Journal of Endocrinology最新文献

Diabetes mellitus is a complex metabolic disorder characterized by hyperglycemia and the associated comorbidities. Type 2 diabetes is also associated with the dysfunction of liver, kidney and nervous system. In addition, an altered microbiota is frequently observed in subjects with type 2 diabetes. In this study, a db/db (diabetic) mouse model of type 2 diabetes was used to elucidate the beneficial effects of the probiotic Lactobacillus johnsonii N6.2. To evaluate metabolic effects, we performed metabolomics on liver samples, and RNA-seq from the liver and visceral adipose tissue, followed by qRT-PCR validation. Using L. johnsonii N6.2 extracellular vesicles, we evaluated lipid accumulation in hepatocytes. Finally, the gut microbiome of db/db mice was profiled using 16S rRNA sequencing. We observed that administration of the probiotic improved glycemic levels and decreased diabetes scores and type 2 diabetes-associated injury to the pancreas, liver and kidneys. Liver metabolomic and transcriptome analyses identified biomarkers of L. johnsonii N6.2 activity, including modulation of the vitamin K pathway, upregulation of FGF21, a key regulator of glucose and lipid metabolism, and alternations in selected circadian genes. This study elucidates the beneficial effects of L. johnsonii N6.2, against the common symptoms of type 2 diabetes, highlighting its potential as an adjuvant therapeutic agent.

TIMELESS is considered a molecular hinge linking circadian rhythms and the cell cycle. We recently identified TIMELESS as one of the upregulated core circadian clock genes during thyroid cancer dedifferentiation, but its expression and significance in thyroid cancer remain unclear. To address this, we assessed TIMELESS expression in thyroid neoplasms using bioinformatics analysis, immunoblotting, and immunohistochemistry. TIMELESS expression progressively increased from normal thyroid tissue to differentiated thyroid cancer and then to anaplastic thyroid cancer. Silencing TIMELESS expression in thyroid cancer cells reduced clonogenicity and spheroid formation, induced G2/M cell cycle arrest, and impeded xenograft growth in NOD SCID mice. In The Cancer Genome Atlas, TIMELESS expression was negatively correlated with recombination proficiency scores. Knocking down TIMELESS increased sensitivity to doxorubicin in thyroid cancer cells and upregulated the mRNA expression of NKX2-1 and SLC5A5. In conclusion, the overexpression of TIMELESS is associated with thyroid cancer dedifferentiation and may serve as a potential target for combination therapies.

Mitochondria are unique intracellular organelles that have their own DNA and are inherited intact in the oocyte. They have multiple functions, the most important of which is producing energy in the form of ATP by oxidative phosphorylation (OXPHOS) using a range of metabolic substrates. As energy requirements increase with intrauterine growth and the onset of new postnatal functions at birth, mitochondria develop structurally and functionally in utero to meet these energy demands. In part, the developmental and prepartum maturational changes in mitochondrial OXPHOS capacity depend on the endocrine environment and the natural rise in the fetal concentrations of hormones, such as cortisol and tri-iodothyronine (T3), towards term. This review discusses the development of mitochondrial respiratory function during late gestation with an emphasis on tissue OXPHOS capacity. It considers the role of cortisol and thyroid hormones, in particular, in the intrauterine development and prepartum maturation of mitochondrial OXPHOS capacity in preparation for extrauterine life. Finally, it briefly examines the potential longer-term consequences of abnormal hormonal exposure before birth on mitochondrial OXPHOS function later in postnatal life. Endocrine regulation of mitochondrial OXPHOS in the fetus is shown to be multifactorial, dynamic and tissue specific with a central role in determining functional development. It optimises energetics for survival both in utero and at birth and has implications for adult metabolic fitness and the inheritance of mitochondrial phenotype.

Cadmium is a heavy metal found widely in the environment, originating from industrial emissions, mining activities, phosphate fertilizers, and cigarette smoke. It is an endocrine-disrupting chemical that mimics essential metals such as calcium and zinc, interfering with hormone signaling. Due to its long biological half-life, cadmium bioaccumulates in organisms, raising concerns about its long-term effects on endocrine and reproductive health. Cadmium's reproductive toxicity is well documented, with studies highlighting its impact on gonadotropin regulation and testicular function. However, its specific effects on calcium (Ca2+) signaling in gonadotrophs remain poorly understood. This study aims to determine whether cadmium disrupts Ca2+-dependent signaling mechanisms essential for gonadotropin secretion. To address this, we used an adult male mouse model to assess pituitary cadmium accumulation, gonadotroph responsiveness to GnRH, and alterations in Ca2+ mobilization patterns. Our results show that cadmium exposure leads to pituitary bioaccumulation, prolonged endocrine disruption, and gonadotroph hyperplasia. Initially, gonadotroph responsiveness to GnRH declines, but over time, altered Ca2+ oscillation patterns and increased gonadotropin secretion emerge. A transition from normal oscillatory Ca2+ signaling to biphasic responses was observed, along with sustained phospholipase C-β (PLCβ) activation, suggesting persistent intracellular signaling disruptions. In addition, cadmium exposure resulted in testicular atrophy, increased apoptosis, and reduced sperm count. Testosterone levels declined, while the gonadotroph population increased, highlighting an imbalance in endocrine regulation. These findings suggest that cadmium induces reproductive toxicity through a combination of direct testicular damage and disruption of gonadotroph calcium signaling and hormone secretion, leading to testicular dysfunction that is relevant to public health.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder with diverse clinical manifestations and metabolic risks. The 2012 NIH phenotypic classification, based on the presence of hyperandrogenism (HA), ovulatory dysfunction, and polycystic ovarian morphology (PCOM), has enabled more nuanced characterization of PCOS into four phenotypes (A-D). Phenotypes A and B, both hyperandrogenic and anovulatory, are consistently associated with the highest metabolic risk, including insulin resistance, dyslipidemia, and increased prevalence of metabolic syndrome. Phenotype C, though ovulatory, still exhibits metabolic abnormalities due to androgen excess. In contrast, phenotype D, lacking hyperandrogenism, generally shows the mildest hormonal and metabolic profiles. This review outlines the evolving diagnostic landscape of PCOS, including the potential use of anti-Müllerian hormone (AMH) as a surrogate marker for PCOM. It explores hormonal and metabolic biomarkers, such as total and free testosterone, SHBG, LH/FSH ratio, HOMA-IR, and lipid parameters, in phenotype differentiation. Furthermore, emerging adipokines (e.g., adiponectin, chemerin, and ZAG) and inflammatory markers (e.g., CRP, IL-6, and TNF-α) provide additional insight into the metabolic heterogeneity of PCOS beyond obesity. Genetic and genomic studies have identified over 19 susceptibility loci involved in gonadotropin regulation, steroidogenesis, and insulin signaling, with distinct gene clusters aligning with adiposity, insulin resistance, and reproductive traits. MicroRNA signatures also show potential as phenotype-specific biomarkers. Recognizing phenotype-specific variations in PCOS is critical for individualized risk assessment and therapeutic strategies. Future research should prioritize standardized diagnostic criteria and large, diverse cohorts to validate emerging biomarkers and improve long-term outcomes for women with PCOS.

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.