## 4 Orexins and Food Intake in Humans  
In humans, feeding behavior is complex since some hypothalamic nuclei are involved in the regulation of food intake, stress response and rewards and, in addition, exert effects on the reward system, cortex or brainstem [4; 5; 101] (Table 4). \begin{table}
\begin{tabular}{c c} \hline \hline
**Findings** & **References** \\ \hline Complex feeding behavior; involvement of some hypothalamic nuclei in regulation of food intake, stress response and & [4; 5; 101] \\ rewards and exert effects on the reward system, cortex, or brainstem & [100; 101] \\ \hline Frequent link between overweight and psychological problems; bridge between certain hypothalamic nuclei towards the & [100; 101] \\ appetite-regulating orexigenic system. Reward signaling encoded by orexins & [100; 101] \\ \hline Orexin level in cerebrospinal fluid higher at night-time and lowest at midday. Orexin A level correlated negatively with & [102; 103] \\ body weight; not related to body adiposity & [102; 103] \\ \hline Orexin A peaked once or more during the whole day. No discernible pattern with eating, wake or sleep (healthy & [103] \\ male volunteers) & \\ \hline Obese individuals: orexin A plasma level lower than lean individuals & [104] \\ \hline Orexin A plasma level: correlated positively to body mass index. Intermittent daily fasting increased peptide plasma level & [103; 105] \\ during fasting hours & & \\ \hline Southwestern American Indians: genetic variant of the _HCRTR1_ gene (gene linked to sleep regulation and feeding). & \\ Regulation of hypothalamic-pituitary-adrenal axis by HCRTR1/hypocretin (orexin receptor/orexin) system. Axis & [106] \\ disruption: high cortisol levels, overeating, night eating syndrome & \\ \hline Alzheimer’s disease and Parkinson’s disease patients: decrease in number of hypothalamic neurons containing orexin and & [107] \\  & in orexin level in the cerebrospinal fluid & \\ \hline Patients with depression: lower levels of orexin A in their cerebrospinal fluid; the higher depression scores, the lowest & [105] \\  & levels of orexin A & [105] \\ \hline Schizophren patients: higher levels of orexin A compared to controls & [105] \\ \hline Patients with chronic schizophrenia: body mass index positively related with orexin A levels and negatively related with & [105] \\ negative symptoms. Orexin A levels might modify metabolic indexes to increase the rates of overweight and obesity & [105] \\ \hline \hline \end{tabular}
\end{table} 
Table 4: Orexins and food intake: humans. Some of these hypothalamic nuclei form a bridge toward the appetite-regulating orexigenic system [101], and reward signaling is encoded in part by neuropeptides, such as orexins [100]; thus, a link between overweight and psychological problems is very frequent (Table 4). Stress is one of the most common problems since it can cause a weight/fat increase, but also a decrease in these parameters in individuals who keep their stress response with less energy intake. Two important stress systems are the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. The prolonged activation of these systems by chronical stress leads to detrimental physiological consequences, often associated with diet alterations. Chronic psychosocial stress may cause uncontrolled eating ranging from emotional eating in response to negative emotions to disinhibition or external eating (eating because food is available) up to binge eating (recurrently eating too much food because of perceiving a lack of control), all of them leading to overweight [101]. These behaviors are also dependent on age; a higher prevalence of stress-eating behaviors was reported in youths compared to adults, being that adolescence is the critical period for the onset of eating disorders [101]. In humans, it was reported that the level of orexin in the cerebrospinal fluid varies; thus, it is higher at night-time and lowest at midday [102] (Table 4).