Endocrinology最新文献

Maternal obesity before and during pregnancy causes maladaptive fetal development with long-term effects on offspring's metabolic health, including a higher risk of metabolic dysfunction-associated steatotic liver disease. Treatment with metformin during obese pregnancy has been suggested to prevent adverse fetal programming, but its long-term effects on offspring liver metabolism remain uncertain. In wild-type C57BL/6NCrl mice, obesity was induced by feeding a high-fat/high-sucrose Western-style diet before and throughout gestation and lactation. A subset of obese dams received metformin during gestation. Offspring from control, obese (OB), and obese with metformin-treated (OB + M) dams were analyzed at postnatal days (P) 21 and 56 for their metabolic phenotype, hepatic histomorphology, and key metabolic proteins. At P21, maternal metformin treatment worsened obesity-related traits in male OB + M offspring, including increased body weight, length, and fat volume, higher plasma leptin, insulin, and resistin levels, and impaired glucose tolerance. Female OB + M offspring also showed a worsening of obesity traits, though less pronounced. Hepatic lipid accumulation displayed sex-specific patterns; male OB + M offspring exhibited reduced lipid accumulation, whereas female OB + M offspring demonstrated increased lipid accumulation. By P56, phenotypic parameters returned to normal, but molecular alterations persisted, involving shifts in hepatic fatty acid metabolism and mitochondrial respiratory chain complexes. Maternal metformin during obese pregnancy has age- and sex-specific effects on offspring, aggravating early obesity traits in a sex-dependent manner and prompting adaptations in hepatic metabolism during adolescence. These findings highlight the controversy surrounding metformin use during obese pregnancy, given its potential to induce sex-specific obesity and metabolic disturbances in offspring.

Type 2 diabetes (T2D) is a heterogenous metabolic condition characterized by varying degrees of insulin resistance and β-cell dysfunction. Preclinical mouse models are essential tools to investigate the mechanisms of T2D pathogenesis and develop therapeutic targets; yet, researchers often fail to specify which aspects of the spectrum of human T2D phenotypes are being modeled. In this mini-review, we critically examine mouse models of T2D and categorize them into recently redefined T2D subtypes according to key pathophysiological features. We focus on models that exhibit (1) insulin deficiency, (2) insulin resistance independent of weight gain, or (3) insulin resistance associated with weight gain. Onset, severity, and progression of metabolic phenotypes are described and discussed in context with clinical presentation in humans. While we find current T2D mouse models do not fully capture the heterogeneity of T2D, strategic model combinations and longer-term phenotyping could help better mimic clinical progression. Existing phenotyping data are often incomplete and largely available only for young male mice. We highlight the urgent need for thorough and standardized phenotyping of both sexes in all models. We also encourage the field to move toward using age-appropriate mice to better reflect human T2D pathophysiology and to advance precision medicine efforts in diabetes research.

Polycystic ovary syndrome (PCOS) is a common reproductive disorder characterized by irregular ovulation, cyst-like follicles on the ovaries, and hyperandrogenism. PCOS is also strongly associated with increased risk of obesity and metabolic diseases such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Hyperandrogenism independently associates with many of the metabolic symptoms observed in women with PCOS, and increased androgen signaling in the female brain is hypothesized to impair central homeostatic mechanisms controlling food intake and body weight. However, peripheral metabolic organs such as pancreas, liver, fat, and skeletal muscle all express the androgen receptor, suggesting that direct androgen signaling in these organs may disrupt peripheral metabolic health. Although it is difficult to separate the impacts of hyperandrogenism from hyperinsulinemia and insulin resistance, tissue explant studies and transgenic knockout models provide the ability to interrogate signaling through the androgen receptor in metabolic organs. This review will summarize and discuss recent evidence implicating hyperandrogenism as a driver of metabolic impairments in PCOS, with an emphasis on the molecular mechanisms by which androgens may alter metabolic function in the periphery in females.

Glucose homeostasis is tightly controlled by hormones secreted from pancreatic islets. The most abundant cell type in islets is the β-cell, which secretes insulin in response to nutritional stimuli. We previously reported that the adverse metabolic effects of high-dose dioxin exposure in mice are regulated by the aryl hydrocarbon receptor (AHR) specifically in β-cells. Additionally, fetal exposure to low-dose dioxin reduced β-cell area in female mice at birth; however, the role of AHR in β-cell development has not been explored. To characterize the AHR pathway in developing human β-cells, we differentiated human embryonic stem cells (hESCs) into "islet-like" cell clusters (SC-islets) in vitro and treated cells with vehicle or dioxin for 24 hours at key stages of differentiation. Dioxin exposure robustly upregulated AHR gene targets (CYP1A1, AHRR) at all stages of differentiation but only had modest effects on markers of islet development and maturity. We next generated an AHR knockout (KO) hESC line and found that basal CYP1A1 expression was profoundly suppressed in AHR-KO cells compared to parental cells at all stages of differentiation. Key markers of developing and mature pancreatic islets were largely unaffected by AHR deletion; however, G6PC2 was consistently downregulated in SC-islets from AHR-KO cells compared to parental cells. Interestingly, AHR-KO SC-islets also showed modestly increased insulin secretion relative to the parental line, suggesting a role for AHR in islet development. This novel AHR-KO cell line will allow for deeper investigation into the impact of AHR on the development of human islets and other cell lineages.

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.