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Endocrinology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Mehul Dattani, Catherine Peters
The incidence of congenital adrenal hypoplasia has been reported as 1 in 12,500 births. Inheritance is either as an autosomal or X-linked recessive condition. Mutations in the DAX1 gene are associated with the X-linked form of the disease. Autoimmune adrenal insufficiency is associated with the two types of polyglandular autoimmune syndrome (Table 13.2). Type I is associated with mutations in the AIRE (autoimmune regulator) gene on chromosome 21. Familial glucocorticoid deficiency (FGD) and triple A syndrome are characterised by an insensitivity to adrenocorticotrophic hormone (ACTH) concentrations. FGD is caused by mutations in the ACTH receptor (MC2R), or mutations in the MC2R accessory protein MRAP. More recently, mutations in the genes encoding nicotinamide nucleotide transhydrogenase (NNT) and minichromosome maintenance-deficient 4 (MCM4) have also been associated with FGD. Triple A syndrome is autosomal dominant and secondary to mutations in the ALADIN gene.
Central and Peripheral Modulators of Appetite and Satiety
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Gabrielle Page-Wilson, Sam Dagogo-Jack
The melanocortins are derived from site-specific post-translational cleavage of the precursor parent molecule POMC. Cleavage of POMC within the anterior pituitary gives rise to adrenocorticotropic hormone (ACTH), which acts through the melanocortin 2 (MC2) receptor to stimulate adrenal steroidogenesis. Elsewhere in the brain, POMC is cleaved to another melanocortin α-MSH, which is an agonist for the MC3 and MC4 receptors. Administration of α-MSH (ICV) in rodents results in weight loss through inhibition of food intake and stimulation of energy expenditure (Neary et al. 2004). These actions are mediated through activation of two neuronal melanocortin receptor subtypes (MC3r and MC4r) and antagonized by an adjacent subset of hypothalamic neurons that express AgRP and NPY. Thus, the MC4 receptor plays a critical role on body-weight regulation. The NPY/AgRP neurons are inhibited by leptin and insulin.
Physiology of the Pituitary Gland
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Mária Hérincs, Karen Young, Márta Korbonits
Abnormalities can occur in the HPA axis at several levels. Depression can cause chronic central stimulation of the HPA axis. ACTH-secreting adenomas, ectopic ACTH-secreting tumours and adrenal cortisol-secreting tumours lead to Cushing’s syndrome. Cushing’s syndrome is a hormone disorder that results from high levels of cortisol in the blood, while Cushing’s disease refers to one specific cause of Cushing’s syndrome, a corticotroph adenoma in the pituitary gland that produces large amounts of ACTH. POMC mutations lead to glucocorticoid deficiency together with altered skin colouring and obesity due to the lack of ACTH and alpha melanocyte-stimulating hormone. Damage to the adrenal gland (causes include autoimmune and infective, e.g. tuberculosis) results in Addison’s disease (primary adrenal insufficiency). Familial glucocorticoid deficiency arises secondary to mutations in the MC2R or its accessory protein MRAP (MC2R accessory protein), and further genes have been recently identified in the steroidogenic pathway. Abnormalities in the steroid synthesis pathway (as seen in congenital adrenal hyperplasia) may lead to glucocorticoid deficiency in some cases. Finally, abnormalities in the pre-receptor metabolism of cortisol or mutations in the glucocorticoid receptor itself will also lead to abnormalities in the HPA axis.
Melanocortin 5 Receptor Expression and Recovery of Ocular Immune Privilege after Uveitis
Published in Ocular Immunology and Inflammation, 2022
Tat Fong Ng, Ambika Manhapra, David Cluckey, Yoona Choe, Srujan Vajram, Andrew W. Taylor
The neuropeptide α-MSH is part of the highly conserved melanocortin family of molecules that includes Adrenocorticotropic hormone (ACTH), and the five G-protein-coupled melanocortin receptors.13–15 While ACTH binds all five melanocortin receptors (MCr), α-MSH binds all but MC2r.15,16 The MC2r is exclusively expressed on the adrenal glands through which ACTH induces corticosteroid production. The melanocortin receptors MC1r, MC3r, and MC5r are expressed on immune cells, and cells of the retina.8,17–23 The literature demonstrates that there is differential regulation of immune cell activity through the different melanocortin receptors. The neuropeptide α-MSH through MC1r and MC3r suppresses pro-inflammatory activity in activated macrophages.21,24–27 Through MC5r, α-MSH promotes the induction of Treg cells and induces suppressor APC with the capacity in an antigen-specific manner to mediate counter-conversion of effector CD4+ T cells into Treg cells.8,18,22,28–31
Understanding neurobehavioral effects of acute and chronic stress in zebrafish
Published in Stress, 2021
Konstantin A. Demin, Alexander S. Taranov, Nikita P. Ilyin, Anton M. Lakstygal, Andrey D. Volgin, Murilo S. de Abreu, Tatyana Strekalova, Allan V. Kalueff
Like in other vertebrates, ACTH is the primary hormone responsible for stimulating cortisol biosynthesis and secretion in fish (Wendelaar Bonga, 1997). Zebrafish ACTH is encoded by a single gene, due to the disappearance of a prohormone convertase cleavage site in the zebrafish POMC-like peptide following a genome duplication (Alsop & Vijayan, 2009; Gonzalez-Nunez et al., 2003). While the genomes of teleost fishes and mammals include five melanocortin receptors (MC1R–MC5R), zebrafish express six of them, including two MC5Rs (Logan et al., 2003). In various species, MC1R regulates the synthesis of dark eumelanin, MC3R and MC4R regulate feeding behavior and energy metabolism, whereas MC5R regulates synthesis of sebum in various tissues, including skin (Chen et al., 1997; Healy et al., 2001; Logan et al., 2003; London & Volkoff, 2019; Marsh et al., 1999; Metz Peters, & Flik, 2006; Richardson et al., 2008; Yang, Zhang, Wen, & Tao, 2019). A Gs-coupled MC2R is a target for ACTH action, that controls cortisol biosynthesis by binding to MC2R expressed on adrenocortical cells (Roebuck, Jones, Robinson, Mitchell, & Thorburn, 1984; Schioth, Chhajlani, Muceniece, Klusa, & Wikberg 1996) to elevate cytoplasmic cAMP and rapidly stimulate the steroidogenic acute regulatory protein (StAR) shuttling to the inner mitochondrial membrane (Stocco & Clark, 1996). The second, delayed phase upregulates the transcription of steroidogenic enzymes under control of the cAMP-activated transcription factor SF-1 (Hu et al., 2001). The newly synthesized cortisol is released into the circulation and then transported to the target organs, bound by plasma proteins corticosteroid-binding globulin (transcortin) and albumin (Goodman, 2009; Hammond, 2016).
Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists
Published in Journal of Receptors and Signal Transduction, 2021
Y. Joyce Huang, Karen Galen, Ben Zweifel, Leah R. Brooks, A. Dale Wright
MC2R plays an important role in the regulation of adrenal corticosteroid secretion [35]. Historically, the clinical efficacy of Acthar Gel was thought to be due to its ability to stimulate endogenous cortisol production through the engagement of MC2R [32]. Interestingly, ACTH1-24 demonstrated the greatest MC2R functional activity of any of the synthetic MCR agonists tested, whereas Acthar Gel showed less full agonist activity at MC2R than the other MCRs (Table 4). We therefore examined differences between Acthar Gel and synthetic ACTH1-24 depot in eliciting corticosterone response in rats (Figure 3). There were significant effects on corticosterone levels with treatment (F [5, 275] = 45.03, p < 0.0001) and time (F [10, 55] = 91.07, p < 0.0001). There was also a significant interaction between treatment and time (F [50, 275] = 9.48, p < 0.0001). Corticosterone levels reached their maximum (490–744 ng/mL) at 1, 0.5, and 4 h after administration of 10, 40, and 400 IU/kg Acthar Gel, respectively; whereas maximum corticosterone levels (654–782 ng/mL) following synthetic ACTH1-24 depot administration were reached at 8 h for 0.6 and 2.4 mg/kg and 24 h for 1.2 mg/kg (Figure 3(A)). Treatment with 10, 40, and 400 IU/kg Acthar Gel resulted in an initial increase followed by a consistent decrease in corticosterone levels, with the 10 and 40 IU/kg Acthar Gel groups returning to baseline within 24 h (Figure 3(A,B)). In contrast, treatment with 0.6, 1.2, or 2.4 mg/kg synthetic ACTH1-24 depot resulted in sustained elevations in corticosterone levels throughout 48 h (Figure 3(A,B)). Post hoc analysis revealed significant differences in corticosterone levels between the Acthar Gel groups and the synthetic ACTH1-24 depot groups at 24 and 48 h (p < 0.05) (Figure 3(A,B)).