ACTH mRNA Research Articles

Stress induces nucleobindin-1 mRNA and nesfatin-1-like peptide stimulates cortisol secretion in goldfish

Stress is a state of disrupted homeostasis triggered by physical or psychological stimuli that elicit adaptive responses at the molecular and cellular levels. In fish, the hypothalamus-pituitary-interrenal (HPI) axis mediates stress responses. Nesfatin-1 and a nesfatin-1-like peptide (NLP), derived from nucleobindin-1 (NUCB1), have been implicated in stress hormone regulation in mammals. This study investigated the cell-specific expression of NUCB1/NLP in HPI tissues and its effects on stress response in goldfish (Carassius auratus). NUCB1 mRNA is abundant in the hypothalamus, pituitary, and several other peripheral tissues of goldfish. NUCB1/NLP-like immunoreactivity was found in the brain and pituitary, co-localized with corticotropin-releasing factor receptor 1 (CRF-R1) in the hypothalamus, and with adrenocorticotrophic hormone (ACTH) in the pituitary. In vivo netting and restraint stress increased nucb1 and crf-r1 mRNAs in the brain and acth mRNA in the pituitary, as determined by RT-qPCR. Intraperitoneal injection of NLP increased cortisol in circulation, crf-r1 mRNA in the brain and acth mRNA in the pituitary. These findings suggest that NUCB1/NLP is a new player in mediating the endocrine stress response of goldfish through the HPI axis.

Micro-polystyrene plastic and benzo[α]pyrene exposure affects the endocrine system and causes physiological stress in Carassius auratus

Microplastics, owing to their hydrophobic properties and the various chemicals used in their production, can act as carriers of persistent organic pollutants, such as polycyclic aromatic hydrocarbons (PAHs). In this study, we exposed the goldfish Carassius auratus to benzo[α]pyrene (BaP, 10 μg/L), a representative PAH, and micro-polystyrene plastic (MP; 10 and 100 beads/L), of size 1.0 μm, as a single or complex environmental stressor, and evaluated the stress response and the resulting DNA damage. The expression of CRH and ACTH mRNA in the pituitary gland and hypothalamus, of the hypothalamus–pituitary–interrenal (HPI) axis, increased significantly after 6 h of exposure. Plasma cortisol levels showed a similar trend to the expression of stress-regulating genes along the HPI axis, and a significant increase was observed in the combined exposure groups (BaP + LMP [low-concentration MP] and BaP + HMP [high-concentration MP]) compared to those in the single exposure group. H2O2 concentration and CYP1A1 and MT mRNA expression levels in the liver were significantly higher in the combined exposure groups compared with in the single exposure groups. In situ hybridization revealed a similar pattern of MT mRNA expression, and many signals were observed in the BaP + HMP group. Furthermore, the BaP + HMP group showed more DNA damage, and the degree of DNA damage increased with exposure time for all experimental groups, except for the control group. Therefore, exposure to BaP and MP alone can induce stress in goldfish; however, when a combination of both substances is provided, their synergistic effect leads to increased stress and DNA damage. MP was confirmed to be a more serious stress-inducing factor in goldfish than BaP, based on the expression levels of stress-regulating genes along the HPI axis.

Liver X Receptors Regulate Adrenal Steroidogenesis and Hypothalamic-Pituitary-Adrenal Feedback

The nuclear hormone receptors liver X receptor alpha (LXRalpha) (NR1H3) and LXRbeta (NR1H2) are established regulators of cholesterol, lipid, and glucose metabolism and are attractive drug targets for the treatment of diabetes and cardiovascular disease. Adrenal steroid hormones including glucocorticoids and mineralocorticoids are known to interfere with glucose metabolism, insulin signaling, and blood pressure regulation. Here we present genome-wide expression profiles of LXR-responsive genes in both the adrenal and the pituitary gland. LXR activation in cultured adrenal cells inhibited expression of multiple steroidogenic genes and consequently decreased adrenal steroid hormone production. In addition, LXR agonist treatment elevated ACTH mRNA expression and hormone secretion from pituitary cells both in vitro and in vivo. Reduced expression of the glucocortioid-activating enzyme 11beta-hydroxysteroid dehydrogenase 1 in pituitary cells upon LXR activation suggests blunting of the negative feedback of glucocorticoids by LXRs. In conclusion, LXRs independently interfere with the hypothalamic-pituitary-adrenal axis regulation at the level of the pituitary and the adrenal gland.

Glycoprotein hormone genes are expressed in clinically nonfunctioning pituitary adenomas.

Approximately 25% of patients with pituitary adenomas have no clinical or biochemical evidence for excess hormone secretion and are classified as having null cell or nonfunctioning adenomas. To characterize the cell type of these tumors, we analyzed pituitary hormone gene expression in clinically nonfunctioning pituitary adenomas using specific oligonucleotide probes for the messenger (m)RNAs encoding growth hormone, prolactin, ACTH, and the glycoprotein hormone subunits, alpha, luteinizing hormone (LH)beta, follicle-stimulating hormone (FSH)beta, and thyroid-stimulating hormone (TSH)beta. Expression of one or more of the anterior pituitary hormone genes was found in 12/14 (86%) of the patients with clinically classified nonfunctioning adenomas. Expression of one or more of the glycoprotein hormone genes (alpha, LH beta, FSH beta, TSH beta) was identified most commonly (79%) with expression of multiple beta-subunit genes in many cases. Expression of alpha-subunit mRNA was found in each of the adenomas from patients expressing one of the beta-subunit mRNAs and in three patients with no detectable beta-subunit mRNA. Although FSH beta and LH beta mRNAs were found with similar frequencies in nonfunctioning adenomas, expression of FSH beta mRNA was generally much more abundant. TSH beta mRNA was detected in only one adenoma. The levels of glycoprotein hormone subunit mRNAs were variable in different adenomas, but the lengths of the mRNAs and transcriptional start sites for the alpha- and beta-subunit genes were the same in the pituitary adenomas and in normal pituitary. Growth hormone and prolactin gene expression were not observed in the nonfunctioning adenomas, but ACTH mRNA was found in a single case. Immunohistochemistry of the adenomas confirmed production of one or more pituitary hormones in 13/14 (93%) nonfunctioning tumors, with a distribution of hormone production similar to that of the hormone mRNAs. These data indicate that pituitary adenomas originating from cells producing glycoprotein hormones are common, but are difficult to recognize clinically because of the absence of characteristic endocrine syndromes and defective hormone biosynthesis and secretion.

Similarity between the corticotropin (ACTH) receptor and a peptide encoded by an RNA that is complementary to ACTH mRNA.

An interesting pattern in the genetic code was recently observed: Codons for hydrophilic and hydrophobic amino acids on one strand of nucleic acid are complemented by codons for hydrophobic and hydrophilic amino acids on the other strand, respectively. The average tendency of codons for "uncharged" (slightly hydrophilic) amino acids is to be complemented by codons for "uncharged" (slightly hydrophilic) amino acids. We have postulated that this pattern can result in the binding of peptides that are encoded by complementary RNA strands and we have presented supporting evidence. In this report we demonstrate the specific and high-affinity binding of naturally occurring peptides [corticotropin (ACTH) and gamma-endorphin] to synthetically derived counterparts that were specified by RNA sequences complementary to the mRNA for ACTH and gamma-endorphin, respectively. That this binding might result from one peptide being an "internal image" of the other was strongly suggested by the observation that antibody to the peptide that was encoded by the complementary RNA for ACTH recognized the adrenal cell ACTH receptor. Based on these findings, a theory on the evolution of peptides and their receptors is suggested.

Control mechanisms of gene expression of an enzyme and a polypeptide hormone involved in the lipid metabolism in higher animals (author's transl)

We have discussed the regulatory mechanisms of gene expression in higher animals, covering the following aspects on the basis of our recent results: 1. The regulation of lactose operon inEscherichia coli has been discussed as a model system for studies on the regulation of gene expression in animal systems. 2. Acetyl-CoA carboxylase plays a critical role in the regulation of biosynthesis of long-chain fatty acids. In an attempt to gain insight into the molecular mechanisms underlying the regulation of synthesis of hepatic acetyl-CoA carboxylase, we have been able to identify specific polysomes involved in the synthesis of this enzyme. Furthermore, it has been demonstrated that the relative content of these polysomes in the liver correlates well with the rate of hepatic synthesis of the enzyme under different dietary and hormonal conditions. 3. The pituitary hormone, corticotropin (ACTH), which is a single polypeptide consisting of 39 amino acids, has some interesting features with respect to the regulation of its biosynthesis. First of all, we have attempted to synthesize ACTH in a cell-free heterologous system. Our studies indicate that ACTH mRNA is translated in wheat germ extracts into a product which contains the amino acid sequence of ACTH but is much larger (M.W. approximately 35,000) than this hormone (M.W. approximately 4,500).