Orexin-A Hyperphagia: Hindbrain Participation in Consummatory Feeding Responses

Abstract

Orexin-A (ORXA) is an orexigenic neuropeptide produced by the lateral hypothalamus that increases food intake when injected into the brain ventricles or forebrain nuclei. We used a licking microstructure analysis to evaluate hindbrain and forebrain ORXA effects in intact and hindbrain-lesioned rats, to identify the motivational and anatomical bases of ORXA hyperphagia. Intact rats with cannulas in the fourth brain ventricle (4V) received vehicle (artificial cerebrospinal fluid) or ORXA (0.1, 0.4, 1, or 10 nm) injections before 90 min access to 0.1 m sucrose. Meal size and frequency were increased in a double-dissociated manner by the 1 and 10 nm doses, respectively. In experiment 2, 4V 1 nm ORXA was applied to rats offered solutions varied in caloric and gustatory intensity (water and 0.1 and 1 m sucrose). ORXA increased meal frequency for all tastants. ORXA increased meal size only for 0.1 m sucrose, by prolonging the meal without affecting early ingestion rate or lick burst size, suggesting that 4V ORXA influenced inhibitory postingestive feedback rather than taste evaluation. In experiment 3, rats with cannulas in the third ventricle (3V) received dorsal medullary lesions centered on the area postrema (APX group) or sham procedures, and licking for water and 0.1 and 1 m sucrose was evaluated after 1 nm 3V ORXA/artificial cerebrospinal fluid injections. The 3V ORXA increased 0.1 m sucrose meal size and meal frequency for all tastants in the sham group, as observed after 4V ORXA in experiment 2. In the APX group, 3V ORXA injections influenced meal frequency, but they no longer increased meal size. However, the APX rats increased meal size for 0.1 m sucrose after food and water deprivation and after 3V angiotensin II injection. They also showed meal size suppression after 3V injection of the melanocortin-3/4 receptor agonist melanotan II (1 nm). These findings suggest that the area postrema and subjacent nucleus of the solitary tract are necessary for increases in consummatory (meal size) but not appetitive (meal frequency) responses to 3V ORXA. The meal size increases may be due to reduced postingestive feedback inhibition induced by ORXA delivered to either the hindbrain or forebrain ventricles.

Roles of orexins in the regulation of body weight homeostasis

“…Furthermore, local application of orexin in the PVH, DMH, and LHA was shown to increase food intake 45,46 . A recent study showed that the area postrema and NTS are involved in the orexin mediated feeding 47 . Application of orexin A into the nucleus of accumbens shell was reported to increase feeding 48 .…”

Anatomical dissociation of melanocortin receptor agonist effects on taste- and gut-sensitive feeding processes

“…The 0.1 M and 1 M sucrose solutions often produce distinct licking microstructure profiles, even though these differences can result in the same volume consumed (4,5,9). We have shown that rats exhibit robust licking responses for 1 M sucrose, as indicated by a rapid initial rate of licking, larger mean lick burst sizes/durations (reflecting taste evaluation), and a steep rate of decline in the ingestion rate due to the caloric load, which generates a meal of moderate duration (2). When offered the less caloric and less preferred 0.1 M sucrose solution, rats exhibit slower initial lick rates and smaller and shorter licking bursts (suggesting weaker ingestive taste reactivity), and a flatter rate of decline in ingestion rate, with a longer meal duration and more bursts of licking, reflecting the reduced caloric inhibition (see also Refs.…”

Deep brain stimulation for obesity: past, present, and future targets

“…3,51 Additionally, the area postrema and nucleus of tractus solitarius have effects on meal size, but not on meal frequency. 3 The area postrema and the nucleus of tractus solitarius both promote orexin-mediated feeding behaviors, suggesting that they represent a robust link to the feeding centers in the LHA.…”

“…3,51 Additionally, the area postrema and nucleus of tractus solitarius have effects on meal size, but not on meal frequency. 3 The area postrema and the nucleus of tractus solitarius both promote orexin-mediated feeding behaviors, suggesting that they represent a robust link to the feeding centers in the LHA. The nucleus of tractus solitarius is the primary satiety relay center to the CNS from the gastrointestinal tract via N-methyl-d-aspartic acid (NMDA) receptor-mediated activation by vagal afferents, 9,13,36,94 making DBS of this region an attractive proposition.…”