Molecular And Cellular Endocrinology[JOURNAL]
Sun
200 papers
Blood-based microRNAs as biomarkers of insulin resistance in childhood obesity: A systematic review and meta-analysis.
Wang L, Liu Z
Mol Cell Endocrinol · 2026 Jul · PMID 42392357 · Publisher ↗
Childhood obesity is closely linked to insulin resistance, but affected children are metabolically heterogeneous. Blood-based microRNAs (miRNAs) have emerged as potential minimally invasive biomarkers of early metabolic...
Childhood obesity is closely linked to insulin resistance, but affected children are metabolically heterogeneous. Blood-based microRNAs (miRNAs) have emerged as potential minimally invasive biomarkers of early metabolic dysfunction. A systematic search of PubMed, Embase, Web of Science, and Scopus was conducted from database inception to April 1, 2026. Eligible studies included children or adolescents with obesity that evaluated blood-based miRNAs, including serum, plasma, or peripheral blood mononuclear cell-derived miRNAs, in relation to IR. Narrative synthesis was the primary approach. Study quality was assessed using the Newcastle-Ottawa Scale, and exploratory quantitative synthesis was performed only for comparable miRNA-outcome pairs with extractable correlation data. Twenty studies met the inclusion criteria; 7 were rated as low risk of bias, 11 as moderate risk, and 2 as high risk. Most studies had cross-sectional or case-control designs, and substantial heterogeneity was present in study populations, biological sample source, insulin resistance definitions, miRNA methods, and outcome reporting. Across the included studies, miR-122 was the most consistent candidate, showing recurrent up-regulation in adverse metabolic phenotypes and positive associations with HOMA-IR (r = 0.53; 95%CI, 0.35-0.67) or related IR markers (r = 0.60; 95%CI, 0.47-0.70). miR-29a also showed relatively consistent positive associations (r = 0.67; 95%CI, 0.59-0.73), particularly in cohorts with more severe metabolic impairment. Other candidates, including miR-146a, miR-34a, miR-191-3p, miR-30d-5p, and miR-221-3p, showed relevant but less consistent findings. Blood-based miRNAs are associated with IR in childhood obesity, with miR-122 emerging as the strongest and most recurrent candidate and miR-29a as another promising marker. However, the evidence remains heterogeneous and insufficient for clinical application. Larger, standardized, and longitudinal studies are needed to validate the most recurrent candidates and define their role in early risk stratification.
Female-specific metabolic genetic liability reveals a separable metabolic dimension of polycystic ovary syndrome.
Wang S, Wang K
Mol Cell Endocrinol · 2026 Jul · PMID 42385931 · Publisher ↗
BACKGROUND: Polycystic ovary syndrome (PCOS) frequently co-occurs with obesity, insulin resistance, dyslipidaemia and metabolic syndrome (MetS). However, whether this metabolic burden represents secondary comorbidity or...
BACKGROUND: Polycystic ovary syndrome (PCOS) frequently co-occurs with obesity, insulin resistance, dyslipidaemia and metabolic syndrome (MetS). However, whether this metabolic burden represents secondary comorbidity or an intrinsic component of PCOS genetic architecture remains unclear. METHODS: We used genomic structural equation modelling to construct female- and male-specific hierarchical MetS latent factors from six sex-stratified cardiometabolic GWAS, including BMI, waist circumference, triglycerides, HDL cholesterol, type 2 diabetes and fasting glucose. Sex-specific MetS genetic architecture was evaluated using latent factor GWAS, sex-difference testing, MiXeR, MAGMA and GSA-MiXeR. To assess the relationship between MetS liability and PCOS, we performed CPASSOC, conjunctional FDR, Bayesian colocalization, GWAS-by-subtraction and GenomicSEM-based mediation analysis. RESULTS: Female and male MetS factors shared a highly overlapping polygenic backbone, but their genetic correlation was significantly below unity. Among comparable lead variants, 9.1% showed sex-dimorphic effects, and MiXeR estimated an approximately fourfold larger female-specific causal component than the male-specific component. Cross-trait analysis identified 45 candidate pleiotropic loci linking PCOS with the female MetS factor, 34 conjFDR-supported shared loci and 10 loci with strong Bayesian colocalization evidence, including FTO, ERBB3, FGFR1, KLF16 and TEX41. GWAS-by-subtraction showed that 16.7% of PCOS genetic variance was shared with female MetS, whereas 83.3% remained MetS-independent and retained stronger reproductive-endocrine features. Variant-level mediation further showed that MetS-mediated effects were locus-specific rather than a global amplifier of PCOS risk. CONCLUSIONS: This study redefines the metabolic comorbidity of PCOS as a separable, female-biased genetic dimension embedded within, but distinct from, the predominant reproductive-endocrine genetic architecture of PCOS. These findings provide a genetic framework for resolving reproductive-metabolic heterogeneity in PCOS and may inform future risk stratification and precision management of metabolic complications in women with PCOS.
The kisspeptin analog C6 elicits greater tachyphylaxis and transcriptional activation than kisspeptin-10 and -54.
Robert V, Lomet D, Dardente H … +2 more , Aucagne V, Beltramo M
Mol Cell Endocrinol · 2026 Jun · PMID 42379494 · Publisher ↗
The discovery of the neuropeptide kisspeptin (Kp) and its receptor has attracted considerable attention as a potential therapeutic target for the treatment of various medical disorders and for the management of reproduct...
The discovery of the neuropeptide kisspeptin (Kp) and its receptor has attracted considerable attention as a potential therapeutic target for the treatment of various medical disorders and for the management of reproduction in livestock. To this end, endogenous agonists (hKp10 and hKp54) as well as synthetic agonists (TAK-448 and C6) have been evaluated in vivo with promising results. However, direct comparative data on the effects of these molecules remain limited, both in vivo and in vitro. Given the importance of such comparisons from a drug discovery perspective, we sought to characterize and directly compare the in vitro pharmacological profiles of hKp10, hKp54, and C6. Using HEK293 cells stably expressing the human Kp receptor, we found that C6 produced the most sustained intracellular Ca mobilization. This prolonged signaling was associated with more pronounced tachyphylaxis, which we propose results from a greater depletion of intracellular Ca stores. In contrast, a second stimulation with low concentrations of hKp54, but not of hKp10, elicited an increased response. We also assessed the expression of a selected panel of genes at different time points following treatment. C6 induced the strongest and most sustained transcriptional response, followed by hKp54 and hKp10. Notably, marked upregulation was observed for immediate-early genes (IER2, EGR1, and KLF10), transcription factors (NR4A1, NR4A2, and NFKB1A), and inflammatory mediators (CXCL8, CXCL1, and CCL2). Collectively, these findings demonstrate distinct in vitro pharmacological profiles among the three agonists. Such differences may have important implications for therapeutic efficacy and the potential induction of adverse effects during drug development.
G1 regulation of BK channel leads to decreased migration of senescent pericytes and improved age-related hearing loss.
Xu S, Si C, Zhang K … +6 more , Wang Y, Deng S, Li X, Si J, Wang M, Li L
Mol Cell Endocrinol · 2026 Jun · PMID 42379493 · Publisher ↗
The pathogenesis of age-related hearing loss (ARHL) remains incompletely understood. The blood labyrinth barrier (BLB) play a crucial role in maintaining cochlear homeostasis, yet in the stria vascularis (SV) of aged C57...
The pathogenesis of age-related hearing loss (ARHL) remains incompletely understood. The blood labyrinth barrier (BLB) play a crucial role in maintaining cochlear homeostasis, yet in the stria vascularis (SV) of aged C57BL/6J mice, pericytes (PCs) undergo migration, potentially increasing BLB permeability and contributing to vascular leakage, which may exacerbate ARHL. The underlying molecular mechanisms, however, remain elusive. Studies have suggested gender disparities in auditory function linked to estrogen levels, with G1, an activator of the estrogen membrane receptor GPER, capable of activating large-conductance calcium-activated potassium channels (BK). Our previous research has indicated a decline in BK channel expression on pericytes with aging. Our study aimed to investigate whether G1 protects against ARHL by modulating BK channels in aged cochlear pericytes, thereby influencing pericyte migration. In vivo experiments revealed reduced BK channel expression in cochlear SV pericytes of aged mice, which was upregulated following G1 administration, accompanied by improved hearing and decreased BLB permeability. In vitro, G1 increased BK channel expression in pericytes and diminished their migratory capacity. Further investigation uncovered a close association between aged pericyte migration and both the BK channel and the MEK/ERK signaling pathway. These findings provide experimental evidence to elucidate he impact of estrogen on auditory function and offer novel targets and strategies for preventing and treating ARHL.
Maternal butyrate administration ameliorates fetal fatty liver and maternal metabolic alterations related to maternal obesity.
Heinecke F, Flores Quiroga JP, Labiano M … +4 more , Galarza R, Faletti AG, Jawerbaum A, White V
Mol Cell Endocrinol · 2026 Jun · PMID 42349743 · Publisher ↗
Obesity negatively impacts maternal and fetal metabolism, leading to the programming of metabolic disturbances in the offspring. We have previously reported numerous maternal, fetal and offspring alterations in a rat mod...
Obesity negatively impacts maternal and fetal metabolism, leading to the programming of metabolic disturbances in the offspring. We have previously reported numerous maternal, fetal and offspring alterations in a rat model of obesity. In this study, we administered butyrate-a short-chain fatty acid derived from gut microbiota metabolism-to obese mother rats during pregnancy and lactation in an attempt to improve maternal health and prevent the fetal features associated with the programming of fatty liver disease. The initial experimental study design comprised female Albino-Wistar rats assigned to either a control diet (C group) or a high-fat diet (FD group) to induce obesity, before being paired with control males. Pregnant rats received either butyrate (CB or FDB) or water as a vehicle (C or FD) during gestation and were euthanized at day 21 of pregnancy. The second experimental design comprised C, FD, and FDB rats that gave birth and breastfed their pups, with mothers being euthanized at the conclusion of the lactation period. At term gestation, rats with obesity exhibited increased adiposity, hepatic lipid accumulation, triglyceridemia, and circulating IL-1β. Their fetuses displayed increased body weight, liver lipid over-accumulation, and altered mRNA levels of genes involved in liver damage. Notably, butyrate administration decreased maternal circulating levels of triglycerides and IL-1β, and prevented fetal overweight status and hepatic lipid accumulation at term gestation. Importantly, butyrate exerted no effect on control rats or their fetuses. Moreover, butyrate administration ameliorated features of fatty liver disease in overweight rats at the end of lactation, further demonstrating its beneficial effects on both mothers and fetuses in this rat model of obesity.
Retraction notice to " Steroid-induced oocyte maturation in Indian shad Tenualosa ilisha (Hamilton, 1822) is dependent on phosphatidylinositol 3 kinase but not MAP kinase activation" [Mol. Endocrinol. 390 (2014) 26-33].
Pramanick K, Kundu S, Paul S … +4 more , Mallick B, Moulik SR, Pal P, Mukherjee D
Mol Cell Endocrinol · 2026 Jun · PMID 42342472 · Publisher ↗
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Sulforaphane preserves hepatocellular metabolic regulation and organelle integrity in a model of diet-induced obesity.
Ajackson M, Monteiro EB, Martins FF … +11 more , do Nascimento Junior JX, Cavadas Neto ES, Medeiros Amarante MDS, da Silva Camillo C, Vieira JRC, Lisboa PC, Tavares DAG, Zancan P, de Barros Mucci D, Soulage CO, Daleprane JB
Mol Cell Endocrinol · 2026 Jun · PMID 42341866 · Publisher ↗
Metabolic-associated steatotic liver disease (MASLD) is strongly associated with obesity and type 2 diabetes (T2D), emerging as a consequence of sustained disturbances in hepatocellular metabolic signaling, inflammatory...
Metabolic-associated steatotic liver disease (MASLD) is strongly associated with obesity and type 2 diabetes (T2D), emerging as a consequence of sustained disturbances in hepatocellular metabolic signaling, inflammatory regulation, and organelle homeostasis induced by nutritional overload. Sulforaphane (SFN), a dietary bioactive compound, has been associated with metabolic protection, yet its ability to preserve hepatic cellular regulation and ultrastructural integrity during MASLD development remains incompletely defined. In this study, C57BL/6 mice were exposed to a high-fat, high-sucrose diet for 14 weeks to induce MASLD, with concomitant SFN administration (2 mg/kg/day, intraperitoneally, 5 days/week). Hepatic and adipose tissue remodeling, insulin signaling, inflammatory pathways, and subcellular architecture were evaluated using biochemical analyses, histology, gene expression profiling, and transmission electron microscopy. SFN markedly attenuated hepatic steatosis, collagen deposition, and glycogen degeneration, while modulating insulin signaling pathway and shifting hepatic gene expression toward oxidative metabolic pathways. These effects were accompanied by suppression of inflammatory mediators, including Nlrp3, Tnfa, and Il1β. At the ultrastructural level, SFN preserved mitochondrial architecture and endoplasmic reticulum organization, preventing diet-induced organelle stress, lipid overload and energy imbalance. Collectively, these findings demonstrate that SFN protects against diet-induced MASLD by maintaining hepatocellular metabolic and inflammatory regulation and preserving organelle integrity, highlighting the relevance of cellular regulatory mechanisms in the control of hepatic intermediary metabolism.
Patient-derived eutopic and ectopic endometrial stromal cells: characterization and development of immortalized lines.
Wang XY, Yang L, Jiang J … +4 more , Sun XC, Guo KN, Zhang TT, Gu WW
Mol Cell Endocrinol · 2026 Jun · PMID 42320595 · Publisher ↗
Ovarian endometriosis is an estrogen-dependent inflammatory disorder in which endometrial stromal cells are key cellular contributors to hormone-immune crosstalk and lesion persistence. Here, we isolated paired eutopic (...
Ovarian endometriosis is an estrogen-dependent inflammatory disorder in which endometrial stromal cells are key cellular contributors to hormone-immune crosstalk and lesion persistence. Here, we isolated paired eutopic (NESC) and ectopic (EESC) endometrial stromal cells from patients with ovarian endometriosis, compared their proliferation, migration/invasion and decidual responsiveness, and profiled their transcriptomes by RNA sequencing. EESCs displayed enhanced proliferative and migratory/invasive capacity and an attenuated decidual response. RNA-seq revealed an inflammatory transcriptional program with enrichment of cytokine-cytokine receptor interaction and MAPK-related pathways and increased expression of chemokines and pro-inflammatory cytokines. Steroid receptor analyses showed reduced ERα and progesterone receptor expression with relative ERβ predominance, consistent with progesterone-resistance-like features. We then generated SV40 large T antigen-immortalized NESC and EESC lines. These lines showed stable growth and retained stromal identity and several disease-relevant phenotypic features, while also acquiring immortalization-associated transcriptomic remodeling involving cell-cycle, DNA-replication and proliferation-related programs. These paired primary and immortalized stromal cell models provide a practical platform to investigate endocrine-immune mechanisms in endometriosis and to facilitate preclinical screening of therapies targeting inflammatory and steroid signaling.
Revisiting hypocholesterolemia during prolonged sepsis: From targeted cholesterol repletion to unresolved adrenal and muscle dysfunction.
De Bruyn L, Van Beek F, Vander Perre S … +5 more , Derde S, Derese I, Pauwels L, Van den Berghe G, Langouche L
Mol Cell Endocrinol · 2026 Jun · PMID 42314824 · Publisher ↗
BACKGROUND: Sepsis HDL- and LDL-hypocholesterolemia associate with adverse outcomes, but whether this necessitates supplementation or merely reflects disease severity remains unclear. We hypothesize that sustained hypoch...
BACKGROUND: Sepsis HDL- and LDL-hypocholesterolemia associate with adverse outcomes, but whether this necessitates supplementation or merely reflects disease severity remains unclear. We hypothesize that sustained hypocholesterolemia can contribute to ICU-acquired weakness and adrenal dysfunction, and that cholesterol supplementation can improve tissue cholesterol availability, muscle and adrenal integrity. METHODS: In a catheterized mouse model of cecal-ligation-and-puncture-induced sepsis (5-days), septic mice received continuous infusion with an LDL- (mouse study 1; n = 51) (3.5 mg/d) or HDL-cholesterol (mouse study 2; n = 47) (5 mg/d) enriched cholesterol mixture, compared to placebo, and healthy reference mice. Plasma HDL-, LDL-cholesterol, CORT, TNF-α and total bile acids were measured, in addition to muscle force, myofiber cholesterol, ex-vivo adrenal ACTH response, adrenal cholesterol and structure. Gene expression markers of cholesterol synthesis were measured in liver, adrenal and muscle tissue. RESULTS: LDL-cholesterol infusion in septic mice increased plasma LDL-, but not HDL-cholesterol, whereas HDL-cholesterol infusion increased plasma HDL- and LDL-cholesterol (P < 0.0001 versus placebo). Cholesterol supplementation attenuated sepsis-induced adrenal cholesterol depletion (P < 0.05), without improving adrenocortical structure or the adrenal ACTH response. Cholesterol supplementation did not affect muscle mass loss, force or myofiber cholesterol, but increased plasma bile acids and reduced markers of cholesterol synthesis in liver, adrenal and muscle versus placebo (P ≤ 0.05). No additional effect on elevated plasma CORT and TNF-α was observed. CONCLUSION: Cholesterol supplementation reversed sepsis-induced hypocholesterolemia, without reversing the sepsis-induced adrenal or muscle phenotype. Together with suppressed markers of cholesterol uptake, synthesis and increased bile acid formation, these findings argue against the need to treat hypocholesterolemia during prolonged sepsis.
Molecular and functional analysis of GnRH2 in hypothalamic-pituitary-gonadal axis activation in Pampus argenteus.
Wang C, Zhang H, Ding M … +4 more , Zhang K, Wang X, Wang X, Guo C
Mol Cell Endocrinol · 2026 Jun · PMID 42302890 · Publisher ↗
This study aimed to identify and characterize the gnrh2 gene in Pampus argenteus, and to systematically investigate the regulatory effects of synthetic GnRH2 decapeptide on the hypothalamic-pituitary-gonadal (HPG) axis t...
This study aimed to identify and characterize the gnrh2 gene in Pampus argenteus, and to systematically investigate the regulatory effects of synthetic GnRH2 decapeptide on the hypothalamic-pituitary-gonadal (HPG) axis through analyses of tissue distribution, expression patterns during gonadal development, and in vitro and in vivo functional experiments. In this study, the gnrh2 gene of the P. argenteus was successfully identified and characterized. Sequence analysis revealed that the gene possesses conserved structural features of the GnRH family, with a highly conserved decapeptide region (QHWSHGWYPG). Phylogenetic analysis indicated that P. argenteus GnRH2 clustered closely with teleost GnRH2 sequences. Tissue distribution analysis demonstrated that gnrh2 was most abundantly expressed in the pituitary, suggesting its critical role in the neuroendocrine regulation of reproduction. During gonadal development, gnrh2 expression exhibited dynamic, stage-dependent variations, with a significant increase at the maturation stage in both males and females. In vitro pituitary culture experiments showed that exogenous synthetic GnRH2 decapeptide altered the expression of lhβ and fshβ. In vivo intraperitoneal injection further revealed that synthetic GnRH2 decapeptide significantly upregulated the expression of gnrh2, lhr, lhβ, fshr, and fshβ in the hypothalamus and gonads, indicating that GnRH2 is associated with the transcriptional regulation of HPG axis-related genes and may be involved in reproductive processes. In summary, these findings suggest that GnRH2 may play a role in reproductive regulation in P. argenteus and provide a molecular basis for the artificial breeding and endocrine control of this species.
Curcusone D improves metabolic dysfunction associated steatotic liver disease via activation of the AMPK signaling.
Yao D, Wen S, Li Q … +5 more , Jia Y, Wan L, Qiu M, Huang Y, Zhao W
Mol Cell Endocrinol · 2026 Jun · PMID 42264076 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide with limited effective clinical treatments. Previous high-throughput drug screening identified Curcus...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide with limited effective clinical treatments. Previous high-throughput drug screening identified Curcusone D as a promising candidate for MASLD treatment. This study aimed to validate its therapeutic effects and underlying molecular mechanism. In vivo efficacy was evaluated in high-fat and high-cholesterol (HFHC) diet-fed mice, while in vitro hepatocyte models were used for mechanistic verification. The results demonstrated that Curcusone D significantly improved liver function, reduced serum pro-inflammatory cytokines, and suppressed hepatic inflammation and fibrosis in MASLD mice. It also markedly reversed excessive lipid accumulation and inhibited inflammatory responses in hepatocytes. Mechanistically, Curcusone D specifically activated the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Pharmacological inhibition of AMPK fully abolished the protective effects of Curcusone D against HFHC-induced hepatic steatosis, insulin resistance, inflammation and fibrosis. In conclusion, Curcusone D ameliorates MASLD progression via AMPK pathway activation, serving as a novel and druggable natural candidate for future MASLD clinical therapy.
The mineralocorticoid receptor and its antagonist finerenone regulate hepatic lipid accumulation via the AMPK/SREBP1/FASN signaling.
Fu S, Zhang M, Wang K … +17 more , Huang S, Xi Y, Chen J, Xie D, Zhang Q, Que W, Ye X, Chen S, Liu Y, Wu M, Xu L, Ye C, Yamamoto T, Koyama H, Li C, Wu Y, Cheng J
Mol Cell Endocrinol · 2026 Jun · PMID 42264075 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD), closely linked to obesity and diabetes, remains poorly understood, with limited therapeutic options. The mineralocorticoid receptor (MR) has been implicat...
Metabolic dysfunction-associated steatotic liver disease (MASLD), closely linked to obesity and diabetes, remains poorly understood, with limited therapeutic options. The mineralocorticoid receptor (MR) has been implicated in metabolic dysregulation, yet its role in hepatic lipid metabolism remains incompletely defined. Finerenone, a non-steroidal MR antagonist, has demonstrated renal and cardiovascular benefits in diabetes, yet its effects on hepatic metabolism have not been fully explored. This study aimed to evaluate the hepatoprotective effects of finerenone in MASLD and elucidate the underlying mechanisms. MASLD models were established using db/db mice and free fatty acid-treated hepatocytes. Treatment with finerenone significantly reduced hepatic lipid accumulation in both in vitro and in vivo models. Mechanistically, MASLD was characterized by overactivation of hepatic MR signaling, evidenced by increased NR3C2 expression and upregulation of canonical MR target genes. Finerenone inhibits and antagonizes excessive MR activation, enhanced AMP-activated protein kinase (AMPK) phosphorylation, and downregulated sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), thereby inhibiting de novo lipogenesis. The lipid-lowering effects of finerenone were abrogated by AMPKα knockdown or inhibition, while NR3C2 knockdown mimicked the metabolic effects of finerenone without additive benefit, supporting an MR-dependent mechanism. Conversely, aldosterone reversed the lipid-lowering effects of finerenone through the AMPK/SREBP1/FASN pathway. In conclusion, finerenone alleviates hepatic lipid accumulation in MASLD, at least in part, by inhibiting MR signaling and modulating the AMPK/SREBP1/FASN pathway. These findings highlight a previously underrecognized role of MR in hepatic lipid metabolism and support finerenone as a potential therapeutic strategy for MASLD.
Altered sulfite oxidase expression contributes to AMP-activated protein kinase-dependent mitochondrial dysfunction and metabolic dysregulation in polycystic ovary syndrome.
Wang X, Zhang K, Hao J … +3 more , Zhao M, Wang X, Xu L
Mol Cell Endocrinol · 2026 Jun · PMID 42250792 · Publisher ↗
BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by reproductive dysfunction and endocrine-metabolic abnormalities. However, its precise pathogenesis remains unclear. Increasing evid...
BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by reproductive dysfunction and endocrine-metabolic abnormalities. However, its precise pathogenesis remains unclear. Increasing evidence indicates that ovarian granulosa cells (GCs) dysfunction and metabolic imbalance play critical roles in the initiation and progression of PCOS. This study investigated the regulatory role of the sulfite oxidase (SUOX)-AMP-activated protein kinase (AMPK) signaling axis in the development and function of ovarian GCs in PCOS. METHODS: PCOS-associated gene variants were identified using high-throughput sequencing and subsequently validated using dual-luciferase reporter assays. SUOX expression was modulated in ovarian KGN cells using gene knockdown and overexpression approaches combined with pharmacological interventions to assess alterations in SUOX-AMPK signaling and its downstream effects. A mouse model of PCOS was established to further evaluate the biological role of SUOX in vivo. RESULTS: SUOX expression was significantly reduced in follicular fluid samples from patients with PCOS. SUOX knockdown was associated with suppression of AMPK signaling, mitochondrial dysfunction, impaired autophagy, and increased lipid synthesis in KGN cells. Conversely, SUOX overexpression or AMPK pharmacological activation effectively reversed these pathological changes. Restoration of SUOX expression partially reduced ovarian metabolic dysfunction in PCOS mouse models. CONCLUSION: These findings demonstrate that the SUOX-AMPK signaling axis plays an important role in the pathogenesis of PCOS. Reduced SUOX expression may contribute to disease progression by promoting oxidative stress, worsening mitochondrial damage, and impairing ovarian function, suggesting that SUOX may represent a potential molecular target for the diagnosis and treatment of PCOS.
A journey toward understanding the vasopressin type 2 receptor function; impact of small molecules and structural biology.
Fouillen A, Couvineau P, Mouillac B … +1 more , Bous J
Mol Cell Endocrinol · 2026 Jun · PMID 42229615 · Publisher ↗
Arginine-vasopressin (AVP) is well known for its antidiuretic effect, which is mediated through activation of the kidney V2 receptor subtype (V2R). Here, we provide a detailed overview of the evolution of our understandi...
Arginine-vasopressin (AVP) is well known for its antidiuretic effect, which is mediated through activation of the kidney V2 receptor subtype (V2R). Here, we provide a detailed overview of the evolution of our understanding of this system, from the pioneering work of Schafer and Oliver to recent studies that characterize its physiological, pharmacological, and molecular mechanistic features. Recent breakthroughs in cryo-electron microscopy (cryo-EM) have significantly advanced our understanding of how V2R interacts with its cognate ligand. Furthermore, these structural insights help explain how small molecules developed over the past three decades bind to and modulate receptor activity. Together, these advances open new therapeutic perspectives for the treatment of V2R-associated diseases.
A novel role of follicular fluid exosomal miR-143-5p in polycystic ovary syndrome: targeting RASAL2 to drive granulosa cell proliferation.
Lian Y, Chen J, Zhang T … +5 more , Zhang W, Huang S, Yang M, Chen Q, Zhou W
Mol Cell Endocrinol · 2026 Sep · PMID 42208847 · Publisher ↗
BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age, in which abnormal follicular development is a major contributor to ovulatory dysfunction and infertility. S...
BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age, in which abnormal follicular development is a major contributor to ovulatory dysfunction and infertility. Studies have shown that granulosa cell dysfunction underlies this aberrant follicular development. Within the follicular microenvironment, exosomes serve as crucial mediators of intercellular communication. Notably, exosomal non-coding RNAs (ncRNAs) are dysregulated in PCOS and have been implicated in its pathogenesis. Nevertheless, the precise mechanisms by which these exosomal ncRNAs influence abnormal follicular development in PCOS remain to be elucidated. METHODS: A total of 40 PCOS patients and 45 non-PCOS controls undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment were included in this study. Exosomes and mural granulosa cells (mGCs) of those patients were isolated from follicular fluid. Cumulus granulosa cells (cGCs) were separated from the cumulus-oocyte complexes (COCs). High-throughput miRNA sequencing were performed to analyze the expression profile of miRNAs in follicular fluid exosomes from 3 PCOS patients and 3 controls, and an additional 37 PCOS and 42 control samples were used for validation. The diagnostic potential of exosomal miR-143-5p for PCOS was evaluated using receiver operating characteristic (ROC) curve analysis, and its correlation with clinical parameters was examined. Quantitative real-time PCR was used to confirm miR-143-5p expression in exosomes and granulosa cells. Functional assays in primary mural GCs (mGCs) and KGN cells investigated the effects of exosomal miR-143-5p on granulosa cell proliferation. Bioinformatic analysis combined with dual-luciferase reporter assays were performed to validate the target gene of miR-143-5p. In vivo, a letrozole-induced PCOS rat model was established to investigate the role of miR-143-5p in the pathogenesis of the disease. RESULTS: In this study, we identified exosomal miR-143-5p as significantly upregulated in follicular fluid from PCOS patients, in which it correlated with serum AMH levels and demonstrated strong diagnostic potential. Functional experiments in primary mGCs and KGN cells revealed that miR-143-5p promotes GC proliferation. Mechanistically, RASAL2 was identified and validated as a direct target of miR-143-5p. Exosomes derived from miR-143-5p-overexpressing cells enhanced recipient GC proliferation, confirming the role of exosomal mediation. In a letrozole-induced PCOS rat model, inhibition of miR-143-5p increased RASAL2 expression and ameliorated key pathological features, including ovarian weight, cystic follicle formation, and hormonal imbalances. CONCLUSIONS: These findings reveal a novel exosomal miR-143-5p/RASAL2 pathway driving GC proliferation and ovarian dysfunction in PCOS, highlighting its potential as both a diagnostic biomarker and therapeutic target.
Effects of tributyltin as an obesogen chemical on mammalian adipose tissue.
Dos Santos FCF, Da Costa CS, Miranda-Alves L … +1 more , Graceli JB
Mol Cell Endocrinol · 2026 Sep · PMID 42191116 · Publisher ↗
Tributyltin (TBT) is an endocrine-disrupting chemical (EDC) with well-established obesogenic properties, promoting adipogenesis and disrupting metabolic homeostasis, thereby contributing to obesity. Owing to its high lip...
Tributyltin (TBT) is an endocrine-disrupting chemical (EDC) with well-established obesogenic properties, promoting adipogenesis and disrupting metabolic homeostasis, thereby contributing to obesity. Owing to its high lipophilicity, TBT readily bioaccumulates through aquatic and terrestrial food chains. Because of these physicochemical characteristics and its environmental persistence, TBT remains detectable worldwide, despite the global ban on its use in antifouling paints implemented in 2008. The obesogenic activity of TBT is primarily mediated through the activation of peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR), key regulators of adipocyte differentiation and lipid metabolism. This review includes original research articles focusing on the effects of TBT on adipose tissue. Evidence indicates that TBT induces upregulation of adipogenic markers in white adipose tissue (WAT), impairs thermogenic capacity in brown adipose tissue (BAT), and suppresses the browning process of WAT. Additionally, TBT modulates estrogen-responsive gene expression in pink adipose tissue (PAT). Notably, these effects have been reported at environmentally relevant, low-dose exposures, underscoring TBT as persistent public health concern and highlighting the need for further epidemiological studies and investigations of human exposure. This review integrates evidence from in vitro models, in vivo mammalian studies, and human data, and identifies critical gaps in the current literature, proposing future research directions to elucidate the molecular mechanisms underlying TBT-induced toxicity in adipose tissues.
Transcript switching during differentiation of mural and cumulus granulosa cells.
Shila S, Pei GJ, Bahadursingh E … +7 more , Peramsetty N, Dahiya V, Marsh CA, Thiyagarajan R, Zhang M, Fields PE, Rumi MAK
Mol Cell Endocrinol · 2026 Sep · PMID 42178055 · Publisher ↗
Despite the expression of multiple transcript isoforms from a gene, conventional gene expression analyses assume that a single transcript is expressed from each gene. We analyzed the transcript isoforms expressed in gona...
Despite the expression of multiple transcript isoforms from a gene, conventional gene expression analyses assume that a single transcript is expressed from each gene. We analyzed the transcript isoforms expressed in gonadotropin-induced mouse mural and cumulus granulosa cells (mGCs and cGCs) isolated from antral follicles to elucidate the potential mechanism of differentiation. Considering that either a single transcript or multiple isoforms are expressed from genes, we identified differential expression of about 70% of transcripts between mGCs and cGCs. Although the differential expressions were similar, the single-transcript-wise differentially expressed genes did not correlate with their corresponding differentially expressed transcript isoforms. We identified transcript isoforms of key transcriptional regulators in ovaries, including Chd1, Ezh2, Kdm5a/5b, Gata4, Esr2, Fos, Myc, and Ybx1, that were not identified in single-transcript-based analyses. Further analysis revealed a transcript switch in more than 30% of the differentially expressed isoforms. While one or more transcript isoforms of Cebpa, Dnmt3a, Pgr, Rest, Runx1, and Sirt1 were switched off, those of Brd7, Chd1, Med21, Nfkbia, Rbm39, Suv39h2, Tcf12, Xist, and Ybx3 were switched on in cGCs. Interestingly, several genes, including Dab2, Ezh2, Gata4, Gnas, Gtf2i, Klf10, Setdb1, and Sp3, exhibited at least one isoform that was switched off and another that was switched on in cGCs. Transcript switching was primarily due to alternative splicing, followed by alternative transcription start sites and polyadenylation sites. We also identified differential expression of the potential regulators of such transcript switching in cGCs. Our results suggest that transcript switching may play an important role in mural and cumulus granulosa differentiation, a key insight that would remain unknown without mRNA isoform analysis.
Activation of AGEs-RAGE axis impairs bone repair in a metabolic syndrome model.
Wanionok NE, Molinuevo MS, Streckwall L … +2 more , Fernández JM, McCarthy AD
Mol Cell Endocrinol · 2026 Sep · PMID 42173431 · Publisher ↗
INTRODUCTION: Metabolic Syndrome (MetS) is a heterogeneous and multifactorial disorder associated with an increased risk of cardiovascular diseases. Preclinical and clinical studies have reported a negative correlation b...
INTRODUCTION: Metabolic Syndrome (MetS) is a heterogeneous and multifactorial disorder associated with an increased risk of cardiovascular diseases. Preclinical and clinical studies have reported a negative correlation between MetS and bone tissue integrity and repair; however, a consensus remains elusive, likely due to the variability observed among individuals with MetS. MATERIALS AND METHODS: Young male Wistar rats were randomly assigned to two groups (n = 5). One group received 20% fructose in their drinking water, while the control group received water alone, for three months. One month prior to euthanasia, a 1 mm bur hole injury was surgically created in the right parietal bones of all animals. Following euthanasia, blood samples were collected, and parietal bones were dissected and processed for histomorphometry and immunohistochemistry to evaluate accumulation of carboxy-methyl-lysine, a prevalent advanced glycation end-product (AGEs). Humeral bone marrow progenitor cells (BMPCs) were also isolated to assess their osteogenic potential and expression of receptor for AGEs (RAGE). RESULTS: Fructose treatment induced metabolic alterations compatible with MetS; and significantly decreased newly formed bone in calvarial injuries, indicating impaired BMPC-mediated bone repair. Furthermore, fructose-rich diet increased the expression of RAGE in BMPCs, increased the accumulation of AGEs in bones and reduced osteogenic potential. CONCLUSION: Oral administration of fructose for three months can impair bone repair in rats, possibly associated with activation of the AGEs-RAGE axis in bone.
Intermuscular adipose tissue drives bone loss in postmenopausal osteoporosis via fibro-adipogenic progenitors-mediated osteoclastogenesis.
Luo L, Tang Y, Huang ZW … +6 more , Dai MX, Lai SQ, Gao JW, Le SY, Wang L, Tu C
Mol Cell Endocrinol · 2026 Sep · PMID 42162908 · Publisher ↗
BACKGROUND: To determine whether intermuscular adipose tissue (IMAT) shows region-specific associations with bone mineral density (BMD) in postmenopausal osteoporosis (PMOP) and to define a muscle-resident stromal mechan...
BACKGROUND: To determine whether intermuscular adipose tissue (IMAT) shows region-specific associations with bone mineral density (BMD) in postmenopausal osteoporosis (PMOP) and to define a muscle-resident stromal mechanism linking IMAT expansion to osteoclast activation. METHODS: In a clinical cohort 120 postmenopausal women were included in the primary analyses. IMAT and muscle cross-sectional areas in the thigh, calf, and paraspinal muscles were quantified by computed tomography and analyzed for associations with BMD using correlation and prespecified multivariable regression models. An ovariectomized (OVX) mouse model was used to assess IMAT accumulation, trabecular microarchitecture by micro-CT, and osteoclast activity by histology. Fibro-adipogenic progenitors (FAPs) were isolated for bulk RNA sequencing, and conditioned media from adipogenically induced FAPs were applied to bone marrow-derived macrophages to evaluate osteoclast differentiation, cytoskeletal maturation, and marker expression. RESULTS: Higher IMAT-to-muscle ratios in thigh, calf, and paraspinal muscles were independently associated with lower BMD at the femur and lumbar spine. OVX mice exhibited increased IMAT infiltration, trabecular deterioration, and elevated osteoclast indices, with IMAT strongly correlating with bone microstructural loss and osteoclast parameters. FAPs showed transcriptional reprogramming enriched for adipogenic, inflammatory, and osteoclastogenic pathways in OVX mice. Conditioned media from adipogenically differentiated FAPs increased osteoclast number, resorptive structures, and expression of Ctsk, Mmp9, and Nfatc1, compared with day-0 conditioned media. CONCLUSION: IMAT is associated with lower BMD in PMOP, and adipogenic and inflammatory reprogramming of IMAT-derived FAPs provides a plausible paracrine route by which muscle adiposity may potentiate osteoclastogenesis and bone loss.
Powder bergamot juice attenuates skeletal muscle complications in an experimental model of metabolic syndrome.
Sormani LE, Cruzeiro J, Belin MAF … +9 more , Dos Santos MPS, Siqueira JS, Vieira TA, Grandini NA, Tanganini MD, Palacio TLN, Romualdo GR, Aldini G, Corrêa CR
Mol Cell Endocrinol · 2026 Sep · PMID 42142734 · Publisher ↗
BACKGROUND: Metabolic syndrome (MetS) promotes skeletal muscle complications, which can impair glucose uptake and contribute to the development of diabetes. In contrast, powder bergamot juice (PBJ) possesses bioactive co...
BACKGROUND: Metabolic syndrome (MetS) promotes skeletal muscle complications, which can impair glucose uptake and contribute to the development of diabetes. In contrast, powder bergamot juice (PBJ) possesses bioactive compounds with potential therapeutic applications. OBJECTIVE: To evaluate the effects of PBJ on skeletal muscle complications in an experimental model of metabolic syndrome. METHODS: Male Wistar rats were fed a control diet (n = 20) or a high-sugar fat diet (n = 20) with 25% sucrose in drinking water (w/v) for 20 weeks to induce MetS. After this period, animals were then redistributed into two groups (n = 7 each): MetS and MetS + PBJ. PBJ was administered by gavage at 250 mg/kg daily for 10 weeks. Systemic metabolic parameters were measured, and lipid content, fatty acid profile, inflammatory and oxidative stress biomarkers, insulin signaling proteins, and histological outcomes were evaluated in the quadriceps. RESULTS: PBJ treatment significantly attenuated systemic adiposity and dyslipidemia. In the quadriceps, PBJ markedly reduced triglyceride accumulation and modulated the fatty acid composition, lowering saturated fatty acid (SFA) levels and increasing the desaturation index. Oxidative stress markers, including malondialdehyde, advanced oxidation protein products, and protein carbonylation, were reduced, while antioxidant defenses were enhanced by upregulating nuclear factor erythroid 2-related factor 2 (NRF-2) signaling. Pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), were significantly decreased and interstitial collagen deposition was also attenuated. Crucially, PBJ modulated the endocrine response and increased total protein expression of glucose transporter type 4 (GLUT-4) without altering IRS-1 phosphorylation. CONCLUSION: PBJ attenuated skeletal muscle complications resulting from MetS. However, due to the absence of a healthy control group, these findings demonstrate an improvement relative to the diseased condition, but cannot confirm a return to a normal physiological baseline.
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