Elsevier

Nutrition

Volume 16, Issue 10, October 2000, Pages 924-936
Nutrition

Ingestive behavior and obesity
Obesity and cortisol

https://doi.org/10.1016/S0899-9007(00)00422-6Get rights and content

Abstract

Cortisol in obesity is a much-studied problem. Previous information indicates that cortisol secretion is elevated but that circulatory concentrations are normal or low, suggesting that peripheral disappearance rate is elevated. These studies have usually not taken into account the difference between central and peripheral types of obesity. Recent studies using saliva cortisol have indicated that the problem is complex with both high and low secretion of cortisol, perhaps depending on the status of the function of the hypothalamic–pituitary–adrenal gland axis. A significant background factor seems to be environmental stress. The results also suggest that the pattern of cortisol secretion may be important. Other neuroendocrine pathways are also involved, including the central sympathetic nervous system, the gonadal and growth hormone axes, and the leptin system. In concert, these abnormalities seem to be responsible for the abnormal metabolism often seen in central obesity. Several associated polymorphisms of candidate genes may provide a genetic background. Cortisol conversion to inactive metabolites may be a factor increasing central signals to secretion and may add to the increased secretion of cortisol induced by centrally acting factors. Perinatal factors have been found to be involved in the pathogenesis of obesity and its complications. The mechanism involved is not known, but available information suggests that programming of the hypothalamic–pituitary–adrenal axis may be responsible.

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

References (120)

  • L Lapidus et al.

    Obesity, adipose tissue distribution and health in women—results from a population study in Gothenburg, Sweden

    Appetite

    (1989)
  • K Spiegel et al.

    Impact of sleep dept on metabolic and endocrine function

    Lancet

    (1999)
  • B.I Yerevanian et al.

    The influence of weight loss on the dexamethasone suppression test

    Psychiatry Res

    (1984)
  • S.H Kennedy et al.

    Pineal and adrenal function before and after refeeding in anorexia nervosa

    Biol Psychiatry

    (1991)
  • P Doerr et al.

    Relationship between weight gain and hypothalamic pituitary adrenal function in patients with anorexia nervosa

    J Steroid Biochem

    (1980)
  • B Pfohl et al.

    Differences in plasma ACTH and cortisol between depressed patients and normal controls

    Biol Psychiatry

    (1985)
  • R.E Dahl et al.

    24-Hour cortisol measures in adolescents with major depressiona controlled study

    Biol Psychiatry

    (1991)
  • C.R.W Edwards et al.

    Localisation of 11 β -hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid receptor

    Lancet

    (1988)
  • P Naeser

    Effects of adrenalectomy on the obese-hyperglycemic syndrome in mice (gene symbol ob)

    Diabetologia

    (1973)
  • J.J Cunningham et al.

    Hypercorticostenuria and diminished pituitary responsiveness to CRF in obese Zucker rats

    Endocrinology

    (1986)
  • R.L Leibel et al.

    Metabolic and hemodynamic responses to endogenous and exogenous catecholamines in formerly obese subjects

    Am J Physiol

    (1991)
  • M O’Connell et al.

    Experimental obesity in man. III. Adrenocortical function

    J Clin Endocrinol Metab

    (1973)
  • A Galvăo-Teles et al.

    Free cortisol in obesityeffect of fasting

    Acta Endocrinol

    (1976)
  • B.S McEwen

    Protective and damaging effects of stress mediators

    N Engl J Med

    (1998)
  • G.P Chrousos et al.

    The concept of stress and stress system disorders. Overview of physical and behavioral homeostasis

    JAMA

    (1992)
  • J.P Henry

    Biological basis of the stress response

    Integr Physiol Behav Sci

    (1992)
  • M Frankenhaeuser

    The sympathetic-adrenal an pituitary-adrenal response to challengecomparison between the sexes

  • D.E Schteingart et al.

    A comparison of the characteristics of increased adrenocortical function in obesity and in Cushing’s syndrome

    Metabolism

    (1963)
  • P Szenas et al.

    Studies of adrenocortical function in obesity

    J Clin Endocrinol Metab

    (1959)
  • S.S Dunkelman et al.

    Cortisol metabolism in obesity

    J Clin Endocrinol Metab

    (1964)
  • J Posinick et al.

    Adrenocortical function in obese women

    J Clin Endocrinol Metab

    (1956)
  • L.Y Carces et al.

    Cortisol secretion rate during fasting of obese adolescent subjects

    J Clin Endocrinol Metab

    (1968)
  • C.J Migeon et al.

    Study of adrenocortical function in obesity

    Metabolism

    (1963)
  • B.P.E Murphy

    Clinical evaluation of urinary cortisol determinations by competitive protein-binding radioassay

    J Clin Endocrinol Metab

    (1968)
  • D.H.P Streeten et al.

    Diagnosis of hypercortisolismbiochemical criteria differentiating patients from lean and obese normal subjects and from females on oral contraceptives

    J Clin Endocrinol Metab

    (1969)
  • B Simkin

    Urinary 17-ketosteroid and 17-ketogenic steroid excretion in patients

    N Engl J Med

    (1961)
  • P Szenas et al.

    Studies of adrenocortical function in obesity

    J Clin Endocrinol Metab

    (1959)
  • P Mlynaryk et al.

    Cortisol production rates in obesity

    J Clin Endocrinol Metab

    (1962)
  • J.A Prezio et al.

    Influence of body composition on adrenal function in obesity

    J Clin Endocrinol

    (1964)
  • G Jacobson et al.

    Importance of body characteristics in the excretion of 17-ketosteroids and 17 ketogenic steroids in obesity

    N Engl J Med

    (1964)
  • G Copinschi et al.

    Cortisol secretion rate and urinary cortisol excretion in normal and obese subjects

    Acta Endocr (Copenh)

    (1966)
  • A.N Gogate et al.

    Adrenal corticol function in “obesity with pink striae” in the young adult

    J Clin Endocrinol

    (1963)
  • D.E Schteingart et al.

    Characteristics of the increased adrenocorticol function observed in many obese patients

    Ann NY Acad Sci

    (1965)
  • S.A Chalew et al.

    Plasma cortisol levels increase with age in obese subjects

    Obes Res

    (1993)
  • P.M Zelissen et al.

    B-endorphin and adrenocortical function in obesity

    Clin Endocrinol

    (1991)
  • P Szenas et al.

    Studies of adrenocortical function in obesity

    J Clin Endocrinol

    (1959)
  • S.A Lottenberg et al.

    Effect of fat distribution on the pharmacokinetics of cortisol in obesity

    Int J Clin Pharmal Ther

    (1998)
  • P Björntorp

    Visceral obesitya “civilization syndrome

    ” Obes Res

    (1993)
  • D.H Streeten et al.

    The diagnosis of hypercortisolismbiochemical criteria differentiating patients from lean and obese normal subjects and from females on oral contraceptives

    J Clin Endocrinol

    (1969)
  • R Pasquali et al.

    The hypothalamic-pituitary-adrenal axis in obese women with different patterns of body fat distribution

    J Clin Endocrinol Metab

    (1993)
  • Cited by (484)

    View all citing articles on Scopus
    View full text