Endocrinology最新文献

Leptin receptor positive (LepR+) cells are multipotent stromal cells and a source of osteogenic and adipogenic cells. Inactivation of Notch signaling in LepR+ cells increases bone mass in mature mice, but the target gene responsible was not identified. Because in LepR+ cells the expression of the Notch target gene Hes1 prevails over that of other genes, we explored the role of the Hes1 deletion in LepR+ cells. To this end, LepR-Cre;Hes1Δ/Δ mice were compared to Hes1loxP/loxP littermates. Male and female 5-month-old LepR-Cre;Hes1Δ/Δ mice exhibited an increase in femoral bone volume/total volume due to an increase in trabecular number; vertebral (L3) and cortical bone was not affected. Bone histomorphometry demonstrated decreased osteoclast number and eroded surface, decreased osteoblast number only in male mice, and no changes in bone formation. Neither osteogenesis nor adipogenesis was modified by the Hes1 deletion in bone marrow stromal cell cultures, although Tnfsf11 (encoding RANKL) was suppressed in osteogenic cultures of Hes1Δ/Δ cells. Single-cell RNA sequencing of femurs from 5-month-old LepR-Cre;Hes1Δ/Δ and control mice revealed the presence of 23 cell clusters including clusters composed of hematological cells (myeloid, B cells, and neutrophils), endothelial cells, and osteoblasts. There were no substantial differences in gene expression, cluster distribution, or trajectory finding between control and Hes1 inactivated cells. In conclusion, Hes1 inactivation in LepR+ cells results in an increase in bone mass secondary to a decrease in RANKL, osteoclast number, and bone resorption, but HES1 has little influence on osteogenesis or adipogenesis in bone.

Follicular thyroid carcinoma (FTC) is prone to early distant metastasis and has a poor prognosis compared with papillary thyroid carcinoma (PTC). This study aimed to unravel the cellular and molecular mechanisms underlying FTC progression and its transformation into the aggressive anaplastic thyroid carcinoma (ATC). Through single-cell RNA sequencing (scRNA-seq) profiling of 46 739 cells from PTC, follicular variant PTC (FVPTC), relapsed FTC (RFTC), and ATC, we reconstructed a comprehensive molecular trajectory of thyroid carcinoma progression. Our analysis revealed that PTC, FVPTC, and FTC possess distinct yet converging pathways of dedifferentiating into ATC, with FVPTC also able to progress to FTC. In RFTC, we identified a unique cluster of cells exhibiting ATC molecular characteristics. These cells interact with endothelial cells and fibroblasts mainly via the COL9A3-integrin α1β1 complex and may exhibit high metabolic and proliferative potential. UBE2C was identified as a specific marker for this population, which we termed "ATC-like cells." Functional validation in vitro and in vivo confirmed that UBE2C was markedly upregulated in FTC and was associated with adverse clinical outcomes. Mechanistically, UBE2C promoted cell proliferation and tumor growth, and regulated D-arginine and D-ornithine metabolism, glutathione metabolism, glycerophospholipid metabolism and tryptophan metabolism in FTC. This reveals a previously unrecognized population of ATC-like cells in RFTC marked by high UBE2C expression. UBE2C contributes to FTC progression by enhancing proliferation and modulating key metabolic pathways, suggesting it as both a critical biomarker of aggressive disease and a potential therapeutic target.

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 those with early-stage breast cancer 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 semiquantitative, label-free mass spectrometry-based analysis. The median number of proteins detected per patient across breast cancer and healthy individuals was 6991 and 6818, respectively. A machine learning-based classifier was trained and validated on patient proteome profiles using a leave-one-out cross-validation approach to identify patients with breast cancer. The classifier achieved an area under the curve 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 patients with breast cancer, 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.

Adipose tissue, long regarded as exclusively an energy reservoir, is now recognized as an active endocrine organ with significant immunomodulatory functions. As global obesity rates rise, understanding how adipokines influence the immune response is increasingly critical. In this review we focus on three key adipokines-leptin, adiponectin and resistin-and how they modulate immune function. With each adipokine, we begin by exploring its basic biology in the context of immune function. We then discuss mouse and human studies that explore each adipokine's role in the response to infection. We close by suggesting potential uses of each adipokine as a biomarker and/or therapy in infection.

Ghrelin acts via the growth hormone secretagogue receptor (GHSR) and increases both food intake and growth hormone (GH) secretion. Studies in mice with genetic manipulations of GH receptor (GHR) revealed that GH action is required for ghrelin's orexigenic effects. However, the biological basis of this interdependence remains unclear. Here, we studied the mechanisms by which GHR contributes to ghrelin-induced hyperphagia in male mice. Transcriptomic analyses of single-cell datasets revealed that Ghr and Ghsr are co-expressed in a small subset of neurons, particularly within the hypothalamic arcuate nucleus (ARH). Systemic ghrelin administration increased food intake, circulating GH, and glycemia but did not induce GHR activation in the brain, as indicated by the absence of pSTAT5 immunoreactivity. Central GH administration failed to enhance ghrelin-induced food intake or glycemia. To evaluate the role of peripheral GHR signaling, we treated mice with the brain-impermeable GHR antagonist pegvisomant. Systemically injected pegvisomant impaired ghrelin's orexigenic effect without affecting its impact on glycemia or hypothalamic c-Fos activation, indicating that peripheral GHR signaling is required for ghrelin-induced hyperphagia. Pegvisomant did not alter refeeding-induced or AgRP neuron-mediated hyperphagia, suggesting a selective blockade of ghrelin's action. Moreover, ghrelin-induced food intake was preserved in hepatocyte-specific GHR knockout mice, despite disrupted hepatic GH signaling. Thus, peripheral, non-hepatic GHR signaling is selectively required for the orexigenic effects of ghrelin. This work reveals a critical GH-dependent, liver-independent mechanism underlying ghrelin-driven feeding, with potential implications for the neuroendocrine regulation of appetite and for therapeutic strategies targeting the ghrelin-GH axis in metabolic diseases.

Disruption of lymphatic function underlies a broad spectrum of inflammatory and metabolic disorders, yet the hormonal pathways that regulate lymphatic biology remain poorly defined. GH, which is implicated in similar disease states, has an unclear role in lymphatic homeostasis. To address this gap, we investigated how chronic alterations in GH signaling alter lymphatic structure and function. Using transgenic mouse lines with increased, decreased, or absent GH action, we quantified the effect of GH on lymphatic pumping rate and lymphangiogenic remodeling during wound healing using near-infrared fluorescent imaging. We also measured markers of lymphatic endothelial cells using Western blot and immunohistochemistry across multiple mouse organs. Lymphatic pumping rate positively correlated with GH action, whereas both elevated and absent GH signaling delayed wound healing. In contrast, the lymphatic vascular density and the expression of protein markers of lymphatic endothelial cells were inversely correlated with GH activity. Additionally, we showed that primary human dermal lymphatic endothelial cells express the GH receptor and exhibit acute GH-activated signaling and that this activation can be blocked with new and Food and Drug Administration-approved GH receptor antagonists. Together, these findings identify GH as a regulator of the lymphatic system and suggest that GH receptor antagonism could be a potential strategy to address lymphatic dysfunction.

Septic shock urgently requires new treatments. We reported that low circulating concentrations of the native glucocorticoid carrier, corticosteroid-binding globulin (CBG), predict a 3-fold increase in human septic shock mortality. To explore this, we used our murine model of high-grade polymicrobial sepsis (cecal ligation and puncture [CLP]) to test CBG therapy. We prefitted adult male C57BL/6 mice (n = 106) with wireless arterial telemetry, then induced high-grade CLP. Mice were randomized with or without intravenous CBG therapy at 6 hours (3.5 mg/kg) and 30 hours (2.5 mg/kg). Terminal bloods, collected on humane endpoints or at 96 hours, were assessed for inflammation and organ damage; positron emission tomography was used to assess [124I]I-CBG biodistribution. CLP mice developed septic shock leading to multi-organ failure and 58% mortality. CBG therapy reduced mortality to 17% (a relative decrease of 72%), reduced hypotension duration by 75%, and lowered organ damage markers. CBG transiently suppressed the pro-inflammatory cytokine peak at 12 hours (45%-59%) and markedly augmented anti-inflammatory interleukin-10 and interferon-β1 (2-fold to 96 hours). The decrease in corticosterone alongside this profile suggests an intrinsic anti-inflammatory response. Combined with PET-confirmed [124I]I-CBG targeting to the injury site, these data suggest CBG survival benefits are due to targeted delivery or direct immunomodulation. While host responses involve a complex interplay of neuroendocrine and metabolic factors, our findings demonstrate marked improvements in disease progression and mortality with CBG therapy in murine-modeled septic shock. These results provide a strong impetus for a study of CBG therapy in patients with septic shock.

Context: Diabetes-associated metabolic stress and anxiety reciprocally influence one another's onset and course. We previously linked excessive selenoprotein P (SeP, encoded by SELENOP in humans) to pathological conditions frequently observed in individuals with diabetes.

Objective: The present study aimed to clarify the role of SeP in the metabolic stress-induced anxiety.

Methods: We visualized Selenop expression in the mouse brain section via RNAscope in situ hybridization and used RT-qPCR to evaluate gene expression in brain regions. We created brain-specific Selenop knockout (bSelenop-/-) mice by mating Selenop-flox and Nestin-Cre mice and conducted behavior tests for anxiety-like behavior and spatial memory under both a standard (STD) and high-fat, high-sucrose diet (HFHSD) conditions. In a cross-sectional general population cohort study, we examined differences in serum selenoprotein P concentrations between individuals with and without anxiety symptoms.

Results: RNAscope in situ hybridization identified glial and endothelial cells as the sources of SeP synthesis in the brain. Selenop was expressed at the same level in the brains of mice fed with an STD and HFHSD. bSelenop-/- mice did not exhibit altered body weight or glucose tolerance associated with HFHSD feeding. High-fat, high-sucrose diet aggravated the anxiety-like behavior in the control mice, whereas Selenop deletion in the brain ameliorated the anxiety-like behavior without affecting spatial memory. Epidemiological data revealed that serum selenoprotein P was significantly higher in subjects with anxiety symptoms.

Conclusion/interpretation: These findings suggest that excess SeP production may be a common trait linking metabolic stress with anxiety.

Thyroid hormone (TH) is essential for cardiovascular function, and women are disproportionately affected by TH disorders and experience worse outcomes following myocardial infarction (MI). However, the role of sex-specific TH regulation in post-MI cardiac recovery remains poorly understood. We investigated TH homeostasis and type 3 deiodinase (D3) activity, an enzyme that inactivates TH, in male and female C57BL/6 mice following MI. Using cardiomyocyte-specific D3-deficient (Dio3ΔHeart) mice, we investigated how impaired TH inactivation influences cardiac function and mitochondrial respiration. We also examined DIO3 messenger RNA expression, which encodes the D3 enzyme, in left ventricular (LV) tissue from human donors with nonfailing (NF) hearts or ischemic cardiomyopathy (ICM). Four weeks post MI, wild-type female mice exhibited sustained cardiac D3 activity, which effectively limited 3,5,3'-triiodothyronine (T3) levels in the LV. In contrast, Dio3ΔHeart females, lacking cardiomyocyte D3, showed impaired systolic recovery, elevated LV thyroxine and T3 levels, and reduced fatty acid-supported mitochondrial respiration, effects not observed in Dio3ΔHeart males. Similarly, DIO3 expression was selectively upregulated in LV tissue from women with ICM, but not in men. These findings identify DIO3 as a key protective mechanism in females that limits T3-induced metabolic stress and preserves mitochondrial function after MI, revealing a sex-dependent pathway with therapeutic relevance for cardiac recovery.