Cortisol and its action on the glucocorticoid receptor in malnutrition
and acute infection
Mark J. Manary
a,
4
, Louis J. Muglia
a
, Sherri K. Vogt
a
, Kevin E. Yarasheski
b
a
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
b
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Received 10 May 2005; accepted 16 November 2005
Abstract
Severe malnutrition alone is believed to cause hypercortisolemia. Cortisol’s effects are mediated through the glucocorticoid receptor,
which binds the hormone in the cytosol, translocates to the nucleus, and promotes gene transcription. This observational study in marasmic
children with and without acute infection tested the hypothesis that marasmus is associated with hypercortisolemia, less glucocorticoid
receptor, and less receptor translocation to the nucleus. Twenty-eight Malawian children participated; 14 with marasmus and infection, 6 with
marasmus without infection, and 8 well nourished with infection. Free serum cortisol, interleukin 6 and tumor necrosis factor a, leucine
derived from whole-body proteolysis, and the amount of whole-cell and nuclear leukocyte glucocorticoid receptor were measured upon
admission. Free serum cortisol concentration was increased in marasmic and well-nourished children with infection compared with
uninfected children with marasmus (14.2 [8.5, 16.3], 24.4 [15.0, 39.2], 5.1 [3.5, 7.0] lg/L, median [25th, 75th percentiles]; P b .05 by
Kruskal-Wallis test). The amount of whole-cell leukocyte glucocorticoid receptor was similar in all children (0.48 F 0.33 signal units), but
the amount in the nucleus was greatest in marasmic children with infection, followed by the amount in uninfected marasmic children, and
then in well-nourished infected children (0.54 F 0.58, 0.19 F 0.13, 0.02 F 0.5 signal units [mean F SD]; P b .05 for all comparisons by
analysis of variance). These findings suggest that hypercortisolemia is not associated with malnutrition alone, but does occur appropriately
with acute infection. The increased nuclear glucocorticoid receptor abundance in marasmus demonstrates that nutritional status modulates
glucocorticoid receptor action by mechanisms in addition to circulating glucocorticoid concentrations.
D 2006 Elsevier Inc. All rights reserved.
1. Introduction
Cortisol production is believed to be increased in
marasmus [1]. The data that support this notion come from
marasmic children in whom serum cortisol was promptly
measured at the time of hospital admission, and these
measurements were then compared with a control popula-
tion [2-4]. In addition, a longitudinal community study of
serum cortisol measurements in a population at risk for
developing malnutrition found that cortisol gradually
increased in conjunction with decreasing serum albumin,
suggesting that nutritional status alone can modulate cortisol
production [5].
Cortisol plays an important role in promoting the
appropriate response to acute infection in the well-nourished
host. Low serum cortisol in patients with septic shock is
common and associated with a poor outcome [6]. The use of
supplemental corticosteroids has improved clinical out-
comes in such patients [7]. Cortisol promotes muscle pro-
teolysis and hepatic protein synthesis [8]. These metabolic
effects enhance the acute-phase response, an essential
component of the successful host response to infection.
These protein metabolic and acute-phase responses to acute
infection are blunted in marasmic children [9,10].
Cortisol exerts its acute effect via the glucocorticoid
receptor, which exists as a large heteromeric complex in the
cytosol [11]. The receptor, upon binding with cortisol,
dissociates from other proteins, undergoes phosphorylation,
and translocates to the nucleus. The cortisol/receptor
complex can then bind to specific DNA sequences and, in
conjunction with coactivators, promote transcription of
0026-0495/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.metabol.2005.11.009
4 Corresponding author. Tel.:+1 1314 454 2178; fax: +1 1314 454
4345.
E-mail address: manary@kids.wustl.edu (M.J. Manary).
Metabolism Clinical and Experimental 55 (2006) 550 – 554
www.elsevier.com/locate/metabol