Aug 2026· Journal of Clinical Endocrinology and Metabolism· 0 citations
Medicine
TL;DR
The temporal decline of circulating miR-1-3p levels and the identification of PKC support a model in which miR-1-3p may contribute to functional maturation of the ZR through modulation of non-canonical intracellular signaling pathways.
Abstract
Context
Adrenarche involves maturation of the adrenal zona reticularis (ZR), but its molecular regulation is poorly understood. MicroRNAs (miRNAs) may contribute to adrenal development.
Objective
To investigate whether circulating miRNAs are associated with ZR maturation during adrenarche and to characterize the functional role of candidate miRNAs in adrenal steroidogenesis.
Design
AND
Setting
Prospective cohort study was nested within the population-based PANIC study with longitudinal follow-up at ages 7, 9, and 15 years, combined with experimental analyses in the human adrenocortical NCI-H295R cell model.
Participants
A total of 34 children (20 girls) with clinical and/or biochemical signs of adrenarche at age 9 as cases, and 24 age-matched controls (11 girls).
Interventions
None.
MAIN OUTCOME MEASURES
Longitudinal serum miRNA expression and in vitro effects of candidate miRNAs on adrenal steroidogenesis and gene expression.
Results
Serum miR-1-3p levels were higher in cases compared to controls at age 7 years (fold change 2, p < 0.001), preceding clinical adrenarche. In both groups, miR-1-3p levels declined during adrenarchal and pubertal development. In vitro, miR-1-3p overexpression increased steroidogenic activity (approximately 1.5-fold on average) without altering the expression of canonical steroidogenic enzyme genes. Transcriptomic analysis identified 208 upregulated and 140 downregulated genes, including PRKCA, encoding protein kinase C (PKC), enriched in the ZR and involved in steroidogenic signaling.
Conclusions
Elevated circulating miR-1-3p precedes clinical adrenarche and enhances steroidogenesis in vitro. The temporal decline of circulating miR-1-3p levels and the identification of PKC support a model in which miR-1-3p may contribute to functional maturation of the ZR through modulation of non-canonical intracellular signaling pathways.
BACKGROUND
Bardet-Biedl syndrome (BBS) is a rare ciliopathy characterized by early-onset obesity and multisystem endocrine dysfunction. The melanocortin-4 receptor (MC4R) agonist setmelanotide is approved for hyperphagia-related obesity in BBS, but its endocrine effects remain incompletely understood.
METHODS
In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally. Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.
FINDINGS
After 6 months, significant reductions in BMI and HbA1c were observed. Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently. IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones. These effects were established within the first 6 months and remained stable thereafter.
INTERPRETATION
Setmelanotide exerts pleiotropic effects beyond weight reduction, modulating multiple endocrine axes in BBS. The observed changes highlight MC4R signaling pathway as a key integrator of metabolic and endocrine function and suggest partially weight-independent therapeutic effects.
FUNDING
German Federal Ministry of Research and Education and Rhythm Pharmaceuticals.
T. Hühne, E. Steidel, J. Holland et al.· Journal of Clinical Endocrin...· 0 citations
Abstract: And dysfunction of reproductive age, which is frequently accompanied by a metabolic disorder and hormonal imbalance. Recent evidence implicates microRNAs (miRNAs), particularly miR-21, as key regulators of metabolic and inflammatory pathways. The current study was designed to evaluate the expression level of miR-21 and its association with selected physiological markers in women with PCOS. Sixty women diagnosed as having PCOS, and 20 healthy women who served as controls were studied in a comparative cross- sectional study. The age of the participants varied between 20 to 41 years with a mean age of 28.18 ± 0.77 years. Serum was obtained from bloods and measured for hormonal biomarkers of luteinizing hormone (LH), follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH) and free testosterone. The expression of microRNA-21 was analyzed by qRT-PCR.
The results reveal a significant increase (p < 0.05) of body mass index, AMH, LH, FSH and LH/FSH ratio in women with PCOS when compared to the control group. MiR-21 expression levels were also higher in the PCOS group. Important associations were also found: miR-21 expression was correlated with age and body mass index. Conclusion: Significant hormonal and metabolic changes associated with increased miR-21 expression occur in women with PCOS. These results indicate that miR-21 could be a potential biomarker for assessing the disease course and metabolic disorders in PCOS. More large-scale studies are needed to validate its diagnostic and prognostic value.
H. Lateef· Al-Kufa University Journal f...· 0 citations
Over recent years, gonadotropins and their receptors have been shown to exert non-traditional actions that bypass the classical hypothalamic–pituitary–gonadal axis. Findings of the expression of receptors for follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in skeletal, fat, and immune cells and in neurons suggest that their functions are much broader than their classical roles. FSH, once believed solely to regulate procreation–gonadal development and maturation at puberty and gamete production during the fertile phase, has been found to regulate body composition, bone metabolism, and cognition, providing the underpinnings of complex integrative physiology, and, in turn, opening potential new therapeutic opportunities. Pre-clinical evidence from genetic and pharmacologic interventions in rodent models and human data from population-based observations, genetic studies, and a small number of interventional studies together support the independent skeletal, adipogenic, and cognitive actions of gonadotropins. Here, we review our current understanding of direct actions of FSH and LH on bone, adipose tissue, and brain and focus specifically on the detrimental health burden during and after the menopause: osteoporosis, obesity, and dementia.
Se-Min Kim, Funda Korkmaz, Sorang Kang et al.· Endocrine Connections· 0 citations
BACKGROUND
The anorectic peptide nesfatin-1 has been identified as a potential mood regulator. Abnormal nesfatin-1 expression has been observed in both depression animal models and clinical cohorts, but its exact role in depression pathogenesis remains unclear.
AIM
This study aimed to detect peripheral and central nesfatin-1 alterations in rats with chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors, and explore their correlations with hypothalamic-pituitary-adrenal (HPA) axis activity and brainstem monoamine synthesis.
METHODS
Rats were subjected to 5-week CUMS. Enzyme-linked immunosorbent assay (ELISA) quantified plasma mature nesfatin-1 peptide, and Western blot (WB) detected full-length nucleobindin 2 (NUCB2)/nesfatin-1 in the hypothalamus and brainstem. Spearman's rank correlation was performed solely within the CUMS group (n = 6); these exploratory correlational findings require cautious interpretation due to small sample size.
RESULTS
CUMS significantly increased plasma nesfatin-1 as well as hypothalamic and brainstem NUCB2/nesfatin-1. In CUMS rats, plasma nesfatin-1 was positively correlated with corticosterone and forced swim test (FST) immobility time, and negatively correlated with sucrose preference index(SPT) and weight gain. Brainstem NUCB2/nesfatin-1 showed a positive correlation with tryptophan hydroxylase (TPH), while no significant correlation was found between hypothalamic NUCB2/nesfatin-1 and all measured parameters.
CONCLUSION
Chronic stress-induced nesfatin-1 elevation accompanies peripheral HPA hyperactivation and aggravated depressive-like behaviors. Brainstem NUCB2/nesfatin-1 positively correlates with TPH, suggesting NUCB2/nesfatin-1 may link neuroendocrine activity and serotonergic plasticity with the brainstem as a core site. This study provides preliminary correlational evidence for coordinated NUCB2/nesfatin-1 changes across peripheral and central systems under stress-induced depression.
Background Central precocious puberty (CPP) results from premature activation of the hypothalamic–pituitary–gonadal (HPG) axis. While hormonal mechanisms underlying pubertal initiation are well established, the molecular regulatory processes accompanying altered pubertal timing remain incompletely understood. Circulating microRNAs (miRNAs), detectable either freely or within extracellular vesicles (EVs), represent a molecular layer of post-transcriptional regulation associated with pubertal development. Methods Serum samples from female patients diagnosed with CPP and age-matched healthy female controls were analyzed by small RNA sequencing to identify differentially expressed miRNAs. Selected miRNAs were validated by quantitative real-time PCR (RT–qPCR) in an expanded cohort using serum RNA and RNA isolated from serum-derived EVs. Functional enrichment analysis was conducted using experimentally validated miRNA target genes. Results Small RNA sequencing identified ten miRNAs with significantly altered expression levels in CPP (adjusted p-value < 0.05, |log2FC| > 0.5). Pathway enrichment analysis highlighted biological processes related to neurodevelopment, growth regulation and cellular maturation. RT–qPCR validation confirmed reduced serum expression of miR-125a-5p, miR-125b-5p and miR-99b-5p in CPP patients. All selected miRNAs were detectable in serum-derived EVs. Notably, miR-148a-3p exhibited a statistically significant increase specifically within the EV-associated fraction of CPP samples. Conclusions This study provides a comprehensive analysis of the circulating miRNA profile in female patients with CPP. The coordinated alteration of freely circulating and EV-associated miRNAs highlight the potential contribution of miRNA-mediated regulation to premature HPG axis activation and provides a framework for further investigation of the molecular mechanisms underlying pubertal disorders.
Maria Morrou, V. Neocleous, M. Toumba et al.· Frontiers in Endocrinology· 0 citations
Adrenal cortisol-producing adenomas (CPAs) represent the most common endocrine disorder among adrenal incidentalomas and are classified as either subclinical Cushing's syndrome (SCS) or Cushing's syndrome (CS) based on the degree of cortisol hypersecretion. The molecular mechanisms driving hypercortisolism remain poorly understood. To address this, we perform comprehensive proteomic profiling of 9 CS, 10 SCS, and 10 non-functioning adenomas (NFAs). Our analysis reveals a central role for cholesterol metabolic reprogramming in the pathogenesis of CPAs. We observe a progressive gradient of dysregulation in cholesterol metabolic components from NFAs to SCS and CS, mirroring disease severity. A protein panel consisting of low density lipoprotein receptor (LDLR), 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), hormone-sensitive lipase (LIPE), and synaptophysin (SYP) are identified as a promising combination of candidate pathological markers for CPAs. Importantly, downregulation of calcium binding protein 39 like (CAB39L) is uncovered as a key driver of pathological cortisol production. These findings provide a foundation for protein-based diagnostic and prognostic strategy in CPAs, and highlight the CAB39L signaling pathway as a contributor to disease development.
Xuyang Shi, Yi Yang, Chunxue He et al.· Metabolism: Clinical and Exp...· 0 citations
Related blog posts
MIT News · Artificial Intelligence· news.mit.eduAug 27, 2026
A new machine-learning framework aims to improve the success rate of computational protein design while moving away from results that reproduce sequences found in nature.