Agouti-related protein antagonizes glucocorticoid production induced through melanocortin 4 receptor activation in bovine adrenal cells: a possible autocrine control

Endocrinology. 2004 Feb;145(2):541-7. doi: 10.1210/en.2003-0605. Epub 2003 Oct 30.


Agouti-related protein (Agrp), primarily expressed in the hypothalamus, is an endogenous antagonist of alphaMSH at the level of melanocortin 3 receptor (MC3-R) and MC4-R, but the adrenal gland represents the second major Agrp-expressing tissue. In adrenal fasciculata cells, the glucocorticoid secretion is under the control of ACTH, which binds specifically MC2-R, the only functional melanocortin receptor described in these cells to date. Nevertheless, using cultured bovine fasciculata adrenal cells, we report that Agrp has no antagonistic properties against ACTH at the level of MC2-R. In our studies, (Nle4, d-Phe7)-alphaMSH (NDP-alphaMSH) stimulated the production of cortisol in a dose-dependent manner, and these effects were abolished by Agrp or SHU9119, a synthetic antagonist of MC3-R and MC4-R. Using a more specific antagonist (JKC-363) and RT-PCR analysis, we can postulate that the effects of NDP-alphaMSH were mediated via MC4-R. These results are suggestive that adrenal glucocorticoid production could be regulated through MC4-R that may have some relevance in the physiology of adrenal cells. Moreover, Agrp might exert an autocrine control on adrenal cells because a protein with biological Agrp-like activity is secreted by these cells. This peptide could then modulate locally the functions of some peripheral tissues such as adrenals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex / chemistry
  • Adrenal Cortex / physiology
  • Adrenal Glands / physiology*
  • Adrenocorticotropic Hormone / pharmacology
  • Agouti-Related Protein
  • Animals
  • Autocrine Communication
  • Cattle
  • Cell Line
  • Cells, Cultured
  • Culture Media, Conditioned
  • Gene Expression
  • Glucocorticoids / biosynthesis*
  • Green Fluorescent Proteins
  • Humans
  • Hydrocortisone / biosynthesis
  • Hydrocortisone / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Luminescent Proteins / genetics
  • Melanocyte-Stimulating Hormones / pharmacology
  • Mice
  • Proteins / metabolism
  • Proteins / pharmacology*
  • RNA, Messenger / analysis
  • Receptor, Melanocortin, Type 4 / antagonists & inhibitors*
  • Receptor, Melanocortin, Type 4 / genetics
  • Receptor, Melanocortin, Type 4 / physiology
  • Recombinant Fusion Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Zona Fasciculata / physiology
  • alpha-MSH / analogs & derivatives*
  • alpha-MSH / pharmacology*


  • AGRP protein, human
  • Agouti-Related Protein
  • Agrp protein, mouse
  • Culture Media, Conditioned
  • Glucocorticoids
  • Intercellular Signaling Peptides and Proteins
  • Luminescent Proteins
  • Proteins
  • RNA, Messenger
  • Receptor, Melanocortin, Type 4
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins
  • SHU 9119
  • alpha-MSH
  • MSH, 4-Nle-7-Phe-alpha-
  • Adrenocorticotropic Hormone
  • Melanocyte-Stimulating Hormones
  • Hydrocortisone