Orexins in the Regulation of the Hypothalamic-Pituitary-Adrenal Axis

Spinazzi, Raffaella; Andreis, P. G.; Rossi, Gian Paolo; Nussdorfer, Gastone G.

doi:10.1124/pr.58.1.4

Cited by 162 publications

(105 citation statements)

References 128 publications

(196 reference statements)

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“…We previously found reduced CSF levels of the hypothalamic peptide orexin in suicide attempters with MDD (Brundin et al, 2007). Orexins modulate the HPA axis by stimulating CRH-Adrenocorticotropic Hormone (ACTH) secretion (Spinazzi et al, 2006). Vasopressin-neurophysins, on the other hand, have not been found to affect the HPA-axis after a DST in suicide attempters (Pitchot et al, 2008).…”

Section: Our Results In Relation To Other Studiesmentioning

confidence: 99%

Salivary cortisol and suicidal behavior—A follow-up study

Lindqvist

Isaksson

Lil-Träskman-Bendz

et al. 2008

Psychoneuroendocrinology

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IntroductionHyperactivity of the Hypothalamic-Pituitary-Adrenal (HPA) axis is a common finding in Major DepressiveDisorder. Similar studies on suicide attempters are less abundant, and the results are divergent. The main aim of the present study was to investigate HPA-axis parameters by the time of a suicide attempt and at follow-up in search for associations between HPA axis function and suicidal behavior. MethodsThirty-five suicide attempters and 16 non-suicidal controls were admitted to a psychiatric ward between the years of 1986 an 1992. Corticotrophin-releasing hormone (CRH) in cerebrospinal fluid and urinary cortisol were obtained for the suicide attempters. The patients were followed up approximately 12 years after the index admission. Cortisol was measured in saliva, and additional suicide attempts and current psychiatric symptoms were registered. ResultsAt follow up, evening salivary cortisol was lower in suicide attempters compared to controls. Low cortisol levels at follow up were associated with severe psychiatric symptoms. Among women, repeated suicide attempts were associated with low morning and lunch salivary cortisol, and in this subgroup we also found significant correlations between salivary cortisol at follow up, and CRH as well as urinary cortisol at index. ConclusionWe found evidence for an association between low HPA axis activity and suicidal behavior. This could be due to long lasting and severe psychiatric morbidity, which in turn has exhausted the HPA axis of these patients. The potential role of hypocortisolism should be given more attention in studies on suicidal patients.

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Section: Our Results In Relation To Other Studiesmentioning

confidence: 99%

Salivary cortisol and suicidal behavior—A follow-up study

Lindqvist

Isaksson

Lil-Träskman-Bendz

et al. 2008

Psychoneuroendocrinology

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“…Orexin regulates motivated behaviours, such as arousal, feeding and reward-seeking, and has important effects on metabolic, autonomic and endocrine functions [28][29][30]. The findings that orexin-A increases oxygen consumption and body temperature even in anaesthetised rats [31], and that orexin neuron-deficient mice display reduced energy expenditure that is independent of sleep/wake, locomotion and food intake [32] indicate that orexin-induced increase in energy metabolism is not simply due to increased wakefulness and physical activity.…”

Section: Discussionmentioning

confidence: 99%

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

et al. 2008

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Aims/hypothesis Orexin/hypocretin is a hypothalamic neuropeptide that regulates motivated behaviours, such as feeding and arousal, and, importantly, is also involved in energy homeostasis. The aim of this study was to reveal the role of orexin in the regulation of insulin sensitivity for glucose metabolism. Methods Orexin knockout mice fasted overnight underwent oral glucose tolerance testing and insulin tolerance testing. The impact of orexin deficiency on insulin signalling was studied by Western blotting to measure levels of Akt phosphorylation and its upstream and downstream molecules in the hypothalamus, muscle and liver in orexin knockout mice. Results We found that orexin deficiency caused the agerelated development of impaired glucose tolerance and insulin resistance in both male mice without obesity and female mice with mild obesity, fed a normal chow diet. When maintained on a high-fat diet, these abnormalities became more pronounced exclusively in female orexin knockout mice that developed severe obesity. Insulin signalling through Akt was disrupted in peripheral tissues of middle-aged (9-month-old) but not young adult (2-to-3-month-old) orexin knockout mice fed a normal chow diet. Moreover, basal levels of hypothalamic Akt phosphorylation were abnormally elevated in orexin knockout mice at every age studied, and insulin stimulation failed to increase the level of phosphorylation. Similar abnormalities were observed with respect to GSK3β phosphorylation in the hypothalamus and peripheral tissues of middle-aged orexin knockout mice. Conclusions/interpretation Our results demonstrate a novel role for orexin in hypothalamic insulin signalling, which is likely to be responsible for preventing the development of peripheral insulin resistance with age.

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“…[167] also called hypocretin 1 and 2 according to the tissue where it has been identified [168] are both generated from pre-prohormone-orexin (pp-orexin; 130 -131 a.a.r.). This is expressed in the lateral hypothalamic area particularly close to the median eminence, DMH and PFA [169,170]. Stability and lipophilicity of orexin A exceeds that of orexin B.…”

Section: Endogenous Peptidic Ligandsmentioning

confidence: 99%

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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Orexins in the Regulation of the Hypothalamic-Pituitary-Adrenal Axis

Cited by 162 publications

References 128 publications

Salivary cortisol and suicidal behavior—A follow-up study

Salivary cortisol and suicidal behavior—A follow-up study

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

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