Endocrinology最新文献

Growth hormone (GH) signaling through signal transducer and activator of transcription 5 (STAT5B) is a central regulator of hepatic metabolism, yet the functional consequences of disease-associated STAT5B variants remain poorly understood. Here, we analyzed mice carrying STAT5BY665F (gain-of-function) and STAT5BY665H (loss-of-function) variants and dissect their impact on metabolic regulation. STAT5BY665F mice developed hypercholesterolemia and enhanced insulin sensitivity, whereas STAT5BY665H mice displayed reduced body weight and impaired insulin responsiveness. Transcriptomic analyses revealed that STAT5BY665F activated lipid, cholesterol, and immune transcriptional programs, while STAT5BY665H failed to induce these pathways. Notably, STAT5BY665F substantially feminized male liver gene expression, inducing 77% of female-biased genes while repressing 51% of male-biased genes, thereby mimicking the persistent STAT5B activation characteristic of female livers. ChIP-seq demonstrated extensive STAT5BY665F enhancer occupancy at metabolic and immune loci, contrasting with the minimal chromatin engagement of STAT5BY665H. Beyond the liver, STAT5BY665F broadly reprogrammed adipose tissue gene expression, activating lipid metabolism and immune regulatory networks, whereas STAT5BY665H exerted more restricted effects. Together, these findings illustrate how alterations in STAT5B activity affect enhancer activation and can lead to changes in metabolic function and hepatic sexual dimorphism.

Estrogen signaling plays an important role in normal ovarian functions, including follicle development, ovulation, and ovarian cell identity maintenance. Estrogen acts through the estrogen receptors alpha (ERα) and beta (ERβ), both of which are involved in ovarian gene regulation. However, the molecular mechanisms that lead to shared and unique receptor actions in the ovary remain poorly understood. Additionally, coregulators that contribute to ER actions in the ovary have remained unexplored. Here, we distinguished the roles of ERα and ERβ at different ovarian stages through characterizing the chromatin binding profile of each receptor in granulosa cells during pre- or peri-ovulation. We found that ERα/β genomic action was prominent during follicle development prior to ovulation. Loss of ERα/β binding after LH-stimulus was associated with the downregulation of folliculogenesis genes, while ERα/β binding contributed little to the activation of genes that are required for ovulation. ERα and ERβ showed highly similar chromatin binding patterns in granulosa cells. Through motif enrichment analysis and integration of other ovarian transcription factor cistromes, we identified potential interactors of ERα and ERβ, including a very strong overlap in chromatin binding with androgen receptor (AR) in pre-ovulatory follicles. These findings demonstrate ERα and ERβ to have highly conserved chromatin interaction functions including interaction with AR to mediate gene expression during folliculogenesis.

Metastatic prostate cancer (PCa) remains a major cause of cancer deaths in Western men. Although androgen deprivation therapy (ADT) initially induces remissions, patients ultimately develop incurable castration resistance, underscoring the need for alternative or complementary therapeutic strategies. Protein-protein interactions (PPIs) play a central role in oncogenic signaling, and aberrant protein dimerization is increasingly recognized as a critical driver of PCa progression and therapeutic resistance. Both homodimeric and heterodimeric protein complexes regulate key pathways involved in androgen receptor signaling, transcriptional control, and adaptation to tumor microenvironmental stress. Here, we review current evidence for oncogenic dimerization events in PCa and discuss their relevance for PCa progression. We highlight how similar dimeric interactions have been successfully targeted for therapy in other malignancies, with several strategies advancing to late-stage clinical trials or regulatory approval, underscoring their translational potential for PCa. We summarize approaches to modulate dimerization and highlight their mechanisms of action, therapeutic advantages, and inherent limitations. By combining pre-clinical and clinical findings with conceptual therapeutic frameworks, this review outlines the opportunities and limitations of targeting protein dimerization in PCa. Collectively, we propose that rational disruption of oncogenic homo- and heterodimers represents an underexplored yet promising therapeutic strategy that could complement existing treatments and help overcome resistance in advanced PCa.

Leptin is a hormone secreted by white adipose tissue that regulates food intake. Leptin also modulates cardiovascular health. Obesity is characterized by elevated circulating leptin concentrations, which can cause leptin resistance, and increased risk of cardiovascular disease. However, the role of leptin sensitivity or leptin resistance in the pathogenesis of cardiovascular disease is unclear in humans. Overall, in vivo rodent studies indicate that factors to consider regarding the relationship between leptin and cardiovascular health are: (1) selective leptin resistance, where the effects of leptin are only impaired for certain outcomes, and (2) mosaic leptin resistance, where, within a certain outcome, leptin signaling may only be impaired in certain tissues/cells. This is further complicated by sex-specific differences. In the current mini-review, the effects of leptin on the cardiovascular system, directly and via the central nervous system, are discussed.

Metabolic syndrome (MetS), including obesity, dyslipidemia, hypertension, insulin resistance, and often testosterone (T) deficiency, is increasingly linked to impaired lung function, worsened by systemic inflammation. COVID-19 highlighted the vulnerability of metabolically impaired patients to respiratory complications. Preclinical mechanistic studies remain limited. This study examined MetS effects on lung function and morphology, and the impact of T therapy in a high-fat diet (HFD)-induced MetS rabbit model. Male New Zealand White rabbits were assigned to: regular diet, HFD 6 weeks, HFD 12 weeks (HFD12W), HFD + T 12 weeks (HFD + T12W), and HFD + T last 6 weeks (HFD12W + T6W). Lung function was measured via airway opening pressure (PAO), and tissues analyzed for macrophages (RAM11), collagen (picrosirius red), and inflammatory/fibrotic gene expression. HFD induced MetS features, hypogonadism, increased PAO, reduced compliance, elevated fatty acids, and early macrophage remodeling. At 12 weeks, inflammation and fibrosis were prominent, with upregulation of IL1β, LOX1, RORγt, TLR2, COL1A1, COL3A1, and TGFβ1. T therapy increased plasma T, improved metabolic parameters, reduced PAO, and reversed inflammatory/fibrotic gene expression. Histology confirmed decreased macrophage clustering and fibrosis. PAO inversely correlated with T, with levels <3.76 nM predicting abnormal PAO with >80% sensitivity and specificity. MetS causes progressive lung injury via macrophage dysregulation, inflammation, and peribronchiolar fibrosis. T deficiency is central, as hormone administration improved lung function and histology. Immune-driven mechanisms, including Th2/Th17 cytokines and epithelial-mesenchymal transition markers, likely contribute. T's anti-inflammatory and antifibrotic effects may involve cAMP signaling. Clinically, assessing T and metabolic status is crucial, and T therapy may help mitigate lung consequences of MetS.

Ovulation is triggered by a surge in luteinizing hormone (LH) secretion from the pituitary. The LH surge is itself driven by a surge in gonadotropin-releasing hormone release induced by estrogen positive feedback action in the hypothalamus. While ERα-expressing kisspeptin (Kiss1) neurons in the preoptic area (in mice, the rostral periventricular region of the third ventricle [RP3V]) are proposed to mediate this estrogen positive feedback event, the functional necessity of RP3V-derived kisspeptin for the LH surge has not been directly tested. Here we leveraged Cre/lox technology and the known high co-expression of tyrosine hydroxylase (TH) with Kiss1 in only the RP3V region to generate novel transgenic mice with selective knockout (KO) of the Kiss1 gene in just RP3V neurons (Kiss1RP3V KO mice). In situ hybridization confirmed a significant 70% reduction in cells expressing Kiss1 in the RP3V region, but not in the arcuate nucleus, along with no change in RP3V Th expression. Kiss1RP3V KO females exhibited normal pubertal timing and estrous cycles. However, functional interrogation of the ability of Kiss1RP3V KO females to generate an estradiol-induced LH surge demonstrated markedly blunted LH surges and reduced occurrence of surges, in line with the partial Kiss1RP3V knockout in this group. Correspondingly, fertility assessment revealed significant subfertility, including fewer and smaller litters. This subfertility is consistent with the observed impaired LH surges, though the downstream ovarian mechanism(s) underlying the smaller litters still needs to be determined. These findings provide direct causal evidence that RP3V-derived kisspeptin is essential for normal LH surge magnitude and optimal fertility.

Polycystic ovary syndrome (PCOS) is a systemic endocrine disorder characterized by perturbations in both androgen and insulin signaling pathways that result in anovulatory infertility and metabolic syndrome. This study aimed to elucidate insulin signaling in the PCOS ovary using a mouse model that develops both the metabolic and reproductive manifestations of PCOS due to chronic postnatal dihydrotestosterone exposure. PCOS mice developed anovulation, cystic follicles, systemic insulin resistance with compensatory hyperinsulinemia and mild excess adiposity, but not hepatic steatosis, adipose inflammation or frank obesity, suggesting that hyperandrogenism is the main driver of the metabolic perturbations in this model. Insulin signaling was then assessed in the ovary, liver, and skeletal muscle from hyperinsulinemic, fasting PCOS mice. Ovarian theca and granulosa cells showed upregulated markers of insulin signaling, while the liver and skeletal muscle from the same mice showed no changes compared to controls. However, cultured primary PCOS hepatocytes were profoundly insulin resistant in vitro, while primary theca cells (TCs) and granulosa cells (GCs) isolated from the same PCOS mice were insulin sensitive. Both PCOS TCs and GCs produced significantly more steroid hormones than control cells when stimulated with insulin and gonadotropins. Our findings indicate that the PCOS ovary remains sensitive to insulin despite systemic insulin resistance and that insulin works synergistically with gonadotropins to stimulate ovarian testosterone production in PCOS. We therefore suggest that insulin resistance is not merely a byproduct of hyperandrogenism but is a disease-driving factor in PCOS and should be treated as a clinical target in PCOS management.

Socio-sexual behaviors, a key aspect of mammalian biology, are governed by evolutionarily conserved neuronal circuits that control partner preference, sexual attraction, and attachment. This mini-review summarizes recent advances in understanding neuroendocrine pathways involved in various levels of socio-sexual interactions, from mating preferences to forming long-term sexual partnerships. We first briefly examine how prenatal hormone exposure shapes brain structures that later influence partner choices, with a particular focus on mechanisms driven by sex steroid hormones in rodent models. We also highlight some of the latest evidence showing how multimodal sensory cues activate neural circuits and neuroendocrine responses to initiate sexual behaviors. Finally, we examine how molecularly defined neuronal populations differently impact sexual performance and socio-sexual attachment in a sex-dependent manner. Some of the evidence presented here might have been overlooked and warrants greater attention to improve guidance and discuss future directions for our field.

Patients with diabetes are disproportionately affected by cardiovascular and kidney disease. Mineralocorticoid receptor (MR) antagonists show organ protection against cardiovascular and renal injury; however, major side effects including hyperkalemia and reduced renal function limit their use in individuals with diabetic complications. The nonsteroidal MR modulator balcinrenone may offer end-organ protection with fewer side effects. We compared responses to balcinrenone and eplerenone delivered from 8 weeks postinduction of streptozotocin (STZ)-induced type 1 diabetes in male mice. RNA sequencing revealed diabetes induced modulation of immune function, and metabolic and vascular targets in the kidney, which were similarly attenuated by balcinrenone or eplerenone treatment. Urine K+ excretion was lower following eplerenone treatment, but not balcinrenone treatment, compared to diabetes without treatment. We identified a 5.90-fold increase in the expression of K+ transporter G protein-activated inward rectifier potassium channel 1 in eplerenone- but not balcinrenone-treated diabetic mice. Balcinrenone and eplerenone similarly attenuated the diabetes-induced reduction in peak E-wave/A-wave velocity compared to mice without treatment at 15 weeks post-STZ. Gene markers of cardiac injury, B-type natriuretic peptide, and β-myosin heavy chain protein were higher in diabetic vs nondiabetic left ventricles (LVs). Conversely, gene expression of Ca2+ ion channel subunits, voltage-dependent L type, calcium channel subunit α 1C, and ryanodine receptor 2 in LV was lower in diabetic but not eplerenone- or balcinrenone-treated diabetic mice. Although balcinrenone and eplerenone similarly modified cardiac changes, potassium excretion was greater with balcinrenone, consistent with a reduced risk of hyperklemia with the nonsteroidal MR modulator.

Growth hormone (GH) controls sexual dimorphism in hepatocyte gene expression programs governing lipid metabolism, bile acid synthesis and xenobiotic processing, which contribute to sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) risk. Although GH-regulated sex-specific transcription is well-studied, the functional cis-regulatory hepatocyte enhancers that orchestrate these sex-dependent metabolic programs remain largely unknown. Here, we integrated single-nucleus multiomic profiling of hepatocyte chromatin accessibility with in vivo functional enhancer assays to identify and validate GH-responsive, sex-biased hepatocyte enhancers in intact mouse liver. We constructed a tiled HDI-STARR-seq library of 23 912 reporters spanning 1839 liver ATAC regions and delivered it to liver by hydrodynamic injection, enabling enhancer activity assessment across different biological conditions. Reporters representing 840 ATAC regions showed sex-biased and/or GH-regulated enhancer activity, in many cases mirroring regulation of their accessibility in hepatocyte chromatin, validating them as functional, physiologically regulated enhancers. The regulated enhancer sequences were enriched for activating histone marks (H3K27ac, H3K4me1), and for binding sites for the STAT5-dependent, sex-specific repressors BCL6 and CUX2; whereas, STAT5 binding was enriched at both regulated and non-regulated enhancers. Motifs for HNF4A and for several novel factors identified de novo were specifically enriched at the regulated enhancers. Sex-biased and GH-regulated enhancers were linked to both MASLD-enabling and MASLD-protective genes, suggesting that GH-dependent chromatin remodeling at these loci contributes to sex-differential metabolic disease susceptibility. This integrated in vivo approach defines a validated set of GH-regulated hepatocyte enhancers through which chromatin accessibility and transcription factor binding drive sexual dimorphism in hepatic metabolism and MASLD risk.