## 2 Orexins
\begin{table}
\begin{tabular}{c c} \hline \hline
**Findings** & **References** \\ \hline Excitatory neuropeptides produced in the lateral hypothalamus/periforrical region & [14] \\ \hline Two adjacent alpha-helices separated by a short 2–3 amino acids turn. Longer helix: identity region for & [18] \\ both peptides & \\ \hline Involved in energy homeostasis, feeding, reward-related appetitive behaviors, glucose metabolism, & [14; 15; 16; 17; 19] \\ motor function, sleep and wakefulness & \\ \hline Orexin A: increase food intake (specially diets rich in saturated fat), decrease tumor development, & [20; 21; 22; 23] \\ excitatory effect on hippocampal neurons; involved in immunomodulatory mechanisms & [24; 21; 22] \\ \hline Stimulation of hypothalamus-pituitary-adrenal axis. Important sexually dimorphic role & [14; 24] \\ \hline Diurnal orexin variations in the brain of mammals & [15] \\ \hline Mammalian hypothalamic orexin-producing neurons: anatomically, genetically, and functionally distinct & [25; 26] \\ subpopulations with heterogeneity in neuronal connectivity and gene expression & [25; 26] \\ \hline Neurons expressing orexin of lateral hypothalamus: inputs from arcuate neurons containing AgRP/NPY & \\ and outputs to ventral tegmental neurons (activation of the mesolimbic pathway) and paraventricular & [13; 27; 28] \\ thalamic nucleus & \\ \hline Orexinergic neurons project to the medial and posterior hypothalamus, ventral forebrain, amygdala, & \\ neocortex, periaqueductal gray matter, locus coeruleus, dorsal raphe, raphe magnus, ventrolateral & [29] \\ medulla and spinal cord & \\ \hline Orexins/ orexin receptors located in adipocytes, thyroid, reproductive tract, pancreas, parathyroid, & [14] \\ adrenal gland, testis, ovary, pituitary and intestines & \\ \hline Derived from the prepro-orexin; _prepro-orexin_ gene encoded on chromosome 17q2l-q24 in humans & [14; 29] \\ \hline Upregulation in the prepro-orexin mRNA expression during fasting & [6] \\ \hline Orexin receptors: coupled to G protein. Orexin B: higher affinity for orexin receptor 2 than for receptor 1. & [30] \\ Orexin A: equal affinity for both receptors & \\ \hline Orexin receptor: can form homodimers, heterodimers, or oligomers. Orexin A increased & [31] \\ dimerization/oligomerization; antagonists decreased both processes & [32; 33] \\ \hline Similar distributions of orexin receptors and melanin-concentrating hormone receptor & [29; 32] \\ \hline Orexin 1 receptor antagonists: inhibited behavioral satiety and hyperphagia mediated by orexin B & [33] \\ \hline Orexin A signaling inhibition: decreased overfeeding from a high fat diet under the condition of satiation & [34] \\ \hline Enhanced orexin 2 receptor signaling: improved leptin sensitivity and prevented diet-induced obesity & [35] \\ \hline Proteins Gq, Gs and Gi: activated by the orexinergic system, with increase in the level of Ca2+ & [36] \\ \hline Orexin 1 receptor: activates adenylyl cyclase via a high potency phospholipase C/protein kinase C & \\ coupling; also coupled to diacylglycerol lipase and phospholipase A2 leading to the production of & [37; 38] \\ 2-arachidonoyl glycerol & \\ \hline Orexin A increased the levels of cyclic adenosine monophosphate and inositol triphosphate and the & [39] \\ labeling of Gi/Gs/Gq but not Go & \\ \hline Orexin receptors: activated the mitogen-activated protein kinase pathway promoting p38 kinase and & [37] \\ extracellular signal-regulated protein kinases 1 and 2 phosphorylation & [37] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Orexins: general characteristics. that orexin deficiency regulates cognitive flexibility (ability to adapt behaviors in response to environment changes) in a sex-dependent manner; this means that the peptide plays an important sexually dimorphic role [24] (Table 1). Orexin is involved in the integration of metabolism and sleep: a recent review focused on this topic [19].