Journal of Endocrinology最新文献

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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.

Prostate cancer is a leading cause of death. As a hormone-driven cancer, prostate cancer is often treated with drugs (luteinizing hormone receptor agonists; LHRHa) or surgical approaches (orchidectomy; ORX) with the goal of reducing androgens. These approaches cause side effects such as bone loss. It is unclear if the side effects of these approaches are due to loss of androgens or loss of estrogens, as these approaches reduce both. We seek to evaluate if LHRHa and ORX have equivalent effects on bone, if the bone loss can be ameliorated by estrogen supplementation, and if estrogen supplementation alone is sufficient to improve bone mass while reducing androgen production. Herein, we evaluated bone microarchitecture, mechanical properties, and the cellular mechanism of LHRHa with subsequent hormone add-back on bone. We find that LHRHa negatively affects bone microarchitecture but has more mild effects on bone than ORX. Estrogen supplementation - but not androgen supplementation - improves bone mass and strength in mice treated with LHRHa. Estrogen supplementation alone is also sufficient to improve bone mass and strength while also reducing androgen production. However, estrogen supplementation also increases osteoblast and osteoclast activity, which may promote prostate cancer metastasis in bone. Future studies should evaluate estrogen as a modulator of the metastatic niche.

Triptolide (TP), a bioactive compound, demonstrates efficacy in ameliorating diabetic nephropathy (DN). This study aimed to investigate the role of TP in renal tubular injury during DN and elucidate the underlying mechanism involving acyl-CoA synthetase long-chain family member 1 (ACSL1) and parkin (PRKN). DN model was induced in HK2 cells by high glucose (HG, 30 mmol/L). Cell counting kit-8, EdU assay, flow cytometry were used to assess cell viability, proliferation, and apoptosis. Inflammatory cytokines were measured via enzyme-linked immunosorbent assay. Ferroptosis was assessed by detecting reactive oxygen species (ROS), lipid peroxidation (MDA), Fe2+, and glutathione (GSH) using kits. The mRNA and protein examination was performed by real-time quantitative PCR and western blotting. Co-immunoprecipitation assay was conducted for protein interaction and ubiquitination detection. DN in mice was established by high-fat diet and streptozocin injection. The effects of TP on mice were analyzed by histopathology analysis, biochemical analysis, and protein detection. TP mitigated HG-induced apoptosis, inflammation, and ferroptosis in HK2 cells. The protective effects of TP against HG-induced injury in HK2 cells were mediated by the inhibition of ACSL1. PRKN promoted ubiquitination of ACSL1 to reduce the protein level of ACSL1. PRKN/ACSL1 inhibited HG-induced HK2 cell dysfunction. The protective effect of TP in HG-stimulated HK2 cells was mediated by the upregulation of PRKN. TP activated anti-ferroptosis NRF2/SLC7A11/GPX4 pathway by targeting ACSL1. TP could ameliorate kidney injury in DN mice through modulating PRKN, ACSL1, and NRF2/SLC7A11/GPX4 pathway. All these discoveries suggested that TP protected HK2 cells from HG-triggered kidney injury through upregulating PRKN that further promoted ubiquitination of ACSL1.

Type 2 diabetes (T2DM) significantly increases the risk of dementia due to overlapping metabolic, molecular, and genetic factors. This review comprehensively analyzes the pathophysiological links between diabetes and cognitive decline, focusing on chronic hyperglycemia, insulin resistance, oxidative stress, mitochondrial dysfunction, neuroinflammation, and cerebrovascular complications. Key genetic and epigenetic contributors to diabetes-associated dementia (DAD), including variations in APOE, PICALM, SORL1, and GSK3B, are discussed. The roles of pathological proteins such as amyloid-beta (Aβ) and hyperphosphorylated tau in neurodegeneration are also highlighted. Preclinical and clinical evidence supports targeting insulin signaling pathways, oxidative damage, and inflammatory responses as potential therapeutic strategies. Promising therapies, including GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, and anti-inflammatory drugs, are reviewed alongside emerging approaches such as gene therapy, stem cell therapy, and immunomodulation. Despite encouraging advances, the clinical translation of these therapies remains challenging due to the complexity of DAD pathogenesis. This review aims to advance understanding of diabetes-induced cognitive impairment and guide the development of personalized dementia therapies by integrating molecular, genetic, and clinical insights. Future research should focus on elucidating the precise molecular mechanisms of DAD progression and on developing targeted, patient-specific therapeutic interventions to overcome translational barriers.

Abstract: The neuropeptide Y1 receptor (Y1R) plays a key role in metabolic regulation, and its peripheral antagonism has shown promise in promoting weight loss and improving glucose metabolism. However, most studies are conducted at room temperature (RT, 21-22°C), where mild cold stress stimulates sympathetic nervous system (SNS) activation. The impact of Y1R blockade under thermoneutral (TN, 30°C) conditions, which eliminate cold stress, remains unclear. In this study, we investigated the effects of BIBO3304 on body weight, energy expenditure (EE), and glucose metabolism in chow- and high-fat diet (HFD)-fed mice housed at TN and compared the results with RT. We found that at RT, BIBO3304 significantly reduced body weight gain and fat mass while increasing EE and fat oxidation. These effects were abolished under TN, where SNS activation is minimized, leading to no changes in body composition or EE. Despite this, BIBO3304 improved glucose tolerance at TN, particularly in the early phase (week 2), independent of insulin sensitivity. However, these glucose-lowering effects diminished by week 6, suggesting a potential SNS-dependent mechanism for long-term benefits. TN-housed mice exhibited greater glucose excursions and reduced insulin sensitivity compared to RT-housed mice, highlighting the impact of ambient temperature on metabolic regulation. In summary, these findings suggest that BIBO3304's effects on energy balance are SNS-dependent, whereas its glucose-lowering benefits persist transiently at TN. This highlights the need to consider environmental temperature in the evaluation of pharmacological interventions for obesity and diabetes, with potential implications for climate-adjusted dosing strategies.

Plain language summary: Peripheral Y1R blockade-induced reductions in body weight and enhancements in energy expenditure at room temperature are abolished under thermoneutrality, irrespective of dietary fat content.Glucose-lowering effects of peripheral Y1R antagonism persist under thermoneutrality, independent of changes in body weight and insulin sensitivity.Chronic thermoneutrality blunts the ability of peripheral Y1R blockade to ameliorate fat-induced glucose intoleranceThese findings emphasize the temperature-dependent efficacy of metabolic drugs and the need for climate-adjusted therapeutic strategies.

This research intended to identify the genes related to PCOS (polycystic ovary syndrome) and verify the regulatory function of miR-486-5p as well as its target PTEN in granulosa cells (GCs). RT-qPCR was used to detect the expression of miR-486-5p in the serum, follicular fluid (FF), and GCs of PCOS patients and normal subjects. ROC curve analysis indicated strong diagnostic performance. Bioinformatic analysis via miRDB and ENCORI databases predicted PTEN as a potential target of miR-486-5p; this prediction was validated through dual-luciferase reporter gene assays. Meanwhile, a series of functional assays were performed. Cellular proliferation capacity was quantitatively assessed using the CCK8 assay, while flow cytometry was used to determine cell apoptosis ratio. The secretion of pro-inflammatory mediators was quantitatively measured employing an ELISA kit. miR-486-5p was found to be reduced in serum from patients, as well as in patient FF and GCs. The enhanced expression of miR-486-5p strengthened the proliferation of GCs and suppressed apoptotic activity, while concurrently attenuating pro-inflammatory cytokine secretion. Conversely, miR-486-5p inhibitor yielded opposing effects. Further investigation revealed that PTEN functioned as a negative regulatory factor of miR-486-5p. The increase of miR-486-5p caused a significant down-regulation of PTEN mRNA expression. Forced expression of PTEN reversed the cellular effects induced by miR-486-5p, including the enhanced proliferation rate, suppressed apoptosis, and attenuated inflammatory response. miR-486-5p can inhibit cell apoptosis and secretion of inflammatory factors by negatively regulating the expression of target gene PTEN, suggesting that miR-486-5p may be a potential target for PCOS.

Mitochondrial dysfunction is a key feature of type 2 diabetes and is closely linked to ageing, a major risk factor for the disease. This study investigated islet cell composition and mitochondrial oxidative phosphorylation protein expression in pancreatic tissue from older donors (≥62 years) with and without type 2 diabetes, matched for age, sex, and BMI. Fixed human pancreatic tissue sections were immunolabelled for insulin, glucagon, NDUFB8 (complex I), MTCO1 (complex IV), and VDAC1 (a mitochondrial mass marker) to quantify islet composition and mitochondrial protein levels. A machine learning-based single-cell segmentation pipeline enabled high-resolution profiling of individual cell populations within islets. In type 2 diabetes, islets exhibited an increased alpha:beta cell ratio, altered spatial organisation with fewer beta-beta and more alpha-alpha interactions, and a significantly higher proportion of bi-hormonal cells co-expressing insulin and glucagon. Within beta cells, we observed significant changes in mitochondrial protein expression, including reduced complex I and elevated complex IV levels. Unsupervised clustering of mitochondrial expression patterns identified three distinct beta cell expression clusters. Donors with type 2 diabetes showed a marked shift in the distribution of beta cells across clusters, with increased proportions of beta cells exhibiting low complex I and high complex IV expression. These results highlight significant alterations in islet architecture and mitochondrial protein expression associated with type 2 diabetes, providing new insights into the mechanisms underlying type 2 diabetes.