Endocrinology最新文献

Some evidence suggests that ghrelin in plasma undergoes proteolytic processing, leading to the generation of shorter peptides containing the bioactive N-terminal end of this peptide hormone. However, the chemical nature and bioactivity of these shorter versions of ghrelin (termed mini-ghrelins) remain to be clearly defined. Mini-ghrelins generated in plasma were analyzed using mass spectrometry. The binding to and action on the GH secretagogue receptor (GHSR) of mini-ghrelins were assessed in vitro in a heterologous expression system using fluorescent imaging and electrophysiology, as well as in vivo in male mice through binding studies, immunohistochemistry, and behavioral assessments. We present the first characterization of peptides derived from ghrelin proteolysis in human, rat, and mouse plasma. We found that the shortest mini-ghrelin in humans and rats is ghrelin(1-11). In vitro, ghrelin(1-11) binds to GHSR, activates it with similar potency to ghrelin, and inhibits further ghrelin binding. In mice, ghrelin(1-11) binds to GHSR in orexigenic neurons of the arcuate nucleus but does not induce detectable changes in food intake or in the levels of the neuronal activation marker c-Fos in the hypothalamus. Instead, it prevents binding of fluorescent ghrelin and blocks its orexigenic effects. Ghrelin(1-14), the shortest mini-ghrelin detected in mice, exhibits similar properties to ghrelin(1-11) both in vitro and in vivo. We propose that ghrelin proteolysis in plasma-and the resulting generation of mini-ghrelins-is not merely a mechanism to reduce plasma ghrelin concentration but also a process that diminishes ghrelin's action by blocking its effects.

A subpopulation of kisspeptin neurons in the arcuate nucleus (ARN) of the hypothalamus functions as the GnRH pulse generator, driving the pulsatile secretion of LH from the anterior pituitary. Recent advances in in vivo GCaMP fiber photometry have allowed the direct measurement of ARN kisspeptin (ARNKISS) neuronal population activity in mice. In both sexes, ARNKISS neurons display large, brief calcium activity episodes, termed synchronization episodes, each corresponding to a correlated LH pulse. Here we present quantitative and comparative analyses of calcium activity in these neurons and LH profiles in male and female mice, based on a combination of previously published and unpublished data. Our findings reveal a significant sex difference in pulse generator frequency in intact mice, with males exhibiting slower and more stochastic synchronization episodes compared to females. Additional sex differences were noted in the profile of synchronization episodes. In gonadectomized mice, the synchronization frequency and the episode profiles became similar across sexes, indicating that gonadal steroids largely drive sex differences in the intact state. However, sex-specific differences in pulse frequency distributions persisted after gonadectomy, suggesting possible steroid-independent differences in the GnRH pulse generator. Sex differences in the LH pulse frequency and amplitude were observed in intact mice and were abolished following gonadectomy, highlighting the correlation between synchronization episodes and downstream hormonal signaling.

The salt-inducible kinases (SIKs), a family of serine/threonine kinases, are emerging endocrine regulators. The 3 isoforms, SIK1, SIK2, and SIK3, compose a subfamily of the 5' adenosine monophosphate-activated protein kinase-related kinases. The SIKs have multiple conserved protein kinase A phosphorylation sites by which they are regulated. Further, a family of well-characterized SIK targets is the cAMP response element binding protein regulated transcription coactivators, which promote cAMP response element-binding protein transcription. As such, the SIKs participate in several cAMP-dependent pathways, including classical GPCR cascades characteristic of endocrine signaling. This review discusses the currently known roles of the SIKs in the endocrine system. Specifically, the research on SIKs in this field up to this point has focused on the adrenal glands, ovary, pancreas, pineal gland, immune function of the thymus, parathyroid hormone signaling in the bone, and hypothalamic regulation of the circadian rhythm and endocrine axes. Furthermore, this review highlights the remaining questions in these areas and the glands in which little to no SIK research has been published: the testis, pituitary, thyroid gland, and parathyroid glands.

The association between perceived stress and reproductive dysfunction is known, yet the underlying mechanisms remain incompletely determined. We previously demonstrated that RF-amide related (RFRP) peptide 3-expressing neurons, putative inhibitors of the central regulation of fertility, are required for both acute restraint stress- and glucocorticoid-induced suppression of LH pulsatility in female mice. The present study complemented this by testing the role of RFRP neurons in the stress-induced suppression of the estrogen-induced preovulatory-like LH surge. We first established a reliable model of acute restraint stress in mice that stimulates glucocorticoid secretion, suppresses a late afternoon estrogen-induced LH surge, and inhibits corresponding kisspeptin neuronal activation in the anteroventral periventricular brain region. Two hours of restraint stress initiated 2 to 6 hours prior to lights off met these criteria. We then ablated RFRP neurons in adult female mice by expressing a diphtheria toxin receptor specifically in these cells and exposing them to diphtheria toxin. RFRP neuron-ablated and control mice that were ovariectomized and estrogen-treated were exposed to the acute, mid-afternoon restraint stress protocol and assessed for their peak LH concentrations several hours later at the expected time of the LH surge. Control mice exhibited stress-induced suppression of the LH surge, as expected, whereas RFRP-ablated mice did not. No differences in peak LH concentrations were observed between nonstressed controls and stressed RFRP-ablated mice. These data suggest that acute psychosocial stress occurring several hours prior to preovulatory LH surge induction invokes RFRP neuron-mediated blockade of the surge. The neural circuitry involved remains to be fully characterized.

High-fat diet (HFD) consumption increases the risk of metabolic syndrome as manifested by insulin resistance, fatty liver, hypertriglyceridemia, and diabetes mellitus type 2. Blood-brain barrier (BBB) disruptions and impaired BBB transport of metabolic hormones, including leptin, insulin, and ghrelin, occur in diabetes mellitus type 2 and contribute to metabolic dysregulation and cognitive impairment. However, it is unclear whether the BBB changes are caused by the HFD, obesity, insulin resistance, elevated glucose or triglyceride levels, or other aspects of the metabolic syndrome. This study examined the effects of chronic HFD and an early stage of metabolic syndrome on BBB disruption and transport of insulin, leptin, and ghrelin. Mice on the HFD demonstrated obesity, increases in insulin, leptin, plasminogen activator inhibitor-1, and resistin, fatty liver and hyperglycerolemia, without elevations in glucose, triglycerides, ghrelin, glucagon, gastric inhibitory polypeptide, or glucagon-like peptide. The vascular markers of sucrose and albumin did not show BBB disruption. HFD did not alter the rate of insulin, leptin, or ghrelin transport across the BBB. However, leptin binding to the luminal surface of the BBB was greater in the hypothalamus and reduced for the rest of the brain with HFD treatment. The liver uptake of insulin, leptin, and ghrelin was reduced in the HFD group. Overall, our findings indicate that chronic HFD consumption with concomitant obesity and insulin resistance in the absence of hyperglycemia does not result in BBB disruption or altered BBB permeability to key metabolic hormones but may selectively affect vascular binding of important metabolic hormones in the brain and liver.

The sense of smell has long been known to exert a profound influence on the reproductive axis in both male and female rodents, yet despite intensive research over the past decades, the neural circuits and individual neurons linking olfaction with reproduction are still incompletely understood. A recent study by Decoster and colleagues uncovered a direct link between cells producing GnRH, the master molecule of reproduction, and the 2 major chemosensory epithelia in the murine nose. This hitherto undescribed GnRH subsystem, which is located in the olfactory bulb of mice as well as humans, may represent an evolutionarily ancient part of the neural circuits linking the olfactory system with the reproductive axis through the previously described classical GnRH system in the mediobasal hypothalamus. Here, we put these seminal new findings into perspective, highlighting their potential implications and their contribution to our current understanding of the neuroendocrine control of reproductive/sexual behavior by olfaction.

Long-term exposure to glucocorticoids (GCs) downregulates SSTR2 expression in corticotroph tumors, limiting the efficacy of octreotide (OCT) in the treatment of Cushing disease (CD). In AtT20 cells, dexamethasone (DEX) increased the expression of miR-375, which has a seed sequence for Ssrt2, supporting the hypothesis that excessive GC exposure can lead to epigenetic SSTR2 downregulation. The current study aims to evaluate miR-375 levels by reverse transcription quantitative polymerase chain reaction in sera from patients with CD, human corticotroph pituitary tumors, normal pituitaries, and AtT20/D16 and GH3 cells, and miR-375 impact on SSTR2 expression in AtT20/D16 and human corticotroph pituitary tumors. SSTR2 protein expression and localization were evaluated by WB and IF in AtT20/D16 and human primary cultures. Proliferation assay and flow cytometry were assessed to investigate the impact of miR-375 regulation on OCT treatment in AtT20/D16. miR-375 levels were higher in sera from patients with CD than in healthy subjects, and in human corticotroph pituitary tumors than in normal pituitaries. AtT20/D16 and GH3 exhibited an inverse expression pattern, with SSTR2 mRNA at low levels and miR-375 at high levels in AtT20/D16 and an opposite expression pattern in GH3. DEX treatment significantly reduced SSTR2 gene expression, while miR-375 inhibition significantly increased SSTR2 membranous protein expression in AtT20/D16 and primary cultures. Receptor internalization appeared stronger when OCT was combined with miR-375 inhibitor. The decreased cell proliferation induced by OCT was potentiated by miR-375 inhibition, increasing cells in early and late apoptosis, by inducing PARP, Caspase3, and ERK1/2 phosphorylation. In conclusion, SSTR2 protein expression can be epigenetically downregulated by GC-induced miR-375 expression, at least partially influencing OCT action in corticotroph pituitary tumors.

Taking advantage of the approaching 40th birthday of seminal articles describing the cloning of the genes that encode the nuclear receptors of thyroid hormone, Endocrinology publishes a collection of review articles dedicated to these receptors. The collection highlights the advances in the understanding of the structure, ligand interactions, and crosstalk with other signaling pathways. It reports ongoing research, which continues to reveal the complexity and physiological relevance of nuclear thyroid hormone receptor (TR) functions in tissues. Despite progress, key questions remain about cell-specific gene regulation, negative feedback mechanisms, and TR involvement in cancer. The new collection of review articles published in Endocrinology represents a milestone in a long-term project that illustrates the diversity of information that TR-centered research brings to basic science. They also outline that there is plenty of room for new and exciting investigations.

Osteogenesis imperfecta (OI) is a rare type I collagenopathy characterized by skeletal fragility. There is no cure and treatments focus primarily on mitigation of fractures. Although severe OI can be diagnosed prenatally, physicians lack tools for in utero intervention. Previous studies demonstrate postnatal inhibition of myostatin, a negative regulator of muscle mass, improves bone mass in OI mouse models, with greater skeletal improvements in genetically myostatin-deficient OI mice. Reduced maternal myostatin during pregnancy improved musculoskeletal health in offspring with unaltered myostatin. These findings suggest prenatal inhibition of maternal myostatin can improve bone strength in OI offspring. We hypothesize that targeting muscle-bone crosstalk through pharmacological myostatin inhibition can improve musculoskeletal health in OI offspring and protect from maternal bone loss. We evaluated maternal and fetal safety, metabolic, and musculoskeletal outcomes during pregnancy and lactation in wild-type and OI mice to assess preclinical safety for potential in utero therapy during critical developmental windows. Pregnant and nonpregnant OI mice were subject to anti-myostatin and control antibody therapy during gestation (embryonic days 3.5-E15.5). Maternal and fetal health were evaluated at embryonic day 17.5 and maternal health following lactation. Prenatal maternal anti-myostatin antibody treatment alone was not sufficient to increase maternal muscle and bone mass, and although the placental size was impacted for some, fetal weights, litter size, and maternal metabolic, and musculoskeletal health remained equivalent to control treated dams. Our findings highlight significant and potentially detrimental changes in maternal bone during lactation in an OI mouse model, consistent with pre/perinatal skeletal findings in non-OI mice and humans.