Stress Obesity and Metabolic Syndrome

The perception and interpretation of stress determines the actual response any individual has to the stress presented [52]. A meta-analysis has shown that in addition to being activated when a physical threat is perceived, the HPA axis is also activated when there is a threat to one's social esteem and status [53]. In the context of schizophrenia, a misinterpretation of harmless environmental cues (psychological or physical) can be deemed a stressor and hence provoke a biological response.

So, can perceived stress and its biological correlate lead to metabolic disturbance? The answer would seem to be yes, in that, stress be it social or work-related leads to an immediate activation of the sympatho-adrenal network which leads to an outpouring of norepinephrine and cortisol which in healthy non-obese individuals results in tachycardia, a reflex vasodilation and the disposal of glucose while the opposite metabolic effects are seen in obesity [54]. The origin of the stress can be work-related or otherwise, as suggested in a study by Chandola et al. [55] who found that such stress was associated with higher cortisol levels in the morning and was directly related to the future development of IHD.

Healthy individuals respond to stress in a unitary fashion with the activation, as mentioned already, of the sympatho-adrenal system and the HPA axis resulting in an increase of cortisol and epinephrine. One immediate consequence of this is an increase in resting heart rate and a reduction of vascular resistance. In those individuals who are obese or have insulin resistance, endothelial dysfunction can dampen the compensatory reduction of blood pressure and limit glucose disposal in response to stress. These events can lead to central obesity and the development of certain features of the MetS.

From a cellular perspective, some investigators have suggested that the MetS may in fact be an intracellular manifestation of Cushing's syndrome [56, 57]. Evidence for this hypothesis has come primarily from examining the workings of 11^-hydroxysteroid dehydrogenase type 1 (11^-HSD1), which converts inactive cortisone to active cortisol. An in vitro study has found that fat-cell derived cytokines (e.g. IL-6 and TNF-a) acted in concert to increase the hepatocyte expression of 11^-HSD1, which increases the intracellular levels of cortisol. The same cytokines acted synergistically to increase the expression of GR receptors thereby potentiating the effects of an already readily available cortisol. The net effect would be to alter lipid and glucose metabolism, both key features of NetS. Furthermore, it would appear that commonly used anti-diabetic agents such as PPARy/PPARa agonists, reduce the transcription of 11^-HSD1 leading to the question of whether agents that directly or indirect impact on the HPA axis can lead to an amelioration of symptoms associated with schizophrenia or indeed the MetS. In an elegant review of the stress-diathesis model of schizophrenia, Walker et al. [58] cite examples of how commonly used antipsychotics have a 'dampening' effect on the HPA axis which is associated with a reduction of psychotic symptoms adding further face validity to the hypothesis that stress dysfunction may play a central role in the pathogenesis of this serious mental illness.

In summary, stress may play an important mediator in both schizophrenia and the MetS. Activation of the HPA axis is a consequence of physical and psychological stressors, the latter including perceived threats to self-integrity and esteem. Dysfunction of the HPA axis occurs in both MetS and schizophrenia. Although cortisol is crucial for life, in excess can become the source of hippocampal shrinkage and visceral fat expansion, resulting in cognitive deficits and possibly insulin resistance. Preliminary evidence would suggest that restoration of normal HPA axis function by anti-diabetic agents in MetS or antipsychotics in schizophrenia may lead to an amelioration of physical or psychological symptoms.

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