Failure of adrenal corticosterone production in POMC-deficient mice results from lack of integrated effects of POMC peptides on multiple factors

Abstract

Karpac J, Czyzewska K, Kern A, Brush RS, Anderson RE, Hochgeschwender U. Failure of adrenal corticosterone production in POMC-deficient mice results from lack of integrated effects of POMC peptides on multiple factors. Am J Physiol Endocrinol Metab 295: E446 -E455, 2008. First published June 17, 2008 doi:10.1152/ajpendo.00762.2007.-Production of corticosteroids from the adrenal gland is a multistep process in which corticosterone is enzymatically processed from its precursor cholesterol. The main hormone regulating the production of corticosterone is the proopiomelanocortin (POMC)-derived adrenocorticotropic hormone (ACTH). Adrenals of POMC-deficient (POMC Ϫ/Ϫ ) mice do not produce corticosterone either at basal levels or in response to acute stimulation with ACTH. However, pharmacological amounts of ACTH delivered continuously elicit corticosterone production over time. To define the relative effects of ACTH on individual factors involved in corticosterone production, parameters of adrenal cholesterol metabolism and steroidogenesis were examined in POMC Ϫ/Ϫ mice compared with wildtype and ACTH-treated mutant mice. POMC Ϫ/Ϫ adrenals lack cholesterol esters (CE); adrenal CE is restored with ACTH treatment. However, discontinuation of ACTH treatment stops corticosterone production despite the presence of adrenal CE. Failure of corticosterone production by POMC Ϫ/Ϫ adrenals occurs despite the constitutive presence of transcripts of genes required for cholesterol metabolism and steroidogenesis. Levels of key proteins involved in selective cholesterol uptake and steroidogenesis were attenuated; ACTH treatment increased these protein levels, most significantly those of the receptor responsible for selective uptake of CE, scavenger receptor class B, type I (SR-BI). Our studies reveal that failure of corticosterone production of POMC Ϫ/Ϫ adrenal glands and its pharmacological reconstitution by ACTH are not mediated by any one individual protein, but rather as an integrated effect on multiple factors from import of the substrate cholesterol to its conversion to corticosterone. proopiomelanocortin; adrenocorticotropic hormone; cholesterol; scavenger receptor class B, type I; gene expression SYNTHESIS OF CORTICOSTEROIDS in the adrenal gland requires cholesterol as the precursor, which is then metabolized in the steroidogenic pathway. Numerous steps, from the import of cholesterol from plasma into adrenal cells, the conversion of cholesterol esters to free cholesterol, movement of free cholesterol into the inner mitochondrial membrane, to the enzymatic conversion in the mitochondria of cholesterol to pregnenolone, progesterone, deoxycorticosterone, and, finally, corticosterone have to function to produce baseline levels of corticosterone. Importantly, they need to be highly regulatable in order to respond to acute stress with high output of corticosterone.Adrenocorticotropic hormone (ACTH), a 39-amino acid peptide processed in the pituitary from the proopiomelanocortin (POMC) prohormone, is the key mediator of adrenal cor...

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“…This is contrary to our hypothesis that increased adrenal responsiveness in critical illness is associated with increased steroidogenic activity in the adrenal. However, these effects on adrenal gene expression observed in sustained critical illness are presumably the consequence of prolonged ACTH depletion observed in these patients, and are consistent with the adrenal alterations observed in mice lacking POMC, the gene that encodes for the precursor of ACTH (Karpac et al 2008). Taken together, these observations suggest that in acute critical illness associated with an inflammatory response, cytokines and other immunemodulators may be responsible for elevated plasma levels of CORT.…”

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“…Considering the extensive acute and chronic impact of ACTH on the adrenal cortex, persistently low plasma ACTH concentrations could thus also profoundly affect the adrenal cortex. Indeed, lack of ACTH, as occurs in pro-opiomelanocortin (POMC) knock-out mice, causes atrophic and hypofunctional adrenal glands (Coll et al, 2004;Karpac et al, 2008), and POMC-deficiency in human patients is characterized by loss of adrenocortical zonational structure, adrenocortical lipid depletion, reduced ACTH signaling and adrenal atrophy/ failure (Krude and Gruters, 2000).…”

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“…Unfortunately, given the nature of the study, blood samples were not available to correlate the observed changes with plasma ACTH and cortisol concentrations. However, these results are strikingly reminiscent of the phenotype of pro-opiomelanocortin-deficient mice, which suggests that a sustained lack of ACTH-effect on the adrenal cortex may indeed explain these findings (44). These changes in the adrenal cortex of prolonged ICU stay-patients also help to explain the reported 20-fold higher incidence of symptomatic adrenal insufficiency in critically ill patients being treated in the ICU for more than 14 days (45).…”