Journal of Endocrinology最新文献

CL316,243 (CL), a beta 3 adrenergic receptor (B3-AR) agonist, has 'exercise mimetic' effects in adipose tissue. CL may also positively affect skeletal muscle (SM), yet the role of estrogen receptor beta (ERβ) in mediating SM-specific effects of CL is not known. We investigated the effects of CL on SM metabolism, as well as the role played by ERβ. High-fat diet-fed male and female wild-type (WT) and ERβ DBD knockout (KO) mice were administered CL daily for 2 weeks. Quadriceps SM protein markers of fatty acid oxidation (FatOx), protein synthesis, and protein catabolism were assessed. CL increased relative lean mass in both sexes (P = 0.012). In females, CL increased FatOx in WT, yet reduced FatOx in KO, while among males, CL reduced FatOx independent of genotype (P = 0.04). Uncoupling protein 2 (UCP2) and fatty acid synthase (FASN) abundance were higher in females (P = 0.004 and 0.037, respectively), and in both sexes, KO mice had higher SM UCP2 abundance (P = 0.022). CL increased phosphorylated acetyl-CoA carboxylase in males, yet reduced it in females (P = 0.015). Similarly, CL affected p706S kinase abundance (indicative of anabolic signaling) in a sexually dimorphic manner, increasing in males and decreasing in females. CL robustly increased SM FASN across sexes and genotypes (P < 0.001). In summary, the most salient finding was that CL increased SM FASN content independent of sex and ERβ genomic activity; additional novel sex-divergent effects of CL on SM metabolism were identified, some of which were affected by ERβ genomic activity.

Gut dysbiosis and an increased risk of respiratory infection in type 2 diabetes have been well recognised. However, the relationship between the gut and respiratory pathobiont carriage rates in the type 2 diabetic Malaysian population is understudied. To address the knowledge gap, we profiled the gut and upper respiratory tract (URT) microbial composition, and the urine metabolome of 31 type 2 diabetic adults and 14 non-diabetic adults. We showed a higher prevalence of opportunistic URT pathogens in diabetes patients. A higher abundance of pro-inflammatory bacteria Escherichia coli was detected in the gut of the diabetic subjects. This coincided with the higher levels of sorbitol and taurine in the urine. The former is produced by aldose reductase, an enzyme strongly associated with airway inflammation, while the latter is a substrate for bacterial antioxidants (i.e. H2S). Despite a small sample size, our study revealed the potential relationship between the carriage rates of URT pathobionts with the gut microbial and urine metabolomic profiles of diabetes patients.

Triclosan (TCS), an antimicrobial agent widely used in personal care products, has been associated with impaired thyroid function and reduced thyroid hormone (TH) levels. However, its potential role in the developmental programming of thyroid dysfunction remains unclear. This study investigated the long-term effects of intrauterine TCS exposure on the hypothalamic-pituitary-thyroid (HPT) axis in adult rat offspring. Pregnant Wistar rats received oral doses of corn oil (control) or TCS (10 or 30 mg/kg/day) throughout gestation. Offspring rats were euthanized on postnatal day 90 (PND90), and tissues from the hypothalamus, pituitary, thyroid, liver, and serum were collected for analysis. Gene and protein expression were evaluated by RT-qPCR and Western blotting; thyroid histology was assessed morphologically; global DNA methylation was measured by ELISA; and serum TSH and THs were quantified through immunoassays. TCS exposure altered hypothalamic TRH content, reduced Gh mRNA expression in the pituitary, and decreased serum TSH levels. In the thyroid, Slc5a5, Tg, Tpo, Tshr, Pax8, and Nkx2.1 were downregulated, accompanied by reduced NIS and TPO protein expression and decreased circulating T4 levels. Histological analyses revealed reduced follicular diameter in both sexes. Epigenetic changes included increased global DNA methylation and H3 histone methylation in both sexes, along with reduced H3 acetylation in males. In addition, TCS exposure altered hepatic enzymes involved in TH metabolism, indicating systemic endocrine disruption. Collectively, these findings demonstrate that intrauterine TCS exposure increases susceptibility to thyroid hypofunction in adulthood, highlighting its potential role as a developmental thyroid disruptor.

Osteosarcopenia (OS) is a syndrome defined by the concurrent presence of sarcopenia and osteoporosis in the elderly population, which markedly elevates the risk of falls, fractures, and mortality. Recent studies demonstrate that disruption of muscle-bone biochemical crosstalk emerges as a key driver of OS pathogenesis, and that targeting pivotal mediators and pathways can concurrently restore musculoskeletal homeostasis. However, the precise molecular mechanisms and targeted therapeutic strategies remain inadequately explored. This review systematically summarizes the epidemiological risk factors and pathophysiological mechanisms underpinning OS, with emphasis on the interplay within musculoskeletal metabolism among myokines (e.g., fibroblast growth factors 21, FGF21, and irisin), osteokines (e.g., osteocalcin, OCN, receptor activator of nuclear factor-κB ligand, RANKL, and sclerostin, SOST), adipokines, and shared signaling pathways such as mitochondria-associated axes, Wnt/β-catenin, and nuclear factor-κB (NF-κB), as well as discusses the potential efficacy of direct and indirect interventions targeting these factors and biochemical signals, which provides innovative strategies and prospective research directions for developing precision-targeted therapies against OS and other degenerative musculoskeletal disorders. In addition, we propose that precise modulation of muscle-bone signaling constitutes a promising approach to treat OS. Future efforts should prioritize standardizing diagnostic criteria and advancing the development of therapies targeting critical muscle-bone biochemical interaction nodes to optimize the management of musculoskeletal comorbidities in the aging population.

Diabetic osteoporosis is a metabolic disease that seriously endangers human health and Previous studies have found that denosumab and metformin have certain effects on bone metabolism and glucose metabolism, respectively. However, there is still a lack of relevant research on the effect of the combined use of two drugs. In this study, we sought to analyze the therapeutic effect of these two drugs combined on the glycemic and bone metabolic parameters in the treatment of type 2 diabetes with postmenopausal osteoporosis. A prospective cohort study was designed to include 537 cases of patients with type 2 diabetes with postmenopausal osteoporosis. Patients were treated with placebo alone (placebo, n=135), metformin alone (MET, n=132), denosumab alone (DEN, n=136), and the combination group (n=134) for 30 months. Baseline data at 10 months, 20 months, and 30 months, Dual Energy X-ray Absorptiometry (DEXA), and pQCT were used to identify spine and tibia bone microstructures, respectively. The combination therapy group demonstrated significantly greater improvements in bone mineral density (tibia, radius, spine, and whole body) and bone microstructure (tibia and radius) compared to MET or DEN monotherapy (P<0.05). Bone absorption markers such as CTX and ALP were decreased, the level of bone formation markers was further increased, and the progression of glucose metabolism was improved significantly (P<0.05) compared to DEN alone or using MET alone. Denosumab monotherapy (DEN) ameliorated bone loss while exerting modest effects on glucose metabolism progression. In contrast, metformin monotherapy (MET) significantly improved glycemic control but demonstrated limited efficacy against bone loss. Crucially, the metformin-denosumab combination synergistically mitigated bone loss in diabetic postmenopausal osteoporosis patients.

The expression of vaspin and GRP78 has been shown in the testis and ovary. The postnatal testis undergoes several changes in the expression of different proteins. The expression of vaspin and GRP78 has not been shown in the postnatal testis. It has also been shown that modulation of adipokine function could affect testicular germ cell proliferation and apoptosis. Whether vaspin regulates testicular proliferation and apoptosis in the early pubertal stage is still unknown. The aim of this study was to determine the expression of vaspin/GRP78 in postnatal testes of mice. Next, we investigated the effects of vaspin on cell proliferation and cell death (apoptosis, ferroptosis, and autophagy) in the pubertal testis. Immunohistochemistry and western blot analyses revealed that vaspin and GRP78 exhibit dynamic expression levels through developmental stages. In the testis, both proteins showed mild to moderate immunostaining in Leydig cells at early stages (PND7 and 14), with increasing intensity at PND21 and 42 in Leydig cells and spermatocytes, and round and elongated spermatids. The expression of vaspin and GRP78 was significantly down-regulated at postnatal day 21 (PND21). Moreover, exogenous vaspin treatment (PND21 to PND35) suppressed germ cell proliferation (BrdU labelling, PCNA, and GCNA) and apoptosis (decreased expression of active caspase-3 and TNFα) in the testis. The marker of autophagy, LAMP2, was elevated by vaspin treatment. Furthermore, vaspin treatment showed both stimulatory and inhibitory effects on markers of ferroptosis. In conclusion, vaspin/GRP78 could be a new regulator of cell proliferation and cell death in pubertal mouse testes.

Cardiovascular disease (CVD) is the leading cause of death among individuals with type II diabetes (T2D), affecting approximately 30 million people in the United States. During insulin resistance, the heart undergoes a metabolic shift, leading to increased reactive oxygen species generation, lipotoxicity, and mitochondrial dysfunction, ultimately contributing to cardiovascular dysfunction. The effects of thyroid hormones (THs) on redox biology and oxidative stress remain inconclusive, necessitating further investigation. In this study, insulin-resistant Otsuka Long Evans Tokushima Fatty (OLETF) rats were used to assess the impact of exogenous thyroxine (exoT4) on NADPH oxidases (NOX) and antioxidant defenses in the heart. Rats were assigned to four groups: i) lean control, Long Evans Tokushima Otsuka (LETO; n = 6), ii) LETO + T4 (8 μg/100 g BM/day for 5 weeks; n = 7), iii) untreated OLETF (n = 6), and iv) OLETF + T4 (n = 7). NOX4 mRNA expression was two-fold greater in OLETF rats compared to LETO. T4 treatment increased NOX4 protein abundance by 56% in OLETF. In addition, T4 normalized lipid peroxidation (4-hydroxynonenal) and tumor necrosis factor-α (TNF-α) levels while increasing nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression by 158% compared to LETO and enhancing nuclear Nrf2 protein expression by 45% compared to untreated OLETF. Thioredoxin (TRX) expression, suppressed in OLETF, was increased by 88% following T4 treatment. ExoT4 increased mitofusin 2 (Mfn2) protein abundance in OLETF by 49% compared to LETO. These findings suggest that TH treatment may have cardioprotective effects mediated by Nrf2 in the heart during metabolic syndrome (MetS).

Osteoporosis (OP) is a systemic osteopathy characterized by a decrease in bone density and mass. Human bone mesenchymal stem cells (hBMSCs) exhibit multidirectional differentiation potential and play a critical role in bone metabolism. Herein, we investigated the diagnostic potential of miR-127-3p in OP and elucidated its regulatory role in hBMSCs, thereby providing novel insights into the diagnosis and progression prediction of OP. The relative expression of miR-127-3p was measured via RT-qPCR analysis. ROC curve and logistic analysis were applied to identify the diagnostic value of miR-127-3p for OP. The CCK8 assay and flow cytometry were used to assess cell viability and apoptosis. A luciferase reporter assay was performed to assess the interaction between VAMP2 and miR-127-3p. The bone differentiation markers RUNX2, OCN, and OPN were assayed using RT-qPCR and western blotting. We observed that the expression of miR-127-3p was reduced in patients with OP, allowing it to effectively distinguish these patients from healthy individuals. Transfection with miR-127-3p mimic inhibited hBMSC apoptosis, increased cell viability, and increased RUNX2, OCN, and OPN levels. Furthermore, miR-127-3p regulated hBMSCs via targeting VAMP2. Overexpression of VAMP2 reversed the effects of miR-127-3p on apoptosis, cell viability, and bone differentiation. In conclusion, these findings suggest that miR-127-3p may be a potential diagnostic tool for OP. In addition, miR-127-3p promotes hBMSC viability and differentiation through downregulating VAMP2; this decreases OP progression. Our findings will inform new ideas for the diagnosis and developmental prediction of OP.

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Abstract: Tributyltin (TBT) is a toxic compound used in antifouling paints and known for its endocrine-disrupting properties, including female reproductive dysfunction. We hypothesized that TBT exposure during gestation and lactation induces long-term reproductive alterations in female offspring. Pregnant Wistar rats were orally exposed from gestational day 7 to the end of lactation to 0.01% ethanol (control), TBT 100 ng/kg, or TBT 1000 ng/kg body weight. Female offspring were evaluated at postnatal days (PND) 21, 45, and 180 for biometric, hormonal, and ovarian parameters. Birth weight was reduced in the TBT100ng group, and body weight was reduced by PND180 in the TBT1000ng group. At PND45, testosterone increased in both TBT groups, while FSH decreased in the TBT100ng group. Estrous cyclicity irregularities, such as a prolonged metestrus-diestrus phase, were noted in the TBT1000ng group. Ovarian analysis showed increased cystic and atretic follicles at PND21 and PND45. Reduction in primordial follicles (TBT100ng) and corpora lutea (both TBT groups) was observed at PND180, along with ovarian fibrosis. TBT exposure led to age- and dose-dependent disruptions in ovarian follicle dynamics: initial increases in healthy follicles at PND21, followed by elevated unhealthy follicles and reduced healthy ones at later stages. At PND21, both TBT doses increased ERα expression, while TBT100ng increased AR expression. These changes were accompanied by a persistent increase in ovarian mast cells and elevated IL-6 protein expression, particularly at PND21 and PND180. Thus, maternal TBT exposure disrupts ovarian development and function, potentially increasing susceptibility to abnormal conditions such as polycystic ovary syndrome and primary ovarian insufficiency later in life.

Bariatric surgery (BS) is the most effective treatment for obesity and its related comorbidities, resulting in significant adipose tissue (AT) loss and functional recovery. However, the molecular mechanisms in the AT that drive these health benefits remain poorly understood, and predictive factors for adequate weight loss are currently needed. This study aimed to identify the proteomic signature of subcutaneous AT (SAT) linked to BS-induced weight loss and metabolic improvement, and to determine potential predictors of individual response. Sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics was performed on paired abdominal SAT samples from individuals with obesity before and after BS. Bioinformatic and correlation analyses were conducted between proteomic data and changes in anthropometric and clinical parameters. In addition, the effect of sera from BS participants on subcutaneous adipocytes was assessed in vitro. The SAT response to BS was characterised by an up-regulation of mitochondrial metabolism and a down-regulation of inflammation, which correlated with different anthropometric and circulating markers. Notably, obesity duration was associated with BS-induced weight loss. Individuals with short-standing obesity (SSO) exhibited greater proteomic remodelling, weight reduction, and clinical improvement post-BS than those with long-standing obesity (LSO). Furthermore, a regulatory axis involving miR-223-3p, glucose metabolism, and cytoskeleton reorganisation in adipocytes might be connected to the positive effects of BS in LSO. Overall, our results indicate that obesity duration is related to BS-induced weight loss through SAT proteomic remodelling. Addressing this relationship could help develop new strategies to enhance weight management and metabolic health in people living with obesity.