Ingestive behavior and obesityObesity and cortisol
Introduction
Certain cases of obesity have clear clinical features of hypercortisolism, including a central fat distribution of excess body-fat mass, sometimes with a tendency to a “Buffalo hump,” elevated blood pressure, insulin resistance with impaired glucose tolerance, and dyslipidemia. This has led many researchers to investigate the possibility of whether human obesity is in fact a hypercortisolemic condition. Since the beginning of the Medline register in 1966, no fewer than 730 publications have been found under the combined search words cortisol and obesity, amounting to 294 during the past decade. These numbers by themselves indicate both the profound interest and importance of the subject and that a consensus on potential abnormalities does not exist.
Therefore, we have attempted to review the literature and compare previous and more recent results with methods that seem more adequate than those used previously for the examination of this complex problem. As apparent from the large numbers of publications, all cannot be included. Therefore, the ambition has been to select publications that seem particularly informative by using sound methodology on a reasonable number of subjects. Animal work has been excluded because the relevance of animal models for human obesity is uncertain. Only when mechanistic studies are referred to, difficult or impossible to perform in humans, has animal work been cited.
Section snippets
Background
The reason for most studies of cortisol secretion in human obesity has probably been the similarities between hypercortisolemic states and certain patients with obesity. Another probable reason is that several animal models of obesity have been characterized by increased secretion of glucocorticoids. This is the case with the ob/ob mouse, and the syndrome can be in essence reversed by adrenalectomy.1 Another well-known rodent model, the Zucker rat, shows similar characteristics.2 It seems
Regulation of the HPA axis
Cortisol secretion is regulated by hypothalamic centers that receive stimulatory signals from the central nervous system. These signals are modified by adrenergic, dopaminergic, and serotoninergic systems and other central factors in a complicated system that is only partly understood.7 The regulatory, central events result in a characteristic diurnal profile of cortisol secretion with high activity in the early morning hours and low activity in the afternoon and evening. Superimposed on this
Recent studies using a different approach to the problem
The studies reviewed in the preceding sections were performed on obese populations in comparisons with controls. Often conventional methods have been used, designed mainly for diagnosis of severe hypercortisolemic states such as Cushing’s syndrome. It seems possible that such methods are not sensitive and discriminating enough to allow detection of mild functional problems in the regulation of the HPA axis. Furthermore, obesity is a slowly developing disease and potential involvement of
Relation between HPA-axis activity and obesity and associated variables
The characteristics of HPA-axis activity were compared with measurements of obesity variables (body mass index, BMI; waist-to-hip circumference ratio, WHR; and sagittal abdominal diameter, a surrogate measurement of visceral fat mass),52 other endocrine factors (testosterone and insulinlike growth factor-I, a surrogate measurement of growth hormone secretion), metabolic variables (fasting glucose, insulin, triacylglycerol, and total, low-, and high-density lipoprotein, cholesterol), and
Comparisons with work in experimental animals
Most of controlled stress research has been performed in experimental animals because similar studies are often difficult to perform in humans. Comparisons with the results of controlled experiments suggest the mechanisms involved in human studies.
The observed abnormalities in the subgroups of HPA-axis function may be considered to consist of different stages, in analogy with findings in prospective experimental work in animals. In these animals studies, a normal stress reaction was found to
The HPA axis
Detailed information concerning the phylogenetic expression of the syndrome studied has allowed us to investigate potential genetic factors by using the candidate gene approach with the technique of restriction fragment-length polymorphism. A first target was the GR gene locus. As reported previously,81, 82, 83 we found that the polymorphism, localized to the first intron of the GR gene, discoverable with the restriction enzyme Bcl I, is associated with abdominal obesity, insulin resistance,
Cortisol metabolism
Cortisol secreted from the adrenals is exposed to enzymic transformations in peripheral target cells. The enzymes involved are the 11-β-hydroxysteroid dehydrogenases (11β-HSD), which transfer cortisol to the less active cortisone (enzyme 2) or cortisone to cortisol (enzyme 1).94 11β-HSD2 was originally thought to protect certain tissues from excess cortisol exposure from the mineralocorticoid receptor, particularly in the kidney,95 but has subsequently been found in a number of other tissues,
Is the increased cortisol secretion in obesity from central or from peripheral factors?
The question then remains as to how critical cortisol is in human obesity. There seems to be two prevailing theories, one suggesting that the perturbations of cortisol secretion is of central origin and another where peripheral cortisol metabolism is the primary factor. There is clearly evidence for both, and an attempt will be made to weigh the arguments for one against the other and examine the potential likelihood of their involvement as primary or secondary events in obesity.
The first
General summary
Cortisol secretion in obesity has attracted considerable attention, and a great number of publications are available. The interest has probably derived from the fact that most animal models of obesity display an increased cortisol secretion and are cured by adrenalectomy. Furthermore, clinicians are aware that certain obese patients have a Cushingoid appearance.
Previous studies in general have shown an increased cortisol secretion and an elevated peripheral fractional turnover rate, resulting
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