROGLY exposure exhibited increased epithelial height and decreased luminal acinar area. Also, hyperplastic and atrophic acini were more prevalent in these animals. PROGLY exposure reduced estrogen receptor beta (ESR2) protein level, particularly in hyperplastic and atrophic acini, without affecting androgen or estrogen receptor alpha. ESR2 decrease was associated with an increased cell proliferation index in hyperplastic acini and a reduction in serum testosterone level in PROGLY-exposed rats. Stromal alterations included increased smooth muscle cell layers and reduced vimentin-positive fibroblasts, with no evidence of myofibroblast presence. This study shows that developmental exposure to PROGLY disrupts normal ventral prostate architecture and hormone signaling in postpubertal rats. These findings highlight the potential long-term risks of combined pesticide exposure on male reproductive health and the importance of evaluating mixture effects.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"614 ","pages":"Article 112730"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908767","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}

{"title":"Hsp90α as a promising therapeutic target for suppressing tumor progression in Lactotroph PitNETs","authors":"Jie Wu,&nbsp;Zhengan Zhou,&nbsp;Chongxue Ding,&nbsp;Hongjie Sun,&nbsp;Ming Xia,&nbsp;Kai Zhou,&nbsp;Tingrong Zhang,&nbsp;Shaoshan Li","doi":"10.1016/j.mce.2026.112733","DOIUrl":"10.1016/j.mce.2026.112733","url":null,"abstract":"<div><h3>Background</h3><div>Aggressive Lactotroph Pituitary Neuroendocrine Tumors (Lactotroph PitNETs) usually exhibit invasive growth behavior and resistance to dopamine agonists, showing difficulty in radical treatment and a high recurrence rate. Heat shock protein 90α(Hsp90α),a pivotal isoform of the heat shock protein 90(Hsp90) family, acts as a central chaperone that stabilizes numerous oncoproteins driving tumor progression, but its role in Lactotroph PitNETs remains unclear.</div></div><div><h3>Objective</h3><div>To study the effect of Hsp90α knockdown on the proliferation and invasiveness of Lactotroph PitNETs cells (MMQ).</div></div><div><h3>Methods</h3><div>Hsp90α and EGFR expression was compared between 18 aggressive and 22 Non-Aggressive human Lactotroph PitNETs by IHC and immunofluorescence. MMQ rat lactosomatotroph cells were transduced with lentiviral shRNA targeting Hsp90α(shHsp90α). Cell proliferation (CCK8),apoptosis (Annexin-V/7-AAD flow cytometry), Prolactin (PRL) secretion (ELISA), migration and invasion (Transwell) were assessed. Western blotting evaluated EGFR,<strong>PRL</strong>,AKT,ERK1/2,mTOR,p-AKT,p-ERK1/2 and p-mTOR.</div></div><div><h3>Results</h3><div>Aggressive Lactotroph PitNETs displayed higher Hsp90α and EGFR expression and showed a notable degree of spatial overlap. Hsp90α knockdown reduced EGFR,AKT,ERK1/2,mTOR,p-AKT,p-ERK1/2 and p-mTOR levels, decreased proliferation, increased apoptosis, lowered PRL secretion, and impaired migration and invasion.</div></div><div><h3>Conclusions</h3><div>Hsp90α knockdown simultaneously destabilizes EGFR and its downstream AKT/mTOR and ERK axes, resulting in multi-modal suppression of Lactotroph PitNETs invasion. Targeting Hsp90α may offer a novel therapeutic strategy for Aggressive Lactotroph PitNETs refractory to standard medical therapy.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"614 ","pages":"Article 112733"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979822","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}

{"title":"Exploring recent insights on intermittent fasting in regulating glucocorticoid levels and diet-induced metabolic disorders with focus on MAFLD and hepatic outcomes","authors":"Jasper Okoro Godwin Elechi ,&nbsp;Carolina Ramos de Mendonça ,&nbsp;Vitor Carlos de Araújo Bandeira ,&nbsp;Maria Surama Pereira Da Silva ,&nbsp;Ana Paula Rocha de Melo ,&nbsp;Rubem Carlos Araujo Guedes ,&nbsp;Sandro Massao Hirabara ,&nbsp;Erika Cione ,&nbsp;Diogo Antonio Alves de Vasconcelos","doi":"10.1016/j.mce.2026.112736","DOIUrl":"10.1016/j.mce.2026.112736","url":null,"abstract":"<div><div>Consumers' risky eating behaviours aided by the current food environment have led to an increase in diet-related metabolic disorders. Metabolic (dysfunction)-associated fatty liver disease origin represents a major global health burden that is increasing at an alarming rate on an annual basis. Modifying the timing of calorie consumption, dietary composition, or caloric intake offers a promising therapeutic approach for the management of this condition. The aim of this review was to provide a concise analysis of the impact of intermittent fasting on the regulation of glucocorticoid levels and diet-induced metabolic disorders with a focus on non-alcoholic fatty liver diseases. We found that intermittent fasting primarily regulates hepatic autophagy via nutritional and hormonal pathways, aiding in the maintenance of energy equilibrium, enhancement of mitochondrial function, regulation of liver quality, preservation of cellular homeostasis, protection of cells from harmful factors, mitigation of liver metabolic disorders, and improvement of liver inflammation. Also, the physiological changes induced by intermittent fasting and their metabolic consequences arise through multiple mechanisms, including alterations in hepatic metabolism, hepatic autophagy, inflammatory responses, liver functional enzymes, hepatic steatosis, fibroblast growth factor signalling, White adipoe tissue browning, adipokines, circadian rhythms, lipid profiles, body composition, the adipose tissue–gut microbiome axis, skeletal muscle, and the autophagy process. Interestingly, we identified the complex interplay among glucocorticoids, intermittent fasting, and non-alcoholic fatty liver diseases highlighting the hepatic macrophage glucocorticoid receptor as a pivotal mediator of fasting-induced reprogramming of the macrophage secretome, including fasting-suppressed cytokines. In conclusion, existing data indicates that intermittent fasting in patients with non-alcoholic fatty liver diseases is a viable, safe, and successful strategy for weight reduction, demonstrating notable trends in the amelioration of dyslipidaemia and non-alcoholic fatty liver diseases.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"614 ","pages":"Article 112736"},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003723","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}

{"title":"SIK1 drives lipid-induced insulin resistance in skeletal muscle by linking TGFβ1-Smad2/3 activation to PDE4-cAMP dysregulation.","authors":"Yanli Liu, Yu Shi, Yu Shen, Hui Qu, Li Qin, Suling Huang, Ying Leng","doi":"10.1016/j.mce.2026.112788","DOIUrl":"10.1016/j.mce.2026.112788","url":null,"abstract":"<p><p>Excessive lipid accumulation in skeletal muscle contributes to insulin resistance. Salt-inducible kinase 1 (SIK1) is known to be involved in myogenic differentiation, yet its role in lipid-induced skeletal muscle insulin resistance remains unclear. Here, we identified the functional role of SIK1 in skeletal muscle insulin resistance under lipid overload and delineated the underlying signaling mechanisms. In C2C12 myotubes, palmitate markedly increased SIK1 expression and phosphorylation at Thr182, and further impaired insulin-stimulated Akt phosphorylation and glucose uptake. These effects were blocked by SIK1 knockdown or pharmacological inhibition of SIK. The palmitate-induced upregulation of SIK1 and the associated insulin signaling defects were abolished by inhibition of TGFβ receptor 1 or knockdown of Smad2/3. Moreover, genetic or pharmacological inhibition of SIK1 restored the palmitate-reduced cAMP levels in myotubes, and inhibition of PDE4 similarly rescued cAMP levels and insulin signaling, mimicking the effects of SIK1 suppression. Consistent with these in vitro findings, SIK1 and TGFβ1-Smad2/3 signaling were upregulated while cAMP levels were decreased in skeletal muscle of diet-induced obese (DIO) mice. Either SIK inhibition or blockade of TGFβ1-Smad2/3 signaling restored the impaired insulin-stimulated Akt phosphorylation in isolated skeletal muscle. Together, we demonstrate that SIK1 is upregulated under lipid overload via TGFβ1-Smad2/3 signaling, thereby triggering PDE4-dependent cAMP degradation and consequent insulin resistance in skeletal muscle. These findings establish SIK1 as a critical mediator of lipid overload-induced insulin signaling defects in skeletal muscle.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112788"},"PeriodicalIF":3.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147486742","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}