Glucocorticoids, chronic stress, and obesity

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Abstract

Glucocorticoids either inhibit or sensitize stress-induced activity in the hypothalamo-pituitary-adrenal (HPA) axis, depending on time after their administration, the concentration of the steroids, and whether there is a concurrent stressor input. When there are high glucocorticoids together with a chronic stressor, the steroids act in brain in a feed-forward fashion to recruit a stress-response network that biases ongoing autonomic, neuroendocrine, and behavioral outflow as well as responses to novel stressors. We review evidence for the role of glucocorticoids in activating the central stress-response network, and for mediation of this network by corticotropin-releasing factor (CRF). We briefly review the effects of CRF and its receptor antagonists on motor outflows in rodents, and examine the effects of glucocorticoids and CRF on monoaminergic neurons in brain. Corticosteroids stimulate behaviors that are mediated by dopaminergic mesolimbic “reward” pathways, and increase palatable feeding in rats. Moreover, in the absence of corticosteroids, the typical deficits in adrenalectomized rats are normalized by providing sucrose solutions to drink, suggesting that there is, in addition to the feed-forward action of glucocorticoids on brain, also a feedback action that is based on metabolic well being. Finally, we briefly discuss the problems with this network that normally serves to aid in responses to chronic stress, in our current overindulged, and underexercised society.

Section snippets

Chronic glucocorticoid actions without a concurrent stressor

Probably the best recognized action of glucocorticoids on the HPA axis is strong reduction for the abolition of activity in the system. Chronic treatment with glucocorticoid in the absence of ongoing stress exerts marked feedback effects and is the basis for the well-accepted model of autoregulation in the system. People with diseases, such as severe asthma, or other autoimmune diseases as well as recipients of organ transplants are treated for prolonged periods with exogenous glucocorticoids,

The central stress response network

It now seems unambiguous that, after the action of elevated glucocorticoids and stress, endogenous CRF networks initiate and recruit the activation of the neural networks that promote the changes from normal in behaviors, autonomic neural activity and neuroendocrine responses, that are characteristic of organisms undergoing a period of chronic stress. Extrahypothalamic CRF neuronal cell groups are found throughout the brain: in the central nucleus of the amygdala, Barrington's nucleus, bed

The downside of the chronic stress response

Although the glucocorticoids appear to make animals and humans more fit to handle stressors, both acute and chronic, through their metabolic actions and multiple effects on the response networks in brain, in our current society there are roadblocks to allowing the normal long-term and life-saving actions to occur (see, e.g., Dallman et al., 2004, Dallman et al., 2005). The incidence of chronic social stress is increased, high calorie palatable foods are readily available and the physical effort

References (373)

  • B. Balkan et al.

    Overfeeding-induced obesity in rats: Insulin sensitivity and autonomic regulation of metabolism

    Metabolism

    (1993)
  • R.N. Bergman et al.

    Free fatty acids and pathogenesis of type 2 diabetes mellitus

    Trends Endocrinol. Metab.

    (2000)
  • A. Bhargava et al.

    Long double-stranded RNA-mediated RNA interference as a tool to achieve site-specific silencing of hypothalamic neuropeptides

    Brain Res. Brain Res. Protoc.

    (2004)
  • S. Bhatnagar et al.

    Neuroanatomical basis for facilitation of hypothalamic-pitutiary-adrenal responses to a novel stressor after chronic stress

    Neuroscience

    (1998)
  • S. Bhatnagar et al.

    Neuroanatomical basis for facilitation of hypothalamic-pituitary-adrenal responses to a novel stressor after chronic stress

    Neuroscience

    (1998)
  • S. Bhatnagar et al.

    Neuroanatomical basis for facilitation of the hypothalamo-pituitary-adrenal responses to a novel stress after chronic stress

    Neuroscience

    (1998)
  • S. Bhatnagar et al.

    The paraventricular nucleus of the thalamus alters rhythms in core temperature and energy balance in a state-dependent manner

    Brain Res.

    (1999)
  • G.A. Bray et al.

    Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity

    Am. J. Clin. Nutr.

    (2004)
  • D.R. Britton et al.

    Intraventricular corticotropin-releasing factor enhances behavioral effects of novelty

    Life Sci.

    (1982)
  • K.T. Britton et al.

    Corticotropin releasing factor (CRF) receptor antagonist blocks activating and ‘anxiogenic’ actions of CRF in the rat

    Brain Res.

    (1986)
  • K.T. Britton et al.

    Corticotropin-releasing factor (CRF) receptor antagonist blocks activating and ‘anxiogenic’ actions of CRF in the rat

    Brain Res.

    (1986)
  • A.W. Bruijnzeel et al.

    Stress-induced sensitization of CRH-ir but not P-CREB-ir responsivity in the rat central nervous system

    Brain Res.

    (2001)
  • M. Bubser et al.

    Thalamic paraventricular nucleus neurons collateralize to innervate the prefrontal cortex and nucleus accumbens

    Brain Res.

    (1998)
  • I.J. Bujalska et al.

    Does central obesity reflect “Cushing's disease of the omentum”?

    Lancet

    (1997)
  • B. Buwalda et al.

    Physiological and behavioral effects of chronic intracerebroventricular infusion of corticotropin-releasing factor in the rat

    Psychoneuroendocrinology

    (1997)
  • B. Buwalda et al.

    Temporal and spatial dynamics of corticosteroid receptor down-regulation in rat brain following social defeat

    Physiol. Behav.

    (2001)
  • G.A. Carrasco et al.

    Neuroendocrine pharmacology of stress

    Eur. J. Pharmacol.

    (2003)
  • S. Chen et al.

    Afferent connections of the thalamic paraventricular and parataenial nuclei in the rat. A retrograde tracing study with iontophoretic application of fluorogold

    Brain Res.

    (1990)
  • F. Cirulli et al.

    Differential influence of corticosterone and dexamethasone on schedule-induced polydipsia in adrenalectomized rats

    Behav. Brain Res.

    (1994)
  • B.J. Cole et al.

    Central administration of a CRF antagonist blocks the development of stress-induced behavioral sensitization

    Brain Res.

    (1990)
  • C.J. Cook

    Measuring of extracellular cortisol and corticotropin-releasing hormone in the amygdala using immunosensor coupled microdialysis

    J. Neurosci. Meth.

    (2001)
  • C.J. Cook

    Glucocorticoid feedback increases the sensitivity of the limbic system to stress

    Physiol. Behav.

    (2002)
  • C.J. Cook

    Stress induces CRF release in the paraventricular nucleus, and both CRF and GABA release in the amygdala

    Physiol. Behav.

    (2004)
  • G. Croiset et al.

    Role of corticotropin-releasing factor, vasopressin and the autonomic nervous system in learning and memory

    Eur. J. Pharmacol.

    (2000)
  • M.F. Dallman

    Stress update. Adaptations of the hypothalamic-pituitary-adrenal axis to chronic stress

    Trends Endocrinol. Metab.

    (1993)
  • M.F. Dallman

    A spoon of sugar: feedback signals of energy stores and corticosterone regulate responses to chronic stress

    Physiol. Behav.

    (2003)
  • M.F. Dallman

    Fast glucocorticoid actions on brain: back to the future

    Front. Neuroendocrinol.

    (2005)
  • M.F. Dallman et al.

    Feast and famine: critical role of glucocorticoids with insulin in daily energy flow

    Front. Neuroendocrinol.

    (1993)
  • S.F. Akana et al.

    Reset of feedback in the adrenocortical system: an apparent shift in sensitivity of adrenocorticotropin to inhibition by corticosterone between morning and evening

    Endocrinology

    (1986)
  • S.F. Akana et al.

    Corticosterone: narrow range required for normal body and thymus weight and ACTH

    Am. J. Physiol.

    (1985)
  • S.F. Akana et al.

    Feedback and facilitation in the adrenocortical system: unmasking facilitation by partial inhibition of the glucocorticoid response to prior stress

    Endocrinology

    (1992)
  • S.F. Akana et al.

    Chronic cold in adrenalectomized, corticosterone (B)-treated rats: facilitated corticotropin responses to acute stress emerge as B increases

    Endocrinology

    (1997)
  • S.F. Akana et al.

    Clamped corticosterone (B) reveals the effect of endogenous B on both facilitated responsivity to acute restraint and metabolic responses to chronic stress

    Stress

    (1996)
  • S. Akana et al.

    Feedback sensitivity of the rat hypothalamo-pituitary-adrenal axis and its capacity to adjust to exogenous corticosterone

    Endocrinology

    (1992)
  • D.S. Albeck et al.

    Chronic social stress alters levels of corticotropin-releasing factor and arginine vasopressin mRNA in rat brain

    J. Neurosci.

    (1997)
  • L. Arborelius et al.

    Chronic administration of the selective corticotropin-releasing factor 1 receptor antagonist CP-154-256: behavioral, endocrine and neurochemical effects in the rat

    J. Pharmacol. Exp. Therapeut.

    (2000)
  • A.G. Arvantis et al.

    Non-peptide corticotropin-releasing hormone antagonists: syntheses and structure-activity relationships of 2-anilinopyrimidines and -triazines

    J. Med. Chem.

    (1999)
  • G. Aston-Jones et al.

    An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance

    Annu. Rev. Neurosci.

    (2005)
  • E.C. Azmitia et al.

    Corticosterone regulation of tryptophan hydroxylase in midbrain of rat

    Science

    (1969)
  • V.P. Bakshi et al.

    Reduction of stress-induced behavior by antagonism of corticotropin-releasing hormone 2 (CRH2) receptors in lateral septum, or CRH1 receptors in amygdala

    J. Neurosci.

    (2002)
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    Preparation of this article and many of the experiments discussed were supported, in part, by NIH grants DK 28172 and DA 16944

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