Although it appears that hypercortisolemia may contribute to

Although it appears that hypercortisolemia may contribute to the development of different features of metabolic syndrome, it is not clear in the literature whether glucocorticoids play a role in the pathogenesis of obesity. Some studies show that Metformin cost levels are not higher in obese subjects, and sometimes they are even lower than in lean subjects [107,108]. This may be, at least in part, a consequence of enhanced cortisol clearance that is thought to accompany obesity, for instance, through increased activity of 5α-reductase in the liver [108]. Mean 24h plasmatic ACTH levels were positively correlated with body mass index, reflecting increased hypothalamic drive and reduced negative feedback of cortisol in obesity [109]. Other factors related to cortisol action are also determinants. In this sense, the local expression of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) plays a role in the relationship between cortisol, adiposity, and metabolic disease [110]. The enzyme 11β-HSD1, expressed in several peripheral tissues, such as liver ad adipose tissue, can modulate HPA axis activity, regenerating active cortisol from its inactive form intracellularly [111]. In humans, 11β-HSD1 expression is increased in subcutaneous adipose tissue from obese subjects compared to lean subjects [112], being stimulated by TNFα, leptin and adipokines [113,114]. In the presence of insulin, cortisol promotes triglyceride accumulation, mainly in visceral adipocytes, thus leading to increased central adiposity. Masuzaki and colleagues have also demonstrated that overexpression of 11β-HSD1 in adipose tissue resulted in visceral obesity and metabolic syndrome in mice fed with a high-fat diet [115]. Adipose tissue that overexpressed 11β-HSD2, the enzyme that inactivates cortisol, protected mice from high-fat diet-induced obesity [116]. The modulation of 11β-HSD1 might be a promising therapeutic target for obesity and metabolic disturbances. Studies focusing the inhibition of 11β-HSD1 in animal models of diabetes and obesity have shown improvement of insulin resistance and glucose levels, beyond weight loss [117,118]. Dysregulation of the HPA axis has been associated with some eating disorders [119,120], mainly due to changes in insulin, NPY levels, and other peptides implicated in food intake regulation that can be modulated by cortisol metabolism [112]. Food intake is stimulated by administration of glucocorticoid prednisone in healthy men [121], while diet influences cortisol metabolism, affecting the HPA axis and the reward circuitry for palatable foods [112,122]. Important effects of altered cortisol levels on weight gain are also reported in Cushing׳s syndrome and Addison׳s disease, which are both associated with effects such as central obesity/hypercortisolism and weight loss/hypocortisolism, respectively [123].
Sleep, stress, and metabolism Because of the new lifestyle imposed by work and family, physical and psychological problems, and social changes due to internet and television, stress and sleep restriction have become endemic, with a major impact on the metabolic process. Importantly, stress hormone levels correlate positively with decreased sleep duration, while both are associated with obesity, metabolic syndrome, and eating disorders [73]. A study by Galvao and colleagues [124] showed that rats subjected to 96h of paradoxical sleep deprivation present increased immunoreactivity for CRH and orexin as well as higher levels of ACTH and corticosterone, in addition to increased diurnal food intake, but without changes in global food intake. A negative correlation was found between corticosterone and body weight gain throughout paradoxical sleep deprivation [124]. Stress is known to reduce SWS, REM sleep, and delta power, as well as to affect metabolism in rodents, with the magnitude varying according to the type and duration of stress exposure [73]. Sleep deprivation, in turn, activates many stress-related pathways including the HPA axis and sympathetic nervous system, which indirectly modulate arousal and affect the metabolism [26,125]. It has been proposed that the bidirectional relationship between sleep and stress and its impact on metabolism are, in part, mediated by hypocretin circuitry. Hypocretinergic cells project to several CRH-responsive regions in the central nervous system, including locus coeruleus, the PVN, the bed nucleus of the stria terminalis and the central amygdala [126].