Endocrinology最新文献

SH2B1β is a multifunctional scaffold protein that modulates cytoskeletal processes such as cellular motility and neurite outgrowth. To identify novel SH2B1β-interacting proteins involved in these processes, a yeast two-hybrid assay was performed. The C-terminal 159 residues of the cytoskeleton structural protein, βIIΣ1-spectrin, interacted with the N-terminal 260 residues of SH2B1β, a region implicated in SH2B1β enhancement of cell motility and localization at the plasma membrane. The interaction between SH2B1β and βIIΣ1-spectrin (2205-2363) requires residues 1-150 in SH2B1β, with residues 105-120 playing a key role. While βIIΣ1-spectrin (2205-2363) was expressed throughout the cell, it co-localized with SH2B1β when co-expressed with SH2B1β mutants with varied intracellular localizations. The SH2B1β-βIIΣ1-spectrin (2205-2363) interaction impaired the ability of SH2B1β to enter the nucleus. A slightly larger βIIΣ1-spectrin fragment (2170-2363) with an intact PH domain localized primarily to the plasma membrane and cytoplasm, similar to SH2B1β. Similarly, full-length βIIΣ1-spectrin co-localized at the plasma membrane and cytoplasm with SH2B1β as well as the SH2B1β-regulated tyrosyl kinase, JAK2. Phosphorylation of spectrins has been shown to regulate their localization and function. Co-expression of βIIΣ1-spectrin, JAK2 and SH2B1β resulted in SH2B1β-dependent tyrosyl phosphorylation of βIIΣ1-spectrin. Finally, stimulation with GH induced formation of an endogenous complex containing βII-spectrin, SH2B1, and JAK2 in 3T3-F442A cells and increased tyrosyl phosphorylation of βII-spectrin. Our results identify a novel interaction between SH2B1β, βIIΣ1-spectrin and JAK2 resulting in JAK2- and SHB1-dependent tyrosyl phosphorylation of βII-spectrin. It seems likely that the many other ligand-activated tyrosine kinases that signal through SH2B1 could form similar complexes with βIIΣ1-spectrin.

Prader-Willi syndrome (PWS) is a rare genetic disease that causes developmental delays, intellectual impairment, constant hunger, obesity, endocrine dysfunction, and various behavioral and neuropsychiatric abnormalities. Standard care of PWS is limited to strict supervision of food intake and growth hormone therapy, highlighting the unmet need for new therapeutic strategies. Environmental enrichment (EE), a housing environment providing physical, social, and cognitive stimulations, exerts broad benefits on mental and physical health. Here, we assessed the metabolic and behavioral effects of EE in the Magel2-null mouse model of PWS. EE initiated after the occurrence of metabolic abnormality was sufficient to normalize body weight and body composition, reverse hyperleptinemia, and improve glucose metabolism in the male Magel2-null mice. These metabolic improvements induced by EE were comparable to those achieved by a hypothalamic brain-derived neurotrophic factor (BDNF) gene therapy although the underlying mechanisms remain to be determined. These data suggest biobehavioral interventions such as EE could be effective in the treatment of PWS-related metabolic abnormalities.

Thyroid hormone (TH) is essential throughout life. Its actions are mediated primarily by the thyroid hormone receptor (THR), which is a nuclear receptor. Classically, the THRs act as inducible transcription factors. In the absence of TH, a corepressor complex is recruited to the THR to limit TH-related gene expression. In the presence of TH, the corepressor complex is dismissed and a coactivator complex is recruited to facilitate TH-related gene expression. These coregulators can interact with multiple nuclear receptors and are also key in maintaining normal physiologic function. The nuclear receptor corepressor 1 (NCOR1) and the nuclear receptor corepressor 2 (NCOR2) have been the most extensively studied corepressors of the THR involved in histone deacetylation. The steroid receptor coactivator/p160 (SRC) family and in particular, SRC-1, plays a key role in histone acetylation associated with the THR. The Mediator Complex is also required for pretranscription machinery assembly. This mini-review focuses on how these transcriptional cofactors influence TH-action and signaling, primarily via histone modifications.

While obesity and diabetes are prevalent in both men and women, some aspects of these diseases differ by sex. A new blockbuster class of therapeutics, glucagon-like peptide 1 (GLP-1) analogs (eg, semaglutide), shows promise at curbing both diseases. This review addresses the topic of sex differences in the endogenous and therapeutic actions of GLP-1 and its analogs. Work on sex differences in human studies and animal research is reviewed. Preclinical data on the mechanisms of potential sex differences in the endogenous GLP-1 system as well as the therapeutic effect of GLP-1 analogs, focusing on the effects of the drugs on the brain and behavior relating to appetite and metabolism, are highlighted. Moreover, recent clinical evidence of sex differences in the therapeutic effects of GLP-1 analogs in obesity, diabetes, and cardiovascular disease are discussed. Lastly, we review evidence for the role of GLP-1 analogs in mood and reproductive function, with particular attention to sex differences. Overall, while we did not find evidence for many qualitative sex differences in the therapeutic effect of clinically approved GLP-1 analogs, a growing body of literature highlights quantitative sex differences in the response to GLP-1 and its analogs as well as an interaction of these therapeutics with estrogens. What also clearly emerges is the paucity of data in female animal models or women in very basic aspects of the science of GLP-1-gaps that should be urgently mended, given the growing popularity of these medications, especially in women.

Radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) accounts for the vast majority of thyroid-related mortality and, until recently, there were limited preclinical models for iodine uptake prediction. In the current study, we aim to establish a primary tumor-derived organoid model of DTC and predict radioiodine (RAI) uptake of tumor residue. The genotypic and phenotypic features between organoid and parental tissue were compared. The RAI uptake assay was used to evaluate the organoid's RAI uptake capacity, and related patients' RAI whole-body scans were used to verify the assay's predictive sensitivity. A total of 20 patient-derived DTC organoids have been established. Whole-exome sequencing and immunofluorescence analysis demonstrated that organoids faithfully recapitulated main features of the original tumor tissue. RAI-avid organoids (n = 11) presented significantly higher RAI uptake than the RAI-refractory (RAI-R) group (n = 9; 384.4 ± 102.7 vs 54.2 ± 13.2 cpm/105 cells, P < .0001). A threshold value in organoids of less than 250 cpm/105 cell was found to have a predictive sensitivity of 95.0% for distinguishing RAI-R from RAI-avid patients when paired to clinical information. Notably, we found that several tyrosine kinase inhibitors moderately re-sensitize iodine uptake by using organoids derived from 3 patients with different genetic mutation backgrounds. In conclusion, patient-derived DTC organoids recapitulated the main characteristics of their parental tissues and preserved ability to uptake radioiodine, showing potential in the development of novel drugs to boost iodine avidity.

The importance of hormones in mediating a behavioral transition in mammals from a virgin or nonparenting state to parental state was established around 50 years ago. Extensive research has since revealed a highly conserved neural circuit that underlies parental behavior both between sexes and between mammalian species. Within this circuit, hormonal action in the medial preoptic area of the hypothalamus (MPOA) has been shown to be key in timing the onset of parental behavior with the birth of offspring. However, the mechanism underlying how hormones act in the MPOA to facilitate this change in behavior has been unclear. Technical advances in neuroscience, including single cell sequencing, novel transgenic approaches, calcium imaging, and optogenetics, have recently been harnessed to reveal new insights into maternal behavior. This review aims to highlight how the use of these tools has shaped our understanding about which aspects of maternal behavior are regulated by specific hormone activity within the MPOA, how hormone-sensitive MPOA neurons integrate within the wider neural circuit that governs maternal behavior, and how maternal hormones drive changes in MPOA neuronal function during different reproductive states. Finally, we review our current understanding of hormonal modulation of MPOA-mediated paternal behavior in males.

The GH secretagogue receptor (GHSR) and the glucagon-like peptide-1 receptor (GLP-1R) are G protein-coupled receptors with critical, yet opposite, roles in regulating energy balance. Interestingly, these receptors are expressed in overlapping brain regions. However, the extent to which they target the same neurons and engage in molecular crosstalk remains unclear. To explore the potential colocalization of GHSR and GLP-1R in specific neurons, we performed detailed mapping of cells positive for both receptors using GHSR-eGFP reporter mice or wild-type mice infused with fluorescent ghrelin, alongside an anti-GLP-1R antibody. We found that GHSR+ and GLP-1R+ cells are largely segregated in the mouse brain. The highest overlap was observed in the hypothalamic arcuate nucleus, where 15% to 20% of GHSR+ cells were also GLP-1R+ cells. Additionally, we examined RNA-sequencing datasets from mouse and human brains to assess the fraction and distribution of neurons expressing both receptors, finding that double-positive Ghsr+/Glp1r+ cells are highly segregated, with a small subset of double-positive Ghsr+/Glp1r+ cells representing <10% of all Ghsr+ or Glp1r+ cells, primarily enriched in the hypothalamus. Furthermore, we conducted functional studies using patch-clamp recordings in a heterologous expression system to assess potential crosstalk in regulating presynaptic calcium channels. We provide the first evidence that liraglutide-evoked GLP-1R activity inhibits presynaptic channels, and that the presence of one GPCR attenuates the inhibitory effects of ligand-evoked activity mediated by the other on presynaptic calcium channels. In conclusion, while GHSR and GLP-1R can engage in molecular crosstalk, they are largely segregated across most neuronal types within the brain.

Significant research interest has been focused on beige adipocytes, the activation of which improves glucose and lipid homeostasis, therefore representing new therapeutic opportunities for metabolic diseases. Various Cre/Lox-based strategies have been used to investigate the developmental history of beige adipocytes and how these cells adapt to environmental changes. Despite the significant advancement of our understanding of beige adipocyte biology, much of the molecular insights of the beige adipocyte, including its origin and cell type-specific function, remain to be further illustrated. It has previously been shown that Chrna2 (cholinergic receptor nicotinic alpha 2 subunit) has selective functionality in beige adipocytes. In this study, we explore the Chrna2-Cre-driven reporter expression in mouse beige adipocytes in vivo and in vitro. Our findings indicate that Chrna2-Cre expression is present selectively in multiple locular beige adipocytes in subcutaneous inguinal white adipose tissue (iWAT) and differentiated stromal vascular fraction from iWAT. Chrna2-Cre expression was detected in iWAT of young pups and mice after cold exposure where a significant number of beige adipocytes are present. Chrna2-Cre-driven reporter expression is permanent in iWAT postlabeling and can be detected in the iWAT of adult mice or mice that have been housed extensively at thermoneutrality after cold exposure, even though only "inactive dormant" beige adipocytes are present in these mice. Chrna2-Cre expression can also be increased by rosiglitazone treatment and β-adrenergic activation. This research, therefore, introduces the Chrna2-Cre line as a valuable tool for tracking the development of beige adipocytes and investigating beige fat function.

Normal ovarian function requires the expression of estrogen receptors α (ESR1) and β (ESR2) in distinct cell types within the ovary. The double estrogen receptor knockout (αβERKO) ovary had the appearance of seminiferous tubule-like structures that expressed SOX9; this phenotype was lost when the animals were repeatedly backcrossed to the C57BL/6J genetic background. A new line of ERKO mice, Ex3αβERKO, was developed for targeted disruption on a mixed genetic background. Histological examination of the ovaries in the Ex3αβERKO showed the appearance of seminiferous tubule-like structures in mice aged 6 to 12 months. These dismorphogenic regions have cells that no longer express granulosa cell-specific FOXL2, while other cells express Sertoli cell-specific SOX9 as examined by immunohistochemistry. Whole ovarian gene expression analysis in Ex3αERKO, Ex3βRKO, and Ex3αβERKO found many genes differentially expressed compared to controls with one Esr1 and Esr2 allele. The genes specific to the Ex3αβERKO ovary were compared to other models of postnatal ovarian transdifferentiation, identifying 21 candidate genes. To examine the genetic background contributions, DNA was isolated from αβERKO mice that did not show ovarian transdifferentiation and compared to DNA from Ex3αβERKO using Mouse Diversity Array. A genomic region putatively associated with transdifferentiation was identified on Chr18 (5-15 M) and genes in this region were compared to the genes differentially expressed in models of ovarian transdifferentiation. This work demonstrates the importance of ESRs in maintaining granulosa cell differentiation within the ovary, identifies several potential gene candidates, and suggests that genetic background can be a confounding factor.