Endocrinology最新文献

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.

The thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor 1 receptor (IGF-1R) have been shown to be involved in the development and perpetuation of thyroid eye disease found in up to 40% of patients with Graves disease-a form of autoimmune hyperthyroidism. While these 2 receptors have been known for many years to interact and exhibit synergy, the exact mechanism and the role of this interaction had not been fully evaluated. Recently, the use of a monoclonal blocking antibody to the IGF-1R has been shown to be an important therapeutic tool in improving the disease in such patients, thus revealing the importance of the IGF-1R in the disease pathogenesis. Since we recently presented direct evidence that the TSHR and IGF-1R bind to form a single complex, it is likely that this conjoining contributes to the enhanced signaling of both receptors. Using molecular dynamics simulations, we have furthered our observation by showing the high strength of their association and also determined that our modeling provides no evidence that β1-arrestin is responsible for bringing the TSHR and IGF-1R together in the cell membrane. We show that it is even difficult to break up the TSHR/IGF-1R complex, and while β1-arrestin does indeed bind well it is not necessary for the conjoining to take place.

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.

Immune cells in the pancreas are known to participate in organ development. However, the resident pancreatic immune system has yet to be fully defined. Immune cells also play a role in pathology and are implicated in diseases such as diabetes induced by intrauterine growth restriction (IUGR). We hypothesized that the resident immune system continues to develop during the neonatal period and is disrupted by IUGR. Using single-cell RNAseq and flow cytometry we identified many immune cell populations in the near-term fetus (at embryologic day 22) and neonatal (postnatal day 1, 7, &14) islets, non-endocrine pancreas, and the spleen in the rat. Using flow cytometry, we observed that the resident immune system dynamically changes during neonatal development in the pancreas and spleen. We identified 14 distinct immune populations in the pancreatic islets and 13 distinct immune populations in the spleen by single-cell RNAseq. There were no sex-specific differences in the relative proportion of immune cells in the pancreas or spleen. Finally, we tested if IUGR disrupted the neonatal immune system using bilateral uterine artery ligation. We found significant changes to the percentage of CD11B+ HIS48- and B cells in the islets and non-endocrine pancreas. IUGR-induced alterations were influenced by the tissue environment. Future research to define the role of these immune cells in pancreatic development may identify disrupted pathways that contribute to the development of diabetes following IUGR.

Mutations in the SOX2 gene have been previously linked to a syndromic form of isolated hypogonadotropic hypogonadism, with additional ocular and neurodevelopmental phenotypes. Recently, we reported a functional role for SOX2 in hypothalamic kisspeptin-expressing neurons and established a mechanistic relationship between SOX2 heterozygous variants and isolated hypogonadotropic hypogonadism. To further test the role of Sox2 in the hypothalamic-pituitary-gonadal axis, we generated mice with a whole-body heterozygous knockout of Sox2 (Sox2WT/KO). We found that heterozygous loss of Sox2 significantly delayed pubertal onset in both male and female Sox2WT/KO mice compared to wild-ype (WT) controls. In females, fertility was also compromised, with fewer estrous cycles and a significant delay in time to first litter of Sox2WT/KO dams compared to WT controls. Circulating levels of gonadotropins were normal in both male and female Sox2WT/KO mice, suggesting a functional pituitary. Finally, we assessed the number of kisspeptin and GnRH neurons and found that Sox2WT/KO mice do not differ from controls in the number of kisspeptin neurons but have significantly fewer GnRH neurons. This deficit occurs before birth, as by embryonic day 15.5, there are already fewer GnRH neurons in the Sox2WT/KO mice. Using luciferase assays, we determined that Sox2 increases expression of GnRH in vitro; thus, the decrease in GnRH-expressing neurons in vivo is likely the result of Sox2 haploinsufficiency. Together, these data further substantiate a critical role for SOX2 in the hypothalamic-pituitary-gonadal axis via effects on GnRH neuron development and, therefore, pubertal timing and reproductive function.

In diabetes, glucagon is typically oversecreted during hyperglycemia but undersecreted during hypoglycemia. Administration of a somatostatin receptor antagonist (SSTR2a) increases glucagon counterregulation during hypoglycemia in rodent models of type 1 diabetes (T1D) but less is known about its effect on glucagon in type 2 diabetes (T2D). Using a rodent model of insulin-requiring diabetes, we evaluated the effects of daily SSTR2a administration with insulin dosing (study A: 8 days) and repeated exposures to hypoglycemia (study B: 4× over 11 days) on glucagon and glycemia. In study A, 8 days of SSTR2a treatment at 3.0 mg/kg transiently increased glucagon levels after dosing but did not significantly affect the glycemic response to basal or bolus insulin. In study B, with daily low-dose SSTR2a treatment (0.3 mg/kg/d), the glucagon counterregulatory response to insulin-induced hypoglycemia increased while time to hypoglycemic onset was delayed on challenge days 1 and 2. SSTR2a treatment did not affect food intake, body mass, or C-peptide levels, but was associated with a lower glycated hemoglobin A1c level at the end of the study relative to controls (4.3 ± 0.9 vs 5.3 ± 0.8%; P < .05). In summary, in a rat model of insulin-treated T2D, daily SSTR2a administration increased glucagon counterregulation to hypoglycemia without worsening overall insulin sensitivity or glycemic control.

Endocrine mediators are essential for pregnancy maintenance, and their functional withdrawal is associated with normal term and preterm birth (PTB). Therefore, the disruption to endocrine functions or agents that can disrupt endocrine functions are naturally suspected as contributors to PTB. One of the well-studied endocrine-disrupting compounds is polybrominated diphenyl ether(s) (PBDE). PBDE is a flame-retardant compound that is contained in several products and is a ubiquitous environmental contaminant. PBDE exists in several different congeners, many harmless compounds, but a few PBDE congeners are linked as endocrine disruptors contributing to adverse pregnancy outcomes like PTB. However, data ambiguity suggests that current platforms are insufficient to conclude PBDE's mechanisms of action as an endocrine disruptor at the fetomaternal interface (FMI) (placenta/fetal membranes). The development of microfluidic-based new approach methods (NAMs) is being introduced to study PBDE and other environmental pollutants. Organs-on-a-chip (OOCs) are an emerging class of NAMs that can replicate human organ-level functions in vitro. OOCs are microfluidic systems comprising multiple cell types from an organ that mimics the environment of a physiological organ. These devices are interconnected through microchannels to maintain intercellular interactions. OOC-based testing and development have accelerated globally as regulatory agencies now emphasize the need for reliable, humanized alternatives to traditional animal models. Multiple reproduction-associated OOCs are being developed, and their utility has been tested in assessing mechanisms of action and toxicological parameters of environmental pollutants. This review provides an overview of FMI OOCs and uses PBDE as an example to demonstrate how OOCs can study endocrine-disrupting compounds.

Progesterone receptor membrane components 1 and 2 (PGRMC1 and PGRMC2) are single-pass proteins that function as multi-ligand regulators. They integrate signals from progesterone (P4), heme, and cytochrome P450 enzymes (CYPs). Accumulating evidence implicates PGRMCs in non-genomic progesterone signaling in cell, cancer, and reproductive biology. Heme binding (through their heme binding domain) and cytochrome P450 enzymes (CYPs) binding provide distinct functional roles for PGRMCs in various cells under specific cellular environment. In reproductive tissues, multiple functional roles have been reported for both PGRMC1 and PGRMC2 in both maternal and fetal organs. Ambiguity still exists about their independent functional role and contributions in pregnancy maintenance or initiation of parturition. Collectively, PGRMC1 and PGRMC2 act in complementary ways to regulate heme biology, metabolism, and P4-responsive signaling in gestational tissues. With the growing interest in PGRMC's role in pregnancy associated tissues, we provide a comprehensive narrative of PGRMCs through this review to facilitate future research and stimulate continued discussions.