Endocrinology最新文献

Chronic food restriction (FR) changes growth hormone (GH) secretion from a pulsatile pattern, observed in ad libitum-fed mice, to a tonic secretion, in which basal (nonpulsatile) GH secretion prevails. However, the physiological mechanisms driving this alteration are not fully understood. We hypothesize that suppressed liver-derived insulin-like growth factor-1 (IGF-1) production may be a key underlying mechanism responsible for changing the GH secretion pattern in FR mice. To test this possibility, GH secretion patterns were investigated in ad libitum-fed hepatocyte-specific GH receptor (GHR) knockout (KO) (AlbuminΔGHR) male mice and compared to those of ad libitum-fed and FR control male mice. As expected, serum IGF-1 and liver Igf1 messenger RNA (mRNA) expression were similarly suppressed in AlbuminΔGHR-fed and FR wild-type (WT) mice. Plasma ghrelin did not differ between ad libitum-fed control and AlbuminΔGHR mice, but increased in FR control mice. Like the results observed in FR animals, AlbuminΔGHR-fed mice exhibited increases in total and basal (nonpulsatile) GH secretion without alterations in GH pulse amplitude compared to control mice. Although AlbuminΔGHR-fed and FR WT mice both exhibited suppressed Ghr mRNA levels in the liver, there were significant differences in the hepatic expression of sexually dimorphic genes and those regulating GH sensitivity. Hepatocyte-specific adeno-associated virus-induced expression of IGF-1 increased circulating IGF-1 levels and prevented most changes in the pattern of GH secretion in FR WT mice. In conclusion, suppressed liver-derived IGF-1 is the primary mechanism behind the changes in the GH secretion pattern observed in FR male mice.

The importance of immunometabolism in the development of metabolic diseases is clear. Yet, how certain metabolic disorders, such as insulin deficiency (ID), influence immune cell function, and vice versa, is poorly understood. Also, therapeutic strategies to harness the interplay between immune cells and metabolism are lacking. Here, we observe that ID rearranges the immune landscape of the liver, causing a decrease of T cells and an increase of the Kupffer cells, accompanied by a shift in the transcriptional signature and polarization of the latter. Treating ID mice with the protein S100A9 rescues the polarization and lipid-related changes caused by ID in the Kupffer cells, and, through them, rescues hypertriglyceridemia and hyperketonemia in a TLR4-dependent manner. Additionally, S100A9 acts on other immune niches to increase glucose uptake in skeletal muscle, improving hyperglycemia. In summary, our findings pinpoint the S100A9-TLR4 axis as a new tool to harness immune cells for improving ID-related metabolic dysfunction.

The endocrine renin-angiotensin system (RAS) is a key regulator of the autonomic nervous system and blood pressure (BP). Research over the past 5 decades has demonstrated that, in addition to this, circulating RAS tissues, including in the brain, express RAS components and have the capacity to generate and respond to angiotensin peptides. Recently, compelling new data have indicated the presence of renin expression within a discrete neuronal population in the nucleus ambiguus (NuAm), a brainstem region traditionally associated with parasympathetic control of heart rate (HR). These findings challenge conventional perspectives on brain RAS function and raise critical questions about its role in autonomic regulation. Here we provide a review of recent studies characterizing the NuAm and the adjacent C1 region of the rostral ventrolateral medulla (RVLM)-a key vasomotor center linked to sympathetic outflow. We revisit the hypothesis that the NuAm may influence BP and HR through both parasympathetic and sympathetic pathways through interactions with the RVLM. Furthermore, we highlight an emerging trend of sex-dependent differences in brain RAS activation. Finally, we emphasize the need for targeted molecular and physiological investigations to clarify the interplay between the NuAm and RVLM, their respective contributions to autonomic balance, and the potential involvement of brain RAS dysfunction in neurogenic hypertension.

Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that are ubiquitous in our environment and found in everyday items. We previously reported that prenatal exposure of rats to a human-relevant mixture of EDCs, NeuroMix (NMX), led to alterations in physiological and behavioral phenotypes. Here, we used hypothalamic-pituitary-gonadal (HPG) tissues from these same male and female rats and conducted 3' Tag-based RNA sequencing (TagSeq) to investigate underlying molecular mechanisms. TagSeq revealed unique tissue- and sex-specific differentially expressed genes (DEGs). In males, among the HPG tissues, NMX had the greatest effects in the hypothalamic arcuate nucleus (ARC), with 613 DEGs. Gene ontology (GO) enrichment analysis revealed that genes upregulated in the ARC of NMX males were involved in synaptic plasticity, while genes downregulated related to responses to estradiol and glucocorticoids. In females, prenatal NMX exposure induced the largest transcriptome change in the ovaries, with 1295 DEGs. GO-enrichment analysis revealed upregulation of genes involved in cilium organization and movement, while genes downregulated in this region were related to immune-related processes. Using Qiagen Ingenuity Pathway Analysis, we identified the β-estradiol pathway to be activated in all NMX female tissues and the NMX male pituitary, and inhibited in NMX male ARC, ventromedial nucleus, and testes. To our knowledge, this is one of the first studies to conduct transcriptomic profiling across HPG tissues, with these results demonstrating that prenatal exposure to NMX affects gene expression across the HPG axis in a sex-dependent manner.

GH acts as a master regulator of body growth in addition to playing a crucial role in various physiological processes. GH is produced by somatotropic cells in the anterior pituitary gland, and its levels in the blood display a pulsatile pattern. Secretion of GH is primarily regulated by hypothalamic factors released into the hypophyseal portal system. The regulation of GH release involves multiple negative feedback mechanisms that detect changes in circulating levels of either GH or IGF-1. These regulatory loops occur at both the pituitary and hypothalamic levels, indicating the presence of redundant control mechanisms. Furthermore, GH is secreted in high amounts during specific situations, including the neonatal period, pregnancy, hypoglycemia, and prolonged food deprivation. Numerous studies published in recent years have revealed new insights into the mechanisms regulating pulsatile GH secretion, including the importance of negative feedback loops, hormonal factors (eg, GH secretagogue receptor and glucagon-like peptide-1 receptor ligands, insulin, and sex steroids), and specific neuronal circuits. Therefore, the objective of this review is to summarize and discuss these novel findings and their implications for understanding the neuroendocrine control of GH secretion.

Vitamin D insufficiency (VDI) is primarily determined by serum levels of calcidiol, which serves as a biomarker for the less abundant but most potent bioactive metabolite, calcitriol. However, population studies often show discordance between calcidiol and calcitriol. Here, a genetically diverse population of 7 inbred mouse strains was used to investigate the role of interindividual genetic differences in driving calcidiol-to-calcitriol discordance under vitamin D sufficient (VDS) vs depleted (VDD) conditions. We found high interstrain variability in calcitriol that was discordant with calcidiol under VDS and VDD conditions. However, under VDS conditions, stratification by calcitriol level revealed that strains with serum calcitriol >60 pM (HighC) exhibited the expected positive calcidiol-to-calcitriol association, whereas strains with low calcitriol (<60 pM, LowC) did not. Thus, discordance under VDS was driven by genetically divergent strains with LowC. Discordance under VDD was not associated with LowC. LowC was not caused by increased calcitriol degradation or by transcriptional dysregulation of canonical vitamin D metabolism enzymes. Instead, LowC strains exhibited low renal expression of Lrp2 (megalin), the primary transporter required for renal calcitriol production. LowC strains also exhibited reduced renal expression of the vitamin D receptor (Vdr) and several target genes, demonstrating impaired vitamin D signaling. These findings reveal novel, naturally occurring genetic determinants of VDI that function by disrupting calcitriol production and signaling in a manner that cannot be predicted by calcidiol levels. Cross-species conservation of this phenomenon would have important implications for clinical management of VDI and related disease risks across genetically diverse populations.

The hypothalamic-pituitary-ovarian (HPO) axis is a complex endocrine feedback mechanism controlling ovulation in female vertebrates. Balance of the HPO axis requires correct secretion of sex steroids from the ovarian follicle to inhibit release of gonadotropins from the pituitary. Several conditions of ovarian dysfunction such as menopause, primary ovarian insufficiency, and polycystic ovary syndrome involve imbalances in the HPO axis, contributing to infertility. Intriguingly, these disorders also share a higher incidence of cognitive and emotional dysregulations, as well as a heightened risk of certain neurodegenerative conditions with age. It is understood that estradiol exerts neuroprotective functions, but gonadotropin signaling is less understood. High concentrations of circulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) have shown to contribute to neurodegenerative disease states, but are not addressed as part of traditional hormone replacement therapy. To identify the mechanistic connections between ovarian disorders and heightened susceptibility of the brain to pathological aging, a multisystem experimental approach is required, considering each HPO axis player as an individual effector. In this review, we will summarize current knowledge on the effects of estradiol, progesterone, FSH, and LH on neuronal susceptibility to pathology. We will describe ways in which the HPO axis becomes imbalanced during ovarian dysfunction, and how systemic inflammation can become an additional HPO axis effector. Finally, we will recommend solutions to the presented gaps in knowledge, and suggest avenues of future research to pursue development of therapeutics targeting both ovarian and brain health in patients.

Fetal Leydig cells (FLCs) are crucial for androgen production during fetal development. Their differentiation from progenitor cells is regulated by various factors, including desert hedgehog (DHH), platelet-derived growth factor (PDGF), and the transcription factor Ad4BP/SF-1 (NR5A1). Our previous research revealed significant upregulation of energy metabolism genes during FLC differentiation; however, the underlying regulatory mechanisms remain unresolved. The present study aimed to elucidate these mechanisms. Through transcriptome analysis, CUT&RUN sequencing (CUT&RUN-seq), and metabolic activity assays, we demonstrated that DHH and PDGF rapidly activate energy metabolism in interstitial cells, involving the FLC progenitor cells, without altering gene expression. In contrast, Ad4BP/SF-1 sustains high metabolic activity in differentiated FLCs through transcriptional activation. Reporter gene assays revealed that GLI1/GLI2, activated by DHH signaling, upregulates Ad4BP/SF-1 gene expression, suggesting a key role for DHH in FLC differentiation. Additionally, DHH signaling activates cholesterogenic gene expression possibly through upregulation of the Srebf2 gene. These findings uncover two distinct mechanisms of metabolism regulation by DHH in progenitor cells: a gene regulation-independent control of energy metabolism and a gene regulation-dependent modulation of cholesterogenesis. Furthermore, our results underscore the pivotal role of Ad4BP/SF-1 in maintaining metabolic activity in FLCs. This study provides novel insights into the regulation of energy and cholesterol metabolisms during FLC differentiation, contributing to a deeper understanding of reproductive system development.

Hypothalamic nuclei, including the arcuate nucleus, the paraventricular hypothalamic area, and the dorsomedial hypothalamus, integrate glucagon-like peptide-1 (GLP-1) signals to regulate feeding behavior, body weight, and glucose homeostasis. Recent advances have revealed that both endogenous GLP-1, produced by preproglucagon neurons in the nucleus tractus solitarius, and pharmacological GLP-1 receptor agonists (GLP-1RAs) engage distinct and overlapping hypothalamic circuits. However, the mechanisms underlying these effects involve circuit redundancy, diverse modes of signal integration, and context-dependent actions of different GLP-1R ligands. In this review, we propose a conceptual framework highlighting opportunities for future research and the therapeutic potential of targeting central GLP-1 pathways for obesity treatment.

Many clinical studies have identified correlations between thyroid dysfunction and reproductive issues, yet the underlying mechanisms behind this interaction remain poorly understood. In this study, we investigated the effect of triiodothyronine (T3) on the activity of gonadotropin-releasing hormone (GnRH) neurons, a key regulator of the central reproductive axis. Dual labeling confirmed that GnRH neurons express thyroid receptor (TR)α and integrin αVβ3 receptors mediating genomic and nongenomic effects of thyroid hormones, respectively. Using calcium imaging in an ex vivo model, we show that T3 induces a rapid and sustained increase of calcium oscillation frequency in GnRH neurons. No change in response was detected after application of T4. The T3 stimulatory effect was not inhibited by a TR-specific antagonist (1-850) but was mimicked by membrane-impermeable T3-BSA, indicating a mechanism independent of nuclear TR signaling. In contrast, the blockade of membrane αVβ3 integrins (with cilengitide) prevented the T3-induced increase in GnRH neurons calcium peak oscillation frequency. Further investigation using modulators of intracellular calcium and calcium entry revealed that binding to αVβ3 integrin can induce distinct calcium responses depending on the ligand, with T3 triggering a complex response involving multiple channels and calcium sources, possibly with compensatory mechanisms. In sum, these results demonstrate for the first time a direct effect of thyroid hormones on GnRH neuronal activity, with T3 stimulating calcium oscillations through the nongenomic αVβ3 integrin pathway. Understanding this thyroid-reproductive axis interaction will help clarify the mechanisms linking thyroid dysfunction to reproductive disorders and pave the way for targeted therapeutic interventions.