Journal of Endocrinology最新文献

Diabetes is an increasingly prevalent global disease and is 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-responsive 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. 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. We found that 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 a 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 was suppressed, while the atrophy marker Fbxo32/Atrogin-1 was upregulated. 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.

Disruptions in iron homeostasis are common during obese states and are related to chronic inflammation and insulin resistance. 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 homeostasis in non-obese and hypothalamic-obese rats submitted to swimming training. Hypothalamic obesity was induced by the administration of monosodium glutamate (MSG; 4 g/Kg) during the initial postnatal 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 30 min/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 hepcidin-iron homeostasis during hypothalamic obesity.

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 test (IPGTT) 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 during 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, which has 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 the 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.

This review summarizes current knowledge on the mineralocorticoid receptor (MR), a nuclear receptor encoded by the NR3C2 gene, and its ligand aldosterone. In epithelial tissues like the kidney, colon, salivary glands and skin, particularly within the sweat glands, the MR plays a key role in regulating sodium reabsorption. In non-epithelial tissues such as the brain, adipose tissue, and heart, glucocorticoids are the main physiological MR ligands due to the absence of the 11β-hydroxysteroid dehydrogenase type 2. MR expression begins during development with tissue-specific patterns. In the kidney, MR levels peak mid-gestation, decrease at birth then increase postnatally. Loss of MR function, as observed in pseudohypoaldosteronism type 1 causes salt-wasting syndrome. Similar patterns are seen in the heart and brain, especially the hippocampus, where it influences stress regulation. On the contrary, MR expression is maintained at birth in the lung for neonatal fluid clearance via epithelial sodium channels. It is also present in tissues like skin, retina, and gastrointestinal tract, indicating broad physiological roles. MR expression during fetal development correlates with adaptations to extra-uterine life, like changes in amniotic fluid osmolality and aldosterone levels. MR gene expression and activity are tightly regulated through multiple mechanisms. These include transcriptional control via two promoters, post-transcriptional regulation involving RNA-binding proteins and microRNAs, and post-translational modifications such as phosphorylation, sumoylation, and ubiquitination. These regulatory levels ensure appropriate MR function across different tissues and developmental stages and may have implications for conditions such as hypertension and heart failure.

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.

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.

Aerobic exercise and resistance exercise have been shown to improve sarcopenia. However, whether combining aerobic and resistance exercise could alleviate sarcopenia symptoms in patients with type 2 diabetes mellitus (T2DM) complicated with sarcopenia remains unclear. This 12-week randomized controlled trial enrolled older patients with T2DM and sarcopenia, diagnosed by grip strength, appendicular skeletal muscle mass index (ASMI), and the short physical performance battery. Participants were randomized to an exercise group (aerobic plus resistance training) or a control group receiving health education. Physical function was evaluated with the 6-min walk and timed up-and-go tests. Serum 25(OH)D3 was measured by liquid chromatography-tandem mass spectrometry, and irisin by enzyme-linked immunosorbent assay. Before the intervention, there were no differences in baseline characteristics between the non-intervention and intervention groups. However, grip strength and ASMI significantly increased in patients in the intervention group after receiving combined aerobic and resistance exercise. Moreover, functional physical fitness also improved in the intervention group after the intervention. In addition, the sarcopenia-associated factors, including irisin and 25(OH)D3, increased significantly in patients with T2DM complicated with sarcopenia following the intervention. Overall, combined aerobic and resistance exercise may help alleviate sarcopenia in patients with T2DM.

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Abstract: Thyroid hormone levels decrease with aging, and low thyroxine levels are correlated with sarcopenia development. While thyroid hormone stimulates myogenesis in young subjects, its effect on aged muscle regeneration is unclear. We aimed to investigate the impact of a low dose of thyroxine (T4) replacement therapy (7.5 ng/g body weight) on tibial anterior regeneration 7 days after injury by 1.2% BaCl2 injection in 24-27-month-old male mice. Our primary data suggest that regenerating aged skeletal muscle exhibits local resistance to thyroid hormone action without altering myogenic regulatory factors expression. However, T4 treatment decreases the number of central nuclei, indicative of newly formed fibers. In addition, we observed a decrease in cross-sectional area and an increase in myonuclei domain, cell death, and laminin expression in T4-treatment injured muscles. Rather than improving regeneration, T4 replacement therapy appears to induce atrophy and tissue remodeling. Our data highlight the need to understand aging physiology since thyroid hormones are crucial for muscle regeneration in young animals, although T4 replacement therapy does not improve muscle regeneration post-injury in elderly mice. This research may support clinical recommendations against treating sarcopenic patients with subclinical hypothyroidism, especially following fall-related injuries.