Hindbrain orexin 1 receptors blunt intake suppression by gastrointestinal nutrients and cholecystokinin in male rats.

Hypothalamic orexin neurons project to many brain areas, including hindbrain structures such as the nucleus of the solitary tract (NTS) and area postrema (AP), where orexin 1 receptors (OX1Rs) are expressed. Hindbrain administration of orexin-A increases feeding and meal size, and blockade of hindbrain OX1Rs with the selective antagonist SB334867 has the opposite effect. Here we asked whether hindbrain OX1R stimulation or blockade alter rats' sensitivity to gastrointestinal satiety signals. Rats received 4th intracerebroventricular (icv) injections of vehicle or orexin-A, at a dose with no effect on its own, prior to an intragastric (IG) infusion of saline or a satiating volume of Ensure. IG Ensure suppressed subsequent chow intake, but orexin-A pretreatment significantly attenuated this IG nutrient-induced satiety at 2 h into the dark phase. In a second experiment, rats received NTS injections of vehicle or orexin-A before intraperitoneal (IP) injection of vehicle or the satiation hormone cholecystokinin (CCK). NTS orexin-A pretreatment completely blocked the intake-suppressive effect of CCK on dark-phase chow intake. Finally, we investigated the role of endogenous hindbrain OX1R activation by pretreating rats with 4th-icv injection of vehicle or SB334867 followed by IG infusion of saline or Ensure just before a chocolate Ensure licking test session. IG nutrient infusion suppressed Ensure intake, and blockade of hindbrain OX1Rs significantly prolonged that intake-suppressive effect. We conclude that hindbrain OX1Rs are a mechanism though which hypothalamic orexin neurons can reduce animals' sensitivity to gastrointestinal nutrient load, allowing them to consume more food.

Intermittent High-Fat Diet Intake Reduces Sensitivity to Intragastric Nutrient Infusion and Exogenous Amylin in Female Rats.

OBJECTIVE: Intermittent (INT) access to a high-fat diet (HFD) can induce excessive-intake phenotypes in rodents. This study hypothesized that impaired satiation responses contribute to elevated intake in an INT-HFD access model. METHODS: First, this study characterized the intake and meal patterns of female rats that were subjected to an INT HFD in which a 45% HFD was presented for 20 hours every fourth day. To examine nutrient-induced satiation, rats received intragastric infusions of saline or Ensure Plus prior to darkness-onset food access. A similar design was used to examine sensitivity to the satiating effect of amylin. This study then examined whether an INT HFD influences amylin-induced c-Fos in feeding-relevant brain areas. RESULTS: Upon INT HFD access, rats consumed meals of larger size. The anorexic response to intragastric Ensure infusion and exogenous amylin treatment was blunted in INT rats on both chow-only and INT-HFD days of the diet regimen, compared with chow-maintained and continuous-HFD rats. An INT HFD did not influence amylin-induced c-Fos in the area postrema, nucleus of the solitary tract, and lateral parabrachial nucleus. CONCLUSIONS: Impaired satiation responses, mediated in part by reduced sensitivity to amylin, may explain the elevated intake observed upon INT HFD access and may play a role in disorders of INT overconsumption, including binge eating.