Endocrinology最新文献

Despite the widespread use of mammography as the standard of care for breast cancer screening, its accuracy remains limited for select patient populations, such as women with high breast density. Liquid biopsy-based tests offer an accessible complement to conventional screening methods. Here, we conducted a case-control study to develop a plasma-based protein classifier to distinguish between early-stage breast cancer patients and healthy individuals. A total of 335 women, comprising 116 patients with newly diagnosed, treatment naïve breast cancer (Stage 0-2) and 219 healthy controls, had plasma samples collected and processed in a blinded manner using a sample preparation method coupled with semi-quantitative, label-free mass spectrometry (MS)-based analysis. The median number of proteins detected per patient across breast cancer and healthy individuals was 6,991 and 6,818, respectively. A machine learning-based classifier was trained and validated on patient proteome profiles using a leave-one-out cross-validation (LOOCV) approach to identify breast cancer patients. The classifier achieved an AUC of 0.96 (95% CI: 0.93-0.97), with a sensitivity of 86.2% (95% CI: 78.8-91.3%) and a specificity of 90.4% (95% CI: 85.8-93.6%). In breast cancer patients, the classifier retained >85% sensitivity regardless of breast density (low density: 87.2%, high density: 90.2%) at 90% specificity. Our workflow demonstrates the potential of plasma proteomics as a potent diagnostic tool in early-stage breast cancer screening.

Fibroblast growth factor 21 (FGF21) is a liver-derived hormone that regulates metabolism across multiple tissues. It can cross the blood-brain barrier and activate its receptor FGFR1c, in conjunction with co-receptor β-Klotho, modulating neuronal activity. Previous studies have mapped the brain-wide distribution of FGFR1c and β-Klotho, suggesting potential FGF21 target regions. Notably, FGF21 has been shown to act on the hypothalamus to regulate feeding behavior and macronutrient preference, positioning it as a promising candidate for antiobesity therapies. In this study, we found that under a diet of normal chow, FGF21 primarily activated hypothalamic regions involved in metabolic control and suppressed activity in cortical areas related to cognition. Prolonged high-fat diet (HFD) treatment increased neuronal activity in regions involved in sensory processing, memory, and reward. In HFD-fed mice, FGF21 broadly activated additional regions linked to reproduction, thermoregulation, sensory function, and arousal. However, its ability to stimulate key metabolic nuclei, such as the periventricular hypothalamic nucleus, was impaired, suggesting the existence of selective central FGF21 resistance. These findings reveal that FGF21 modulates brain activity in a diet-dependent manner and that obesity alters its central effects.

Gene expression profiles and the heterogeneity among hormone-producing pituitary cells remain poorly characterized in most vertebrates, especially in chicken embryos. Using single-cell RNA sequencing, the transcriptomes of 4346 basal and 10 835 corticosterone (CORT)-treated embryonic day 11 chicken pituitary cells were sequenced. Classical endocrine cell clusters were identified, and some were shown to express previously unreported marker genes. A cluster of uncommitted cells was identified that expressed markers for multiple endocrine cell types, with ∼30% coexpressing Gh and Pomc mRNA. We named this population of cells the cortico-somatotrophs. The existence of cortico-somatotrophs were confirmed at both the mRNA and protein level. We further characterized the corticosomatotrophs by utilizing the known effect of CORT to increase somatotroph abundance. Identification of cortico-somatotrophs challenges the prevailing view that corticotrophs and somatotrophs develop from distinct cell lineages.

Estrogens have considerable effects on energy homeostasis and metabolic health. In mice, signaling through estrogen receptor α (ERα) alters energy intake and expenditure, effects that may be mediated by specific regions or cellular subpopulations of the hypothalamus. This study investigates the function of ERα signaling in the lineage that expresses Rprm (reprimo), a gene we previously linked to thermoregulation in females. Here, we engineered a novel ReprimoCre mouse to selectively knock out ERα in Rprm lineage cells (Reprimo-specific ERα knockout [KO]; RERKO). We report modest changes in core temperature, higher brown adipose tissue (BAT) mass, elevated BAT temperature during the light phase, and lower tail temperature during the light phase in RERKO females relative to controls. RERKO females also exhibited a subtle difference in locomotion and no differences in feeding or body mass. These phenotypes suggest sex-specific effects on the patterns of body temperature instead of overall increases or decreases in heat generation or dissipation. Labeling of the Rprm lineage was detected in the brain, but not in BAT or white adipose, suggesting that temperature changes may be mediated by the nervous system. To test for centrally mediated effects on temperature, we ablated Rprm-expressing cells in the mediobasal hypothalamus. Although this approach eliminates the cells entirely instead of selectively eliminating ERα in Rprm-expressing cells, we observed a phenotype similar to RERKO mice, with effects on core temperature and BAT mass. Together, these results indicate that estrogen signaling in the Rprm lineage is important for thermoregulation in female, but not male, mice.

LH/choriogonadotropin (hCG) receptor (LHCGR) and the G protein-coupled estrogen receptor (GPER) are coexpressed in the ovary and support reproduction. The latter is involved in pathophysiological conditions and has been suggested as a potential therapeutic target. However, its role is still controversial, and several studies reported GPER to form heterocomplexes with other class A G protein-coupled receptors, modulating their signaling cascades. We evaluated if GPER interacts with LHCGR and impacts ligand-mediated pathways. In HEK293, LHCGR-GPER heteromers allosterically modulate LH/hCG-mediated signaling by preventing receptor coupling with Gq protein, leading to inhibition of phospholipase C pathway, and related transcriptional and mitogenic functions. This effect is prevented by mutant GPER unable to form heteromers with LHCGR. Interestingly, GPER expression has no effect on LH/hCG-induced Gs/cAMP/protein kinase A pathway activation, demonstrating selective inhibition of Gq pathway. These results were not recapitulated in cells displaying insufficient endogenous Gq protein expression levels, whereas they are recovered under exogenous Gq overexpression. Our data strengthen the concept that GPER may act as a modulator of other membrane G protein-coupled receptors, and a potential new target for treatment of tumors displaying Gq signalling.

17β-hydroxysteroid dehydrogenase 1 (HSD17B1) is the primary enzyme responsible for the activation of estrone (E1) to estradiol (E2) in ovaries and extra-gonadal tissues of both humans and rodents. In the present study, molecular modeling identified the substitution of His222 in the human HSD17B1 enzyme with glycine in the mouse as the key determinant for the different steroid specificity between the species. Furthermore, Ser143Ala mutation at the active site of mouse HSD17B1 resulted in a total loss of E1 to E2 conversion by HSD17B1. This resulted in elevated intraovarian and circulating E1 concentrations in adult HSD17B1 Ser143Ala knock-in (HSD17B1-KI) females, but no changes in E2 concentrations were observed compared to the wild-type mice. Androstenedione and dihydrotestosterone were also elevated in the HSD17B1-KI ovaries, associated with elevated circulating LH. However, the effect of HSD17B1 inactivation on female reproductive development and function was mild, primarily resulting in a slight decrease in ovarian weight in older HSD17B1-KI mice, without notable effects on fertility. Expression of genes related to steroid biosynthesis, mitochondrial metabolism, and known markers of polycystic ovary syndrome was found to be upregulated in adult HSD17B1-KI ovaries. However, no alterations in the structure or function of extra-gonadal tissues were observed, and the uterus and bone phenotypes in the HSD17B1-KI females were unaffected. Our results demonstrate that the blockade of HSD17B1-dependent E2 synthesis is successfully compensated for in mouse in vivo, resulting in only a mild ovarian estrogen and androgen imbalance but no significant adverse effects on reproductive or bone health.

Polycystic ovary syndrome (PCOS) is associated with a high prevalence of insulin resistance (IR) and obesity. Adiponectin, an insulin-sensitizing hormone, is reduced in PCOS and inversely correlated with IR and obesity. This study tested whether androgens reduce adiponectin, and if the adiponectin receptor agonist AdipoRon improves IR and obesity in a PCOS model. Four-week-old female Sprague Dawley rats were implanted with dihydrotestosterone (DHT) or control Silastic tubes for 12 weeks. After 6 weeks of DHT treatment, rats received AdipoRon or vehicle in their food for 6 weeks. DHT increased body weight, fat and lean mass, food intake, serum leptin, adipose mitochondrial oxidative stress, inflammatory markers, HOMA-IR, adipocyte size, and decreased serum adiponectin levels. DHT upregulated GLUT4, PPARγ, and adiponectin mRNA expression in subcutaneous adipose tissue (SAT), while PPARγ was downregulated in visceral adipose tissue (VAT). DHT also reduced Akt protein expression in SAT and p(S473)-Akt phosphorylation in VAT and caused a depot-specific effect on androgen receptor expression. AdipoRon reduced body weight, fat, and lean mass, food intake, serum leptin, adipocyte size, and IR markers in DHT-treated rats. AdipoRon upregulated Akt, AMPK, and AdipoR1 mRNA expression in SAT and increased p(S473)-Akt phosphorylation in both white adipose tissue (WAT) depots. AdipoRon also reduced mitochondrial oxidative stress in both WAT depots and decreased androgen receptor expression in VAT. AdipoRon attenuates hyperandrogenemia-induced adiposity and IR in a PCOS model by improving adipose insulin and adiponectin signaling, reducing mitochondrial oxidative stress and food intake, supporting its therapeutic potential in managing IR and obesity in PCOS women.