Plasma concentrations of adipocyte fatty acid binding protein in patients with Cushing's syndrome.

Abstract

Serum adipocyte fatty acid-binding protein (FABP-4) concentrations are linked to human obesity and other features of metabolic syndrome. Patients with Cushing´s syndrome (CS) develop numerous features of metabolic syndrome due to chronic cortisol excess. Here we tested the hypothesis that chronically increased cortisol levels in CS patients may alter circulating levels of FABP-4. Fourteen patients with CS, 19 patients with simple obesity (OB) and 36 healthy control subjects (C) were included in the study. Serum FABP-4 concentrations were significantly higher in both CS and OB patients relative to C group, but they did not differ between CS and OB groups. In a combined population of all groups, serum FABP-4 levels correlated positively with BMI, body fat content, serum glucose, triglycerides, HbA1c and HOMA index and were inversely related to HDL-cholesterol, resting energy expenditure and freeT3 levels. We conclude that FABP-4 levels are significantly increased in both patients with simple obesity and obese patients with Cushing´s syndrome. We suggest that increased FABP-4 concentrations in CS patients are rather due to their excessive fat accumulation and related metabolic abnormalities than due to a direct effect of cortisol on FABP-4 production.

Full text

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Plasma concentrations of adipocyte fatty acid binding protein in patients with
Cushing's syndrome

Viktória Ďurovcová 1, Josef Marek 1, Václav Hána 1, Martin Matoulek 1, Vít Zikán 1,
Denisa Haluzíková 1, 2, Petra Kaválková 1, Zdena Lacinová 1, Michal Kršek 1, Martin
Haluzík 1
1 3rd Department of Medicine, 2 Department of Sports Medicine, 1st Faculty of Medicine,
Charles University and General University Hospital, Prague, Czech Republic

Corresponding author:
Prof. Martin Haluzik, MD, DSc.
3rd Department of Medicine
1st Faculty of Medicine, Charles University
General University Hospital
U Nemocnice 1
128 00 Prague 2
Czech Republic
E-mail: mhalu@lf1.cuni.cz
Fax number: +420 224919780

Short title: Adipocyte fatty acid binding protein 4 in Cushing's syndrome

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Summary:
Serum adipocyte fatty acid-binding protein (FABP-4) concentrations are linked to
human obesity and other features of metabolic syndrome. Patients with Cushing´s
syndrome (CS) develop numerous features of metabolic syndrome due to chronic cortisol
excess. Here we tested the hypothesis that chronically increased cortisol levels in CS
patients may alter circulating levels of FABP-4.
14 patients with CS, 19 patients with simple obesity (OB) and 36 healthy control
subjects (C) were included in the study. Serum FABP-4 concentrations were significantly
higher in both CS and OB patients relative to C group but they did not differ between CS
and OB groups. In a combined population of all groups, serum FABP-4 levels positively
correlated with BMI, body fat content, serum glucose, triglycerides, HbA1c and HOMA
index and were inversely related to HDL-cholesterol, resting energy expenditure and
freeT3 levels.
We conclude that FABP-4 levels are significantly increased in both patients with
simple obesity and obese patients with Cushing´s syndrome. We suggest that increased
FABP-4 concentrations in CS patients are rather due to their excessive fat accumulation
and related metabolic abnormalities than due to a direct effect of cortisol on FABP-4
production.

Key words: Adipocyte fatty acid binding protein 4, hypercortisolism, obesity

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INTRODUCTION
Cytoplasmic fatty acid binding proteins (FABPs) are a family of proteins that
have an important role in fatty acids shuttling to cellular compartments, modulation of
intracellular lipid metabolism and regulation of gene expression (Binas et al. 1999; Levy
et al. 2001; Wolfrum et al. 2001, Chmurzynska 2006). They are expressed in various
tissues, including fat, and play an important role not only in lipid metabolism, but also in
other metabolic regulations (Coe and Bernlohr 1998, Hertzel and Bernlohr 2000, Boord
et al. 2002, Chmurzynska 2006). Adipocyte fatty acid-binding proteins belong to the
most abundant proteins in mature adipocytes (Makowski and Hotamisligil 2004). Recent
clinical studies have shown that FABP-4, produced primarily by adipocytes, is released
into the circulation suggesting its possible systemic effects (Karpisek et al. 2007; Stejskal
and Karpisek 2006; Xu et al. 2007; Xu et al. 2006).
It has been demonstrated that FABP-4 concentrations are increased in patients
with obesity and/or metabolic syndrome and may represent a novel marker of this clinical
entity (Karpisek et al. 2007; Stejskal and Karpisek 2006; Xu et al. 2006). Circulating
levels of FABP-4 are strongly positively linked to BMI, blood glucose and glycated
hemoglobin levels in patients with type 2 diabetes mellitus and have an inverse
relationship to the parameters of insulin sensitivity measured by isoglycemic-
hyperinsulinemic clamp (Haluzik et al. 2009). On the other hand, experimental studies
have shown that both the knockout of adipocyte fatty acid-binding protein gene or its
inhibition by a small molecule inhibitor improved insulin sensitivity and atherosclerosis
in mice (Maeda et al. 2005, Furuhashi et al. 2007).

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Cushing’s syndrome, a disease caused by chronic cortisol excess, is
commonly accompanied by numerous features of metabolic syndrome such as
development of insulin resistance, type 2 diabetes mellitus, dyslipidemia and arterial
hypertension. Here we tested the hypothesis that chronically increased cortisol levels
in patients with Cushing's syndrome may alter circulating levels of FABP-4. Such
alterations could in turn contribute to the metabolic disturbances seen in these
patients. To analyze the possible influence of concomitant obesity and related metabolic
abnormalities present in patients with Cushing´s syndrome, we compared FABP-4
concentrations in these patients with both lean healthy control subjects and patients with
obesity and type 2 diabetes mellitus.
METHODS

Study subjects

Fourteen patients with active Cushing's syndrome (12 women, 2 men, age:
45.8 ± 3.39 yrs, body mass index (BMI): 33.7 ± 1.42 kg/m2), nineteen obese patients
(17 women, 2 men, age: 54.6 ± 3.3 yrs, BMI: 45.8 ± 2.42 kg/m2) and thirty six healthy
controls (28 women, 8 men, age: 43 ± 2.07 yrs, BMI: 22.7 ± 0.26 kg/m2) were included in
the study.
The diagnosis of Cushing's syndrome (CS) was based on clinical status,
diminished circadian rhythm of cortisolaemia (nocturnal cortisol over 150 nmol/l),
unsuppressed cortisolaemia in 1 mg Dexamethasone test (cortisol over 86 nmol/l) and
increased free urinary cortisol excretion (urinary free cortisol over 500 nmol/day). All

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patients had clinical signs of abdominal fat accumulation as measured by increased waist
circumference. All 14 patients with CS had arterial hypertension, 12 of them had been
already treated pharmacologically, 11 of them with a combination of antihypertensive
drugs (with ACE inhibitors or sartans in 10 cases, calcium channel blockers in 6 cases,
beta-blockers in 8 cases, diuretics in 7 cases, imidazoline receptor antagonist in 1 case
and an alpha-blocker in 1 case). Twelve patients had disturbances in serum lipid spectrum
(10 patients had elevated total and LDL (low density lipoprotein) cholesterol levels, in 7
cases together with elevated triglycerides, in 3 patients also with decreased HDL (high
density lipoprotein) cholesterol levels; 2 patients had only elevated triglycerides and
decreased HDL cholesterol serum concentrations). One patient had been already treated
with a combination of statin and fibrate. One patient was diagnosed with impaired
glucose tolerance (IGT), nine patients with type 2 diabetes mellitus (DM) - four of them
had been already treated, three with antidiabetic drugs (PAD; metformin in 2 cases,
gliclazide in 1 case), one with a combination of PAD (metformin) and insulin. They
had had no history of renal or vascular complications.
The group of patients with obesity (OB) was characterized by BMI > 30 kg/m2.
Sixteen out of nineteen patients in this group had arterial hypertension, all had been
already on antihypertensive treatment, thirteen of them on a combination of
antihypertensive drugs (ACE inhibitors or sartans in 14 cases, calcium channel blockers
in 4 cases, beta-blockers in 10 cases, diuretics in 11 cases and imidazoline receptor
antagonist in 3 cases). Fifteen out of nineteen patients had pathological serum lipid
spectrum (10 patients had elevated total and LDL cholesterol levels, in 2 cases together
with elevated triglycerides and decreased HDL cholesterol, in 5 cases only with HDL