Agouti Related Protein (AgRP) is Upregulated in Cushing's Syndrome

Abstract

Alpha melanocyte-stimulating hormone (α‐MSH) is an agonist at the melanocortin 3 (MC3-R) and melanocortin 4 (MC4-R) receptors. α‐MSH stimulates corticosterone release from rat and human adrenal cells. Patients with Cushing's syndrome have elevated levels of serum α‐MSH. Agouti related protein (AgRP) is an endogenous antagonist at the MC3-R and MC4-R and is expressed in the rat adrenal cortex. AgRP antagonises α‐MSH-induced corticosterone release from rat and bovine adrenal cells. This suggests that AgRP may have an inhibitory paracrine role in the adrenal gland. We measured adrenal AgRP mRNA expression and circulating AgRP in 2 patients with Cushing's syndrome and controls. Adrenal AgRP mRNA expression and plasma AgRP were higher in the patients with Cushing's syndrome compared to controls. Plasma AgRP in the patients with Cushing's syndrome following bilateral adrenalectomy and hydrocortisone replacement were similar to the levels seen in controls. Our results suggest that AgRP may have a novel inhibitory paracrine role in the human adrenal gland.

AgRP - adrenal - Cushing's - melanocortin receptor

References

• 1 Barsh G S, Schwartz M W. Genetic approaches to studying energy balance: perception and integration.  Nat Rev Genet. 2002;  3 589-600
• 2 Bewick G A, Dhillo W S, Darch S J, Murphy K G, Gardiner J V, Jethwa P H, Kong W M, Ghatei M A, Bloom S R. Hypothalamic cocaine- and amphetamine-regulated transcript (CART) and agouti related protein (AgRP) neurons co-express the NOP1 receptor and nociceptin alters CART and AgRP.  Endocrinology. 2005;  146 3526-3534
• 3 Bicknell A B, Lomthaisong K, Gladwell R T, Lowry P J. Agouti related protein in the rat adrenal cortex: implications for novel autocrine mechanisms modulating the actions of pro-opiomelanocortin peptides.  J Neuroendocrinol. 2000;  12 977-982
• 4 Coates P J, Doniach I, Wells C, Hale A C, Rees L H, Besser G M. Peptides related to alpha-melanocyte-stimulating hormone are commonly produced by human pituitary corticotroph adenomas: no relationship with pars intermedia origin.  J Endocrinol. 1989;  120 531-536
• 5 Dhillo W S, Small C J, Gardiner J V, Bewick G A, Whitworth E J, Jethwa P H, Seal L J, Ghatei M A, Hinson J P, Bloom S R. Agouti-related protein has an inhibitory paracrine role in the rat adrenal gland.  Biochem Biophys Res Commun. 2003;  301 102-107
• 6 Doghman M, Delagrange P, Blondet A, Berthelon M C, Durand P, Naville D, Begeot M. Agouti-related protein antagonizes glucocorticoid production induced through melanocortin 4 receptor activation in bovine adrenal cells: a possible autocrine control.  Endocrinology. 2004;  145 541-547
• 7 Elias C F, Saper C B, Maratos-Flier E, Tritos N A, Lee C, Kelly J, Tatro J B, Hoffman G E, Ollmann M M, Barsh G S, Sakurai T, Yanagisawa M, Elmquist J K. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area.  J Comp Neurol. 1998;  402 442-459
• 8 Henville K L, Hinson J P, Vinson G P, Laird S M. Actions of desacetyl-alpha-melanocyte-stimulating hormone on human adrenocortical cells.  J Endocrinol. 1989;  121 579-583
• 9 Katsuki A, Sumida Y, Gabazza E C, Murashima S, Tanaka T, Furuta M, Araki-Sasaki R, Hori Y, Nakatani K, Yano Y, Adachi Y. Plasma levels of agouti-related protein are increased in obese men.  J Clin Endocrinol Metab. 2001;  86 1921-1924
• 10 Liakos P, Chambaz E M, Feige J J, Defaye G. Expression and regulation of melanocortin receptor-5 (MC5-R) in the bovine adrenal cortex.  Mol Cell Endocrinol. 2000;  159 99-107
• 11 Ollmann M M, Wilson B D, Yang Y K, Kerns J A, Chen Y, Gantz I, Barsh G S. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.  Science. 1997;  278 135-138
• 12 Schioth H B, Muceniece R, Wikberg J E. Characterisation of the melanocortin 4 receptor by radioligand binding.  Pharmacol Toxicol. 1996;  79 161-165
• 13 Shen C P, Wu K K, Shearman L P, Camach R, Tota M R, Fong T M, Van der Ploeg L H. Plasma agouti-related protein level: a possible correlation with fasted and fed States in humans and rats.  J Neuroendocrinol. 2002;  14 607-610
• 14 Shutter J R, Graham M, Kinsey A C, Scully S, Luthy R, Stark K L. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice.  Genes Dev. 1997;  11 593-602
• 15 Taheri S, Gardiner J, Hafizi S, Murphy K, Dakin C, Seal L, Small C, Ghatei M, Bloom S. Orexin A immunoreactivity and preproorexin mRNA in the brain of Zucker and WKY rats.  Neuroreport. 2001;  12 459-464
• 16 Vinson G P, Whitehouse B J, Dell A, Etienne A T, Morris H R. Specific stimulation of steroidogenesis in rat adrenal zona glomerulosa cells by pituitary peptides.  Biochem Biophys Res Commun. 1981;  99 65-72
• 17 Vinson G P, Whitehouse B J, Dell A, Bateman A, McAuley M E. Alpha-MSH and zona glomerulosa function in the rat.  J Steroid Biochem. 1983;  19 537-544

1 These 2 authors contributed equally to the work in this manuscript.