Download PDF
Horm Metab Res 2007; 39(6): 430-438
DOI: 10.1055/s-2007-981462
Review

© Georg Thieme Verlag KG Stuttgart · New York

Stress Mechanisms and Metabolic Complications

I. Kyrou 1 , C. Tsigos 1
  • 1Endocrinology, Metabolism and Diabetes Unit, Evgenidion Hospital, Athens University Medical School, Athens, Greece
Further Information

Publication History

received 4.12.2006

accepted 29.1.2007

Publication Date:
18 June 2007 (online)

Also available at
    Permissions and Reprints

Abstract

Stress can be defined as a state of threatened homeostasis or disharmony. An intricate repertoire of physiologic and behavioral responses is mobilized under stressful situations forming the adaptive stress response that aims to reestablish the challenged body equilibrium. The hypothalamic-pituitary-adrenal axis and the central and peripheral components of the autonomic nervous system constitute the two main pillars that subserve the vital functions of the stress system. Chronic stress represents a prolonged threat to homeostasis that can progressively lead to a deleterious overload with various complications caused by both the persistent stressor and the detrimental prolongation of the adaptive response. Recent data indicate that chronic stress is associated to derangement of metabolic homeostasis that contributes to the clinical presentation of visceral obesity, type 2 diabetes, atherosclerosis and metabolic syndrome. Notably, indices of stress in the modern western societies correlate with the increasing incidence of both obesity and the metabolic syndrome which have reached epidemic proportions over the past decades. The pathogenetic mechanisms that accommodate these correlations implicate primarily the chronic hyperactivation of the HPA axis under prolonged stress, which favors accumulation of visceral fat, and vice versa; obesity constitutes a chronic stressful state that may cause HPA axis dysfunction. In addition, obesity is being now recognized as a systemic low grade inflammatory state that contributes to the derangement of the metabolic equilibrium, implicating the adipocyte secretion of adipokines to the pathogenesis of several components of the metabolic syndrome. Understanding the mechanisms that mediate the documented reciprocal relationships between stress and metabolic homeostasis will hopefully provide novel insights to the pathophysiology of obesity, type 2 diabetes, and their cardiometabolic complications, and will help the quest for more specific and effective therapeutic interventions.

Key words

Stress - glucocorticoids - cytokines - obesity - metabolic syndrome - inflammation - depression

References

  • 1 Chrousos GP, Gold PW. The concepts of stress system disorders: Overview of behavioral and physical homeostasis.  JAMA. 1992;  267 1244-1252
    CrossrefPubMedGoogle Scholar
  • 2 Tsigos C, Kyrou I, Chrousos GP. Stress, endocrine manifestations, and diseases. In: Cooper CL. (ed.) Handbook of Stress, Medicine, and Health. 2nd Edition Boca Raton FL: CRC Press 2005: 101-131
    Google Scholar
  • 3 Calogero AE, Gallucci WT, Gold PW. et al . Multiple regulatory feedback loops on hypothalamic CRH secretion. Potential clinical implications.  J Clin Invest. 1988;  82 767-774
    PubMedGoogle Scholar
  • 4 Vale W, Spiess J, Rivier C. et al . Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin.  Science. 1981;  213 1394-1397
    CrossrefPubMedGoogle Scholar
  • 5 Perrin MH, Vale WW. Corticotropin releasing factor receptors and their ligand family.  Ann N Y Acad Sci.. 1999;  885 312-328
    PubMedGoogle Scholar
  • 6 Grammatopoulos DK, Chrousos GP. Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists.  Trends Endocrinol Metab. 2002;  13 436-444
    PubMedGoogle Scholar
  • 7 Tsigos C, Chrousos GP. Physiology of the hypothalamic-pituitary-adrenal axis in health and dysregulation in psychiatric and autoimmune disorders.  Endocrinol Metab Clin North Am. 1994;  23 451-466
    PubMedGoogle Scholar
  • 8 Rivier C, Rivier J, Mormede P. et al . Studies on the nature of the interaction between vasopressin and corticotropin-releasing factor on adrenocorticotropin release in the rat.  Endocrinology. 1984;  115 882-886
    PubMedGoogle Scholar
  • 9 Korbonits M, Kaltsas G, Perry LA. et al . The growth hormone secretagogue hexarelin stimulates the hypothalamo-pituitary-adrenal axis via arginine vasopressin.  J Clin Endocrinol Metab. 1999;  84 2489-2495
    CrossrefPubMedGoogle Scholar
  • 10 Heilig M, Widerlov E. Neurobiology and clinical aspects of neuropeptide Y.  Crit Rev Neurobiol. 1995;  9 115-136
    PubMedGoogle Scholar
  • 11 Jessop DS, Chowdrey HS, Larsen PJ. et al . Substance P: multifunctional peptide in the hypothalamo-pituitary system?.  J Endocrinol. 1992;  132 331-337
    PubMedGoogle Scholar
  • 12 Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress.  J Psychosom Res. 2002;  53 865-871
    CrossrefPubMedGoogle Scholar
  • 13 Horrocks PM, Jones AF, Ratcliffe WA. et al . Patterns of ACTH and cortisol pulsatility over twenty-four hours in normal males and females.  Clin Endocrinol (Oxf). 1990;  32 127-134
    PubMedGoogle Scholar
  • 14 Chrousos GP. Ultradian, circadian, and stress-related hypothalamic-pituitary-adrenal axis activity - a dynamic digital-to-analog modulation.  Endocrinology. 1998;  139 437-440
    CrossrefPubMedGoogle Scholar
  • 15 Pratt WB. Glucocorticoid receptor structure and the initial events in signal transduction.  Prog Clin Bilo Res. 1990;  322 119-320
    PubMedGoogle Scholar
  • 16 Bamberger CM, Schulte HM, Chrousos GP. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids.  Endocr Rev. 1996;  17 245-261
    CrossrefPubMedGoogle Scholar
  • 17 Dostert A, Heinzel T. Negative glucocorticoid receptor response elements and their role in glucocorticoid action.  Curr Pharm Des. 2004;  10 2807-2816
    CrossrefPubMedGoogle Scholar
  • 18 Rozanski A, Blumenthal JA, Davidson KW. et al . The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology.  J Am Coll Cardiol. 2005;  45 637-651
    Google Scholar
  • 19 Roth RH, Tam SY, Ida Y. et al . Stress and the mesocorticolimbic dopamine systems.  Ann N Y Acad Sci. 1988;  537 138-147
    CrossrefPubMedGoogle Scholar
  • 20 Chrousos GP. Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture.  Ann N Y Acad Sci. 1998;  851 311-335
    CrossrefPubMedGoogle Scholar
  • 21 Fuchs E, Flugge G, Czeh B. Remodeling of neuronal networks by stress.  Front Biosci. 2006;  11 2746-2758
    CrossrefPubMedGoogle Scholar
  • 22 Richard D, Lin Q, Timofeeva E. The corticotropin-releasing factor family of peptides and CRF receptors: their roles in the regulation of energy balance.  Eur J Pharmacol. 2002;  440 189-197
    CrossrefPubMedGoogle Scholar
  • 23 Egawa M, Yoshimatsu H, Bray GA. Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats.  Am J Physiol. 1991;  260 328-334
    PubMedGoogle Scholar
  • 24 Heiman ML, Ahima RS, Craft LS. et al . Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress.  Endocrinology. 1997;  138 3859-3863
    CrossrefPubMedGoogle Scholar
  • 25 Bornstein S, Uhlmann K, Haidan A. et al . Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly.  Diabetes. 1997;  46 1235-1238
    CrossrefPubMedGoogle Scholar
  • 26 Kalra SP, Dube MG, Pu S. et al . Interacting appetite-regulating pathways in the hypothalamic regulation of body weight.  Endocr Rev. 1999;  20 68-100
    CrossrefPubMedGoogle Scholar
  • 27 Cavagnini F, Croci M, Putignano P. et al . Glucocorticoids and neuroendocrine function.  Int J Obesity. 2000;  24 S77-S79
    PubMedGoogle Scholar
  • 28 Kyrou I, Valsamakis G, Tsigos C. The endocannabinoid system as a target for the treatment of visceral obesity and metabolic syndrome.  Ann N Y Acad Sci. 2006;  1083 270-305
    CrossrefPubMedGoogle Scholar
  • 29 Chrousos GP. The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes.  Int J Obesity. 2000;  24 S50-S55
    CrossrefPubMedGoogle Scholar
  • 30 Kyrou I, Chrousos GP, Tsigos C. Stress, visceral obesity, and metabolic complications.  Ann N Y Acad Sci. 2006;  1083 77-110
    CrossrefPubMedGoogle Scholar
  • 31 MacAdams MR, White RH, Chipps BE. Reduction in serum testosterone levels during chronic glucocorticoid therapy.  Ann Intern Med. 1986;  140 648-651
    PubMedGoogle Scholar
  • 32 Rivier C, Rivier J, Vale W. Stress-induced inhibition of reproductive function: Role of endogenous corticotropin releasing factor.  Science. 1986;  231 607-609
    CrossrefPubMedGoogle Scholar
  • 33 Tsigos C, Papanicolaou DA, Kyrou I. et al . Dose-dependent effects of recombinant human interleukin-6 on the pituitary-testicular axis.  J Interferon Cytokine Res. 1999;  19 1271-1276
    CrossrefPubMedGoogle Scholar
  • 34 Burguera B, Muruais C, Penalva A. et al . Dual and selective actions of glucocorticoids upon basal and stimulated growth hormone release in man.  Neuroendocrinology. 1990;  51 51-58
    PubMedGoogle Scholar
  • 35 Benker G, Raida M, Olbricht T. et al . TSH secretion in Cushing's syndrome: Relation to glucocorticoid excess, diabetes, goiter, and the “the sick euthyroid syndrome”.  Clin Endocrin. 1990;  133 779-786
    PubMedGoogle Scholar
  • 36 Tsigos C, Papanicolaou DA, Defensor R. et al . Dose effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure.  Neuroendocrinology. 1997;  66 54-62
    CrossrefPubMedGoogle Scholar
  • 37 Torpy DJ, Tsigos C, Lotsikas AJ. et al . Acute and delayed effects of a single-dose injection of interleukin-6 on thyroid function in healthy humans.  Metabolism. 1998;  47 1289-1293
    CrossrefPubMedGoogle Scholar
  • 38 Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.  New Eng J Med. 1995;  332 1351-1362
    CrossrefPubMedGoogle Scholar
  • 39 Kyrou I, Tsigos C. Hypothalamic-pituitary-adrenal axis, cytokines and metabolic syndrome.  Obesity Metab. 2006;  2 116-126
    PubMedGoogle Scholar
  • 40 Elenkov IJ, Chrousos GP. Stress hormones, pro-inflammatory and anti-inflammatory cytokines, and autoimmunity.  Ann N Y Acad Sci. 2002;  966 290-303
    CrossrefPubMedGoogle Scholar
  • 41 Black PH. The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X.  Brain Behav Immun. 2003;  17 350-364
    CrossrefPubMedGoogle Scholar
  • 42 Selye H. A syndrome produced by diverse nocuous agents.  Nature. 1936;  138 32
    PubMedGoogle Scholar
  • 43 Selye H. The general adaptation syndrome and the diseases of adaptation.  J Clin Endocrinol. 1946;  6 117-230
    PubMedGoogle Scholar
  • 44 Charmandari E, Tsigos C, Chrousos GP. Endocrinology of the stress response.  Annu Rev Physiol.. 2005;  67 259-284
    CrossrefPubMedGoogle Scholar
  • 45 Bjorntorp P. Do stress reactions cause abdominal obesity and comorbidities?.  Obes Rev. 2001;  2 73-86
    PubMedGoogle Scholar
  • 46 Hainer V, Kunesova M, Parizkova J. et al . Serum cortisol and sex hormone binding globulin (SHBG) levels, body fat distribution and the role of genetic factors in obese females.  Sb Lek. 2002;  103 471-475
    PubMedGoogle Scholar
  • 47 Bjorntorp P, Rosmond R. Neuroendocrine abnormalities in visceral obesity.  Int J Obes Relat Metab Disord. 2000;  24 S80-S85
    CrossrefPubMedGoogle Scholar
  • 48 Rosmond R, Holm G, Bjorntorp P. Food-induced cortisol secretion in relation to anthropometric, metabolic and haemodynamic variables in men.  Int J Obes Relat Metab Disord. 2000;  24 416-422
    CrossrefPubMedGoogle Scholar
  • 49 Chandola T, Brunner E, Marmot M. Chronic stress at work and the metabolic syndrome: prospective study.  BMJ. 2006;  332 521-525
    CrossrefPubMedGoogle Scholar
  • 50 Scherer PE. Adipose tissue: from lipid storage compartment to endocrine organ.  Diabetes. 2006;  55 1537-1545
    CrossrefPubMedGoogle Scholar
  • 51 Snijder MB, Zimmet PZ, Visser M. et al . Independent and opposite associations of waist and hip circumferences with diabetes, hypertension and dyslipidemia: the AusDiab Study.  Int J Obes Relat Metab Disord. 2004;  28 402-409
    CrossrefPubMedGoogle Scholar
  • 52 Alberti KG, Zimmet P, Shaw J. IDF Epidemiology Task Force Consensus Group. The metabolic syndrome - a new worldwide definition.  Lancet. 2005;  366 1059-1062
    CrossrefPubMedGoogle Scholar
  • 53 Schaffler A, Muller-Ladner U, Scholmerich J. et al . Role of adipose tissue as an inflammatory organ in human diseases.  Endocr Rev. 2006;  27 449-467
    CrossrefPubMedGoogle Scholar
  • 54 Tsigos C, Kyrou I, Chala E. et al . Circulating tumor necrosis factor a levels are higher in abdominal than peripheral obesity.  Metabolism. 1999;  48 1332-1335
    CrossrefPubMedGoogle Scholar
  • 55 Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue.  Br J Nutr. 2004;  92 347-355
    CrossrefPubMedGoogle Scholar
  • 56 Tsigos C, Papanicolaou DA, Kyrou I. et al . Dose-dependent effects of recombinant human interleukin-6 on glucose regulation.  J Clin Endocrinol Metab. 1997;  82 4167-4170
    CrossrefPubMedGoogle Scholar
  • 57 Dallman MF, Pecoraro N, Akana SF. et al . Chronic stress and obesity: a new view of “comfort food”.  Proc Natl Acad Sci USA. 2003;  100 11696-11701
    CrossrefPubMedGoogle Scholar
  • 58 Anderson RJ, Freedland KE, Clouse RE. et al . The prevalence of comorbid depression in adults with diabetes. A meta-analysis.  Diabetes Care. 2001;  24 1069-1078
    CrossrefPubMedGoogle Scholar
  • 59 Kawakami N, Takatsuka N, Shimizu H. et al . Depressive symptoms and occurrence of type 2 diabetes among Japanese men.  Diabetes Care. 1999;  22 1071-1076
    CrossrefPubMedGoogle Scholar
  • 60 Everson-Rose SA, Meyer PM, Powell LH. et al . Depressive symptoms, insulin resistance, and risk of diabetes in women at midlife.  Diabetes Care. 2004;  27 2856-2862
    CrossrefPubMedGoogle Scholar
  • 61 Bjorntorp P, Holm G, Rosmond R. Hypothalamic arousal, insulin resistance and type 2 diabetes mellitus.  Diabetic Med. 1999;  16 373-383
    CrossrefPubMedGoogle Scholar
  • 62 Rubin RR, Peyrot M. Was Willis right?. Thoughts on the interaction of depression and diabetes.  Diabetes Metab Res Rev. 2002;  18 173-175
    CrossrefPubMedGoogle Scholar
  • 63 Surwit RS, van Tilburg MAL, Zucker N. et al . Stress management improves long-term glycemic control in type 2 diabetes.  Diabetes Care. 2002;  25 30-34
    PubMedGoogle Scholar
  • 64 Adriaanse MC, Dekker JM, Nijpels G. et al . Associations between depressive symptoms and insulin resistance: The Hoorn Study.  Diabetologia. 2006;  49 2874-2877
    CrossrefPubMedGoogle Scholar
  • 65 Barzilay JI, Abraham L, Heckbert SR. et al . The relation of markers of inflammation to the development of glucose disorders in the elderly. The Cardiovascular Health Study.  Diabetes. 2001;  50 2384-2389
    CrossrefPubMedGoogle Scholar
  • 66 Schmidt MI, Duncan BB, Sharrett AR. et al . For the ARIC Investigators. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study.  Lancet. 1999;  353 1649-1652
    CrossrefPubMedGoogle Scholar

Correspondence

C. TsigosMD, PhD 

82 Vas. Sophias Avenue

115 28 Athens

Greece

Phone: +30/210/748 00 09

Fax: +30/210/748 00 10

Email: ctsigos@gmail.com

      >