Journal of Endocrinology最新文献

Obesity, officially recognised as a global epidemic by the World Health Organization, will soon overtake smoking as the largest preventable risk factor for cancer. By 2035, more than half the world's population is expected to be overweight or obese with a significant increase in obesity-related health expenditures. However, despite the increase in prevalence and the overall lower life expectancy associated with obesity, mechanisms underpinning obesity-driven disease are not well understood. Adipocytes pose many challenges for in vitro culture due to their poor cell to surface attachment and low viability. Their large size and high lipid content can also present methodological challenges for downstream experiments. Several mouse and human-derived primary pre-adipocyte cell lines have been established over the years. However, they show limited renewal capacity and they cannot be cultured long term in vitro. Commercial cell lines available, which can be cultured long term, fail to represent organ-specific adipocyte heterogeneity. Adipose tissue from different organs and fat-depots can show significant heterogeneity in terms of metabolism, overall secretome and extracellular-matrix production. The prostate, for example, is surrounded by peri-prostatic adipose tissue (PPAT), volume of which is associated with increased risk of lethal prostate cancer and reduced therapy- response. Here we outline a protocol for ex vivo culture of fresh PPAT and non-prostatic adipose tissue (NPAT), which reflects donor and depot-specific characteristics. Ex vivo culture of PPAT/NPAT explants maintains cell-cell interactions and preserves local tissue architecture within adipose tissue. We have also described establishment of immortalised, patient PPAT-derived pre-adipocytes and patient-matched NPAT pre-adipocytes that can be in vitro-differentiated into mature adipocytes. The protocols outlined here could be readily adapted to other organ-specific fat depots such as mammary/bone marrow adipose tissue, and to tissues of non-human origin.

Objective: Clinical use of glucocorticoids in large quantities over a long period of time causes osteoporosis (GIOP). LncRNA OIP5-AS1 has elevated levels in delayed fracture healing, so the present study explored the role of OIP5-AS1 in a model of GIOP.

Methods: The GIOP model was induced in mice by different doses of dexamethasone. The levels of OIP5-AS1, miR-335-5p, LC3-II, P62 mRNA, and four markers of osteogenic differentiation were assessed by RT-qPCR in the serum of GIOP mice and MC3T3-E1 cells. Cell proliferation was assessed by CCK-8 kit. Lactic acid (LA) was assayed by a lactic acid kit. The binding sites of OIP5-AS1 and miR-335-5p were predicted by the ENCORI database. DLR assay verified the binding relationship between OIP5-AS1 and miR-335-5p.

Results: GIOP mice had elevated levels of OIP5-AS1 expression, elevated lactate levels, increased oxidative stress, active autophagy and reduced levels of osteogenic differentiation. After knocking down OIP5-AS1 in cellular models, miR-335-5p levels were elevated, lactate levels were decreased, oxidative stress levels were decreased, autophagy was inhibited, and osteogenic differentiation was increased. However, after transfection of miR-335-5p inhibitor, the cells had elevated lactate levels, decreased proliferative capacity, increased oxidative levels, active autophagic behavior and decreased osteogenic differentiation.

Conclusion: OIP5-AS1 levels were elevated in the GIOP model. Knockdown of OIP5-AS1 resulted in elevated miR-335-5p levels, enhanced proliferation and differentiation of osteoblasts, and suppression of autophagy and oxidative stress. Therefore, OIP5-AS1 may alleviate the development of GIOP through miR-335-5p.

Polycystic ovary syndrome (PCOS) is characterized by reproductive and metabolic dysfunction that may also impact bone metabolism and its structural integrity. This study aims to assess the progressive impact of PCOS on bone health over time. It focuses on how the duration of the condition influences hormonal profiles, bone metabolism, its microstructural and mechanical properties in the PCOS-induced mice model. Female BALB/c mice are separated into three groups, each further subdivided into PCOS induced and age matched control groups. PCOS was induced by letrozole (6mg/kg b.w.) administered continuously for 21 days; among them, group II underwent a one-month observation period, while group III was observed for two months. Bone quality markers were assessed through hormonal profiling, serum bone turnover markers, micro-CT, three-point bending test, nanoindentation, and FTIR. Hormonal profiling revealed persistent hyperandrogenism, elevated LH/ FSH ratio, reduced estrogen levels, and insulin resistance collectively affected bone health. Micro-CT analysis showed a decline in trabecular quality in the femur and tibia of PCOS group. Three-point bending test pointed towards increased susceptibility to micro-damage and fracture. Nanoindentation indices, elasticity, and hardness, were also decreased. FTIR analysis indicates alterations in bone material properties. These indices showed slight improvement in the third month, but deviate significantly from control. Our result suggests that PCOS has an adverse impact on bone's structural, mechanical, and compositional properties and negative impact of PCOS on skeletal integrity is not fully reversible in the short term. Overall, these findings highlight the importance of evaluating and monitoring bone health in PCOS individuals.

Aims/introduction: Diabetes is an increasingly prevalent global disease and often accompanied by sarcopenia, particularly in older adults. While insulin resistance is a well-known contributor to muscle loss in diabetes, the role of glucose signaling in diabetic skeletal muscle atrophy, particularly under insulin-deficient conditions, remains poorly understood. This study aimed to elucidate the pathophysiological role of the carbohydrate response element-binding protein (ChREBP), a glucose-sensing transcription factor encoded by the Chrebp gene in mice, in diabetic sarcopenia by generating Chrebp-deficient, insulin-deficient Ins2Akita/+ mice.

Materials and methods: We evaluated Chrebp+/+, Chrebp-/-, Ins2Akita/+; Chrebp+/+, and Ins2Akita/+; Chrebp-/- mice for muscle strength, endurance, survival, body composition, and muscle histology. Skeletal muscles were analyzed for gene expressions related to anabolic and catabolic pathways. Results: Ins2Akita/+; Chrebp-/- mice exhibited significant reductions in body weight, grip strength, survival, and skeletal muscle mass-particularly in the tibialis anterior, soleus, gastrocnemius, and quadriceps-compared to Ins2Akita/+ controls, despite similar hyperglycemia. Histological analysis revealed smaller mean muscle fiber size and reduced cross-sectional area of type 2A and 2B fibers, without changes in fiber-type composition. Furthermore, Igf-1 expression were suppressed, while the atrophy marker Fbxo32/Atrogin-1 was upregulated.

Conclusions: These findings demonstrate that Chrebp deletion exacerbates muscle atrophy and frailty in insulin-deficient mice, underscoring a key role for ChREBP-mediated glucose signaling in maintaining muscle mass under diabetic conditions. The Ins2Akita/+; Chrebp-/- model provides a valuable platform for exploring diabetic sarcopenia mechanisms and potential therapeutic targets.

Hyperglycemia is common in extremely preterm infants, and the treatment of neonatal hyperglycemia should be associated with a low risk of hypoglycemia. Incretin-based therapies are characterized by a low risk of hypoglycemia and are efficacious and safe in adults. We aimed to investigate the extent to which the glucose-lowering effect of incretin hormone-enhanced insulin secretion contributes to glucose regulation in healthy, developing rat pups, and to evaluate the associated risk of hypoglycemia. We performed oral glucose tolerance (OGTT) and intraperitoneal glucose tolerance (IPGTT) testing in 2-week-old Wistar rats and compared the serum concentrations of glucose, insulin, and incretin hormones. OGTT was associated with significantly higher serum incretin hormone concentrations than IPGTT in the pups, and the serum insulin concentrations were higher during OGTT than IPGTT (the incretin effect was 63%). Thus, the incretin effects were present and substantial in the rat pups. We next administered two drugs (a dipeptidyl-peptidase 4 (DPP-4) inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist) with incretin effects and evaluated the risk of adverse hypoglycemic events in normal developing rats. Standard therapeutic doses of linagliptin and liraglutide did not influence the blood glucose concentrations of 2-week-old pups, and no hypoglycemia developed. In conclusion, we have shown that endogenous incretin hormones stimulate insulin secretion in normal 2-week-old rats, as in adults. Furthermore, neither a DPP-4 inhibitor nor a GLP-1 receptor agonist induced hypoglycemia as an adverse effect. Therefore, incretin hormones may be safe therapeutic targets for hyperglycemia in preterm infants.

Lung ischemia-reperfusion injury (LIRI) is a complex pathological condition that significantly impairs clinical outcomes following lung transplantation and thoracic surgery. Leonurine (LEO), an alkaloid derived from Leonurus japonicus, compound with known anti-inflammatory and antioxidant properties, has shown therapeutic potential in various oxidative stress-related diseases. However, the effects of LEO on LIRI and its underlying mechanisms remain unclear. In present study, a murine model of LIRI was established using wild-type mice. LEO treatment significantly improved lung histopathology, reduced oxidative stress, decreased pulmonary edema, and enhanced survival. Bioinformatics analyses-including volcano plot, KEGG enrichment, and GSEA-identified ferroptosis as a key regulatory pathway. In vivo and in vitro assays (HE, 4-HNE and DHE labeling, immunofluorescence, and immunoblotting) confirmed that LEO inhibited ferroptosis in lung tissue and in MLE-12 cells. Mechanistically, LEO upregulated the RORα/Nrf2/GPX4 axis, thereby reducing lipid peroxidation and iron overload, as validated by BODIPY581/591 C11 and FeRhoNox-1 staining. Moreover, RORα inhibition abolished the anti-ferroptotic effects of LEO, indicating that its protective function is RORα-dependent. Molecular docking further supported a potential direct interaction between LEO and RORα. Collectively, LEO alleviates LIRI by inhibiting ferroptosis through activation of the RORα/Nrf2/GPX4 signaling pathway. These findings suggest that LEO may serve as a promising therapeutic agent for the treatment of LIRI.

Sexual dimorphism in endocrinology refers to the biological differences between males and females in hormone production, secretion, metabolism, and action, shaped by genetic, epigenetic, and hormonal influences. These differences are fundamental to thyroid physiology and disease, affecting regulatory pathways from central hypothalamic-pituitary control to peripheral hormone metabolism. Clinically, women have a higher prevalence of autoimmune thyroid diseases, nodules, and differentiated thyroid cancer, while men more often present with advanced and aggressive disease. In this review, we integrate current evidence on sexual dimorphism in thyroid function, spanning from central regulation through the hypothalamic-pituitary-thyroid axis to thyroid hormones biosynthesis and peripheral metabolism, and discuss how these differences influence disease susceptibility and progression.

Disruptions in iron homeostasis are common during obese states and are related to chronic inflammation and insulin resistance (IR). Exercise exerts well recognized anti-adiposity and anti-inflammatory effects, besides modulating iron control. The vagus nerve (VN) influences immune and metabolic responses, in a spleen-dependent manner with an unknown impact on iron. Here, we evaluated the effects of the absence of the VN and of the spleen on adiposity, metabolism and iron homoeostasis in non-obese and hypothalamic-obese rats submitted to swimming training. Hypothalamic obesity was induced by the administration of monosodium glutamate (MSG; 4g/Kg) during the initial post-natal days (PNDs). Non-obese control (CTL) rats received equimolar saline. At PND 60, MSG and CTL were submitted to surgery consisting of bilateral subdiaphragmatic vagotomy (Sv), splenectomy (Spl), Sv+Spl or Sham surgery. At PND 80, the rats were subdivided into exercised (Ex) or sedentary (Sd). Exercised rats swam for 30min/day for 40 days. At PND 120, the growth, adiposity, metabolism and iron homeostasis of rats were evaluated. Major results indicate that the absence of the VN and spleen favors the anti-adiposity effects of exercise, particularly in MSG-obese rats. In CTL rats, exercise increased plasma iron, in association with changes in iron transport capacity and a reduction in circulating hepcidin levels, a response that is influenced by the VN and spleen. In contrast, in the MSG-obese animals, vagal and splenic absence resulted in increased hepcidin, including following exercise, via a response that is independent of systemic iron fluctuations, suggesting disturbed iron-hepcidin homeostasis during hypothalamic obesity.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. The study aimed to characterize changes in steroidogenesis in PBMAH through immunohistochemistry (IHC), transcriptomics and exome analysis with detailed clinical data assessment. Our cohort included 22 PBMAH patients who underwent adrenalectomy, and we investigated IHCs for five key steroidogenic enzymes (CYP11B1, CYP11B2, CYP17A1, HSD3B2 and CYB5A), covering the adrenocortical hormone secretion pathways. Unsupervised clustering of IHC staining identified three clusters: Cluster 1 exhibited low CYP11B1 and CYP17A1 expression, elevated HSD3B2 expression, smaller tumors, and included ARMC5 mutants. Cluster 2 showed higher enzyme staining for CYP11B1, CYP17A1 and CYB5A and included KDM1A mutants and female-only cases. Cluster 3 was characterized by slightly increased CYP11B2 staining and comprised of wild-type samples lacking ARMC5 and KDM1A variants. Exome sequencing identified steroidogenic pathway germline variants across the three clusters. Importantly, in Cluster 1, a higher burden of predicted damaging variants across various steroidogenic genes were found potentially leading to reduced enzyme staining through altered functions of the variant. However, this distinctive variant pattern was less evident in Cluster 2 and Cluster 3. Transcriptomics identified no differences between the clusters in terms of gene expression, hinting the influence of possible epigenetic factors on IHC. In summary, our study identified distinct groups in PBMAH based on their IHC staining patterns and highlights the importance for integrated molecular profiling for comprehensive characterization of heterogeneity in PBMAH.

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Abstract: Excessive accumulation of visceral adipose tissue induced by a high-fat diet promotes epigenetic modifications in DNA, increasing Nfkb transcription and pro-inflammatory cytokine synthesis. This study evaluated the epigenetic effects of obesity and 7 days of strength exercise on DNA demethylation in the Nfkb transcription region. Swiss mice were divided into three groups: lean controls (CT = 6), obese sedentary (OB = 6), and obese strength training (OBexT = 6). OB and OBexT received a high-fat diet (59% lipids) for 14 weeks; OBexT performed daily climbing sessions for 7 days. OB animals showed higher pro-inflammatory cytokine expression and NFKB protein content in mesenteric adipose (mean ± SD: OB = 4.35 ± 3.37; OBexT = 0.59 ± 0.28; CT = 1.00 ± 0.70), with significant reduction after training (P < 0.05; η 2 = 0.502). Pairwise comparison revealed a large effect size between OB and OBexT (d = 1.57). Demethylation in adipose tissue was elevated in OB mice, increasing gene availability and Nfkb transcription (OB = 4.01 ± 1.23; OBexT = 1.70 ± 1.06; CT = 0.99 ± 0.22), with a strong reduction post-exercise (P < 0.01; η 2 = 0.6546; d = 2.01). This reduction limited gene accessibility for Nfkb p65 phosphorylation, highlighting epigenetic modulation. These results demonstrate, for the first time, that only seven sessions of strength training can reprogram epigenetic marks in mesenteric adipose tissue, attenuating transcription of inflammatory mediators during an obesogenic state. Collectively, our findings support strength training as an effective short-term epigenetic regulator of inflammatory gene expression in adipose tissue.

Highlights: Short-term strength training promotes a reduction in the mass of subcutaneous and visceral adipose tissues. Obesity increased DNA demethylation, demonstrated by increased Nfkb gene expression and protein levels in mesenteric adipose tissue. Exercise has the potential to induce epigenetic modifications, such as interrupting DNA demethylation in mesenteric adipocytes. Short-term strength training alters the specific genomic region controlling NFκB transcription in the context of pre-existing obesity.