## 2 Orexins
### Physiological Actions Mediated by Orexins
In addition, orexin A decreased the release of glycerol, suggesting that the peptide regulates fat metabolism by inhibiting lipolysis [56] (Table 2). It is also important to note that orexins A and B promoted and inhibited, respectively, the proliferation of 3T3-L1 cells, which show an adipocyte-like phenotype [14] (Table 2). It was reported that the distribution of orexins in the central nervous system of obese animals lacking the leptin receptor was more widespread than that observed in lean animals [58] (Table 2). This is due to the lack of leptin receptors since leptin negatively regulates the expression of orexin and hence, the orexin tone is augmented in obese individuals [66]. It is also known that a fat diet and triglycerides stimulate orexin tone [57] (Table 2). It was reported that orexins increase the motility of the gastrointestinal tract, that are involved in glucose metabolism, and that in neurons expressing orexin, fasting increased the level of pCREB (phosphorylated cAMP response binding protein) [59; 60] (Table 2). It is also known that orexin A promoted the acid secretion and decreased the rate of gastric emptying and plasma leptin level [14] (Table 2). It was demonstrated that the neuroendocrine regulatory peptide-2 regulated both gastric emptying and secretion and that these mechanisms were mediated by the orexin system [67]. Orexin A increased the plasma level of adrenocortic hormone and corticosterone, but this effect was not observed with orexin B [61] (Table 2). Both orexins increased the plasma level of norepinephrine, suggesting that the peptides stimulated the adrenal medulla [14] (Table 2). Orexin A increased the release of cortisol and mRNA levels of CYP11B1/B2, CYP21 and HSD3B2 (steroidogenic enzymes), but the levels of other enzymes, such as CYP11A and CYP17, were not affected [62] (Table 2). Protein kinase C and ERK 1/2 (extracellular signal-regulated protein kinases 1 and 2) are also involved in these mechanisms mediated by orexin A. This orexin also decreases the level of circulating TSH (thyroid-stimulating hormone), although several studies have shown that orexin A does not exert a significant action on the thyroid-pituitary axis [14]. In avian liver, it was reported that hepatocytes express/secrete orexin and that orexin A regulates hepatic lipogenesis via activation of the ERK1/2 signaling pathway [68]. In humans, orexin A is colocalized with insulin in the pancreatic islets, and the release of orexin A is dependent on a low glucose level; this means that the peptide regulates the secretion of the pancreatic hormones and glucose modulation [60] (Table 2). Orexin plays an important role in the maintenance of normal insulin sensitivity with advanced age, and the data show that the peptide is crucial in maintaining the hypothalamic insulin signaling that is responsible for the prevention of the onset of peripheral insulin resistance, which tends to increase with age [63] (Table 2). This could explain why diabetes (type 2) incidence is augmented in normal weight individuals showing a deficiency in orexin. Hyperglycemia blocks the expression of orexin, and it was reported that the circadian clock of the suprachiasmatic nucleus could be reset through arousal promoting signals from neurons containing orexin [60] (Table 2). In hypoglycemic animals, the hypothalamic level of orexin B was higher than in control animals [64] (Table 2). Orexins A and B increase food consumption and, in fasting animals, the level of prepro-orexin also increased in the hypothalamus [6] (Table 2). The administration of orexin A into the Perifornical area or lateral hypothalamus increased food intake. It is known that neurons containing orexin are sensitive to the levels of triglyceride, leptin, and glucose [29] (Table 2). It is important to note that a long-term administration of orexin A did not modify daily food intake, the level of glucose in blood, and body weight, suggesting that the actions of orexin A could be limited to the short-term, due to increased wakefulness [29] (Table 2).