Glucocorticoid action networks and complex psychiatric and/or somatic disorders

Figures & data

Table I.  Expected clinical manifestations in target tissue hypersensitivity or resistance to glucocorticoids.

Target area	Glucocorticoid excess = glucocorticoid hypersensitivity	Glucocorticoid deficiency = glucocorticoid resistance
Central nervous system	Insomnia, anxiety, depression, defective cognition	Fatigue, somnolence, malaise, defective cognition
Liver	+ Gluconeogenesis, + lipogenesis	Hypoglycemia, resistance to diabetes mellitus
Fat	Accumulation of visceral fat (metabolic syndrome)	Loss of weight, resistance to weight gain
Blood vessels	Hypertension	Hypotension
Bone	Stunted growth, osteoporosis
Inflammation/immunity	Immune suppression, anti-inflammation, vulnerability to certain infection and tumors	+ Inflammation, + autoimmunity, + allergy

Modified from Chrousos et al. (2004), Chrousos and Kino (2005).

Figure 1 A: Feedback regulation of the HPA axis. ACTH, Adrenocorticotropic hormone; AVP, arginine vasopressin; CRH, corticotropin-releasing hormone; DOC, deoxycorticosterone; B, corticosterone. B: Feedback-regulated compensatory changes in the activity of the HPA axis and their effects in peripheral tissues, such as the liver, fat and blood vessels. Note that glucocorticoid sensitivity in the HPA axis and the peripheral tissues can be independently regulated and the former determines the serum free cortisol levels, thus combination of their directions of change from normal influence net peripheral action of this hormone. Modification from Kino et al. (2001), Charmandari et al. (2004).

Table II.  Factors influencing GR functions.

Ligands	Membrane transporters of glucocorticoids
	11β-hydroxysteroid dehydrogenases
	Agonists, antagonists (ex. RU 486)
Chemical compounds	Ursodeoxycholic acid, cortivazol, thiredoxin, carnitine
Chemical modifications	Phosphorylation, nitrosylation, acetylation, methylation
Chaperones, co-chaperones	Heat shock proteins, RAP46, FK506-binding proteins
Receptor isoforms	Glucocorticoid receptor α and β isoforms (16 or more, 256 or more combinations of dimers)
Transcriptional co-regulators	Coactivators/corepressors, SWI/SNF, TRAP/DRIP complex, SMAD6
	Viral proteins: adenoviral E1A, human immunodeficiency virus type-1 Vpr and Tat
Transcription factors	Nuclear factor-κB, activator protein-1, CREB-binding protein, p53, chicken ovalbumin upstream promoter-transcription factor-II, GATA-1, SP-1, nuclear factor-1, PPARα
Other proteins	14-3-3, FLASH, Rho-type guanine nucleotide exchange factors (Brx and c-Lbc), autoimmune regulator gene (AIRE), guanine nucleotide-binding protein β
RNAs	SRA, Gas5

Data from Lanz et al. (1999), Kino and Chrousos (2003, 2004), Kino et al. (2003b, 2003c, 2004, 2006), Chrousos and Kino (2005), Lu and Cidlowski (2005), Ichijo et al. (2005).

Figure 2 Endogenous/exogenous inputs to the stress system and their effects on the metabolic and cardiovascular systems and bone. ABP, arterial blood pressure; APR, acute phase reactants; AVP, arginine vasopressin; CRH, corticotropin-releasing hormone; E, epinephrine; E2, estradiol; GH, growth hormone; HDL, high-density lipoprotein; HPA axis, hypothalamic–pituitary–adrenal axis; IGF-1, insulin-like growth factor-1; IL-6, interleukin-6; LC, locus caeruleus; LDL, low-density lipoprotein; LH, luteinizing hormone; NE, norepinephrine; T, testosterone; T3, triiodothyronine; TG, triglyceride; TSH, thyroid-stimulating hormone.

Table III.  Gene networks subserving functions important for human survival and species preservation, which may produce pathology in contemporary western societies.

Response to survival threat	Selective advantage	Contemporary diseases
Combat starvation	Energy conservation	Obesity
Combat dehydration	Fluid and electrolyte conservation	Hypertension
Combat infectious diseases	Potent immune reaction	Autoimmunity/allergy
Anticipate adversaries	Arousal/fear	Anxiety/insomnia
Minimize exposure to danger	Withdrawal from danger	Depression
Prevent tissue strain and injury	Retain tissue integrity and reserve	Pain and fatigue syndromes

Modified from Chrousos (2004).

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