Stress system function in abdominal obesity. The hypothalamic-pituitary-adrenal axis and the sympathetic nervous system in middle-aged men

Abstract

Background: There is a strong relationship between central (abdominal, visceral) obesity, impaired glucose tolerance, insulin resistance, dyslipidemia and elevated blood pressure. These abnormalities are included in the term Metabolic Syndrome, and indicate an elevated risk for cardiovascular disease and diabetes type 2. Although obesity per se is considered to be a major health hazard, a predominance of abdominal distribution of adipose tissue has shown a higher predictive power for various forms of health problems. Aims: The objective of these studies was to further elucidate the neuroendocrine perturbations found in abdominal obesity.Subjects and Methods: Healthy, middle-aged men with varying body fat distribution were examined. Dexamethasone (dex) suppression tests, using different dexamethasone doses, were performed and the activity of lipoprotein lipase (LPL) in adipose tissue was studied, exposing the tissue for cortisol in a dose-response manner. The men underwent oral glucose tolerance test (OGTT), stimulation with corticotropin releasing hormone (CRH) and arithmetic stress test. Furthermore, diurnal concentrations of adrenocorticotropic hormone (ACTH), cortisol and growth hormone (GH) were measured. Some of the abdominally obese men were treated for six months with the selective serotonin reuptake inhibitor (SSRI) citalopram and for six months with placebo using a double-blind, cross-over design, with a two months wash-out period between treatment periods.Results: Men with abdominal obesity showed less inhibition of serum cortisol by dex, and LPL activity in adipose tissue was blunted, compared to controls. Men with a high waist/hip circumference ratio (WHR), in comparisons with men with a low WHR but similar body mass index (BMI), had higher insulin, glucose and triglyceride concentrations in the basal state and higher glucose and insulin concentrations during OGTT. They also had elevated diurnal ACTH values but similar cortisol values, except lower cortisol values in the morning. Diurnal growth hormone concentrations showed reduced peak size. Stimulation of the HPA axis with CRH and acute laboratory stress showed no difference in ACTH concentrations, but cortisol concentrations were lower in men with high WHR. Men with a high WHR also had elevated pulse pressure and heart rate in the basal state and after challenges by CRH and acute laboratory stress. Furthermore, men with a high WHR had increased 24 h urinary excretion of catecholamine metabolites. After treatment with citalopram morning cortisol rose to normal. Cortisol concentrations after stimulation with CRH or stress were elevated by citalopram treatment but urinary cortisol excretion was unchanged. Glucose concentrations during OGTT were reduced, with unchanged insulin concentrations, while other metabolic values did not change during treatment. Heart rate, in the basal state and after administration of CRH or during laboratory stress test, and diurnal urinary excretion of metoxycatecholamines, decreased by citalopram treatment. Neither BMI nor WHR decreased. Depression scores were within normal limits before treatment and did not change.Conclusions: Visceral obesity is associated with not only aberrations in the HPA axis, but also in the sympathetic nervous system. These neuroendocrine abnormalities, which act in concert, are most likely the origin of the increased risk for disease in visceral obesity, and are reminiscent of those seen in mental depression. SSRI might be a useful tool in the treatment of the metabolic syndrome.