ABSTRACT
Abdominal obesity seems to be associated with a moderately deranged feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis where central glucocorticoid receptors (GR) are involved. Therefore, functions of central and peripheral GR were compared in this study. Furthermore, since trinucleotide repeats in early exons of steroid hormone receptor genes influence transcription, and therefore may influence receptor density, this was also studied. Ten middle-aged men, 5 with abdominal obesity and 5 controls, were studied. The suppression of dexamethasone (dex) on serum cortisol was used in dose-response tests to assess the function of central GR. Abdominal adipose tissue biopsies were incubated and exposed to cortisol in different concentrations, and the function of the peripheral GR assayed as induction of lipoprotein lipase (LPL) activity. Aberrant expansion of exonic trinucleotide repeats in the first coding exon of the GR gene was studied by sequencing of genomic DNA. Results showed that men with abdominal obesity showed less inhibition of serum cortisol by dex, particularly at lower concentrations, while in the controls cortisol secretion was inhibited in an apparent dose-response manner. LPL activity in adipose tissue was lower in abdominal obese men than in controls. However, the sensitivity to cortisol was not different between the groups. There was no evidence for expansion of trinucleotide repeats. These results suggest that the central GR and the peripheral GR in adipose tissue exhibit functional differences in abdominal obesity.
Subject(s)
Body Constitution , Obesity/physiopathology , Receptors, Glucocorticoid/physiology , Abdomen , Adipose Tissue/enzymology , Body Mass Index , Dexamethasone , Glucocorticoids , Humans , Hydrocortisone/blood , Hydrocortisone/pharmacology , Lipoprotein Lipase/metabolism , Male , Middle Aged , Receptors, Glucocorticoid/genetics , Repetitive Sequences, Nucleic Acid , Sequence Analysis, DNAABSTRACT
OBJECTIVE: To investigate the effects of a selective serotonin reuptake inhibitor (SSRI) on the neuroendocrine and autonomic nervous system perturbations found in abdominal obesity. DESIGN: Treatment for 6 months with citalopram and for 6 months with placebo using a double-blind, cross-over design, with a 2-month wash-out period between treatment periods. SUBJECTS: Sixteen healthy men, 45-60 years, moderately obese and with an abdominal fat distribution. MEASUREMENTS: Anthropometry, three different depression rating scales, serum lipids, testosterone, IGF-I, oral glucose tolerance test (OGTT), pituitary stimulation with corticotropin releasing hormone (CRH), arithmetic stress test, and excretion of cortisol and metoxycatecholamines in urine, collected during 24 h. RESULTS: Cortisol concentrations in the morning were low before treatment, indicating a perturbed function of the hypothalamic-pituitary-adrenal (HPA) axis. After treatment with citalopram morning cortisol concentrations rose to normal. Cortisol concentrations after stimulation with CRH or stress were elevated by citalopram treatment, but urinary cortisol excretion was unchanged. The glucose concentrations after OGTT (120 min) tended to be reduced, with unchanged insulin concentrations, whilst other metabolic values did not change during treatment. Heart rate after administration of CRH, and during laboratory stress test, decreased by treatment with citalopram. Diurnal urinary excretion of metoxycatecholamines tended to decrease. Neither body mass index nor waist/hip circumference ratio decreased. Depression scores were within normal limits before treatment and did not change. CONCLUSION: The results of this pilot study indicate improvements in the regulation of neuroendocrine-autonomic systems as well as metabolism in abdominal obesity during treatment with an SSRI.
Subject(s)
Body Constitution , Citalopram/therapeutic use , Obesity/drug therapy , Selective Serotonin Reuptake Inhibitors/therapeutic use , Body Constitution/physiology , Catecholamines/urine , Citalopram/adverse effects , Cross-Over Studies , Double-Blind Method , Glucose Tolerance Test , Humans , Hydrocortisone/blood , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/physiopathology , Insulin/blood , Male , Middle Aged , Obesity/physiopathology , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/physiopathology , Selective Serotonin Reuptake Inhibitors/adverse effects , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/physiopathologyABSTRACT
Eleven moderately obese women, aged 46-62 years, with a body mass index of 29-34 and with borderline hypertension (repeated diastolic blood pressure greater than 90 mmHg) fasted for 48 hours. Before the fast and after 48 hours of fasting, plasma noradrenaline, urinary noradrenaline, urine potassium, urine sodium and weight were measured. In six of the patients muscle nerve sympathetic activity was recorded from the peroneal nerve by tungsten microelectrodes for 15 min each time. The efferent muscle sympathetic activity (MSA) was expressed as the number of bursts/min. The recordings were done before the fast and after 48 hours of fasting. We found significant decreases in body weight from 88.4 +/- 2.5 kg to 86.4 +/- 2.5 kg. Systolic blood pressure (BP) was reduced from 158 +/- 3 mmHg to 146 +/- 5 mmHg (p less than 0.001) and diastolic BP from 96 +/- 3 mmHg to 89 +/- 3 mmHg (p less than 0.01) during the fast. MSA was significantly increased from 42.0 +/- 5.5 bursts/min to 44.5 +/- 5.8 (n = 6), while plasma and urine noradrenaline concentrations (n = 11) showed a non-significant tendency to increase. We conclude that the hypotensive response during the first days of extensive caloric reduction is not due to a decreased sympathetic activity. If anything, there may be weak increase of efferent sympathetic nerve activity and venous plasma levels of circulating noradrenaline. The mechanisms behind the acute hypotensive response to negative caloric balance are thus still unclear, but obviously different from long-term adaptation of the blood pressure.
