Central glucagon-like peptide 1 receptor (GLP-1R) stimulation suppresses food intake, and hindbrain GLP-1 neurons project to numerous feeding-relevant brain regions. One such region is the nucleus accumbens (NAc), which plays a role in reward and motivated behavior. Using immunohistochemical and retrograde tracing techniques in rats, we identified a robust projection from GLP-1 neurons in the nucleus of the solitary tract to the NAc. We hypothesized that activation of NAc GLP-1Rs suppresses feeding. When injected into the NAc core of rats at doses subthreshold for effect when administered to the lateral ventricle, GLP-1 significantly reduced food intake relative to vehicle at 1, 2, and 24 h posttreatment. The same doses had no effect when injected into the NAc shell. NAc core treatment with ventricle-subthreshold doses of the GLP-1R antagonist exendin (9–39) caused significant hyperphagia at 2 h posttreatment, suggesting that endogenous stimulation of NAc core GLP-1Rs plays a role in limiting food intake. It has been suggested that GLP-1 can cause nausea, but we found that NAc core administration of GLP-1 did not cause a conditioned taste aversion to saccharin, suggesting that the anorexic effect of NAc core GLP-1 is not caused by malaise. Finally, we observed that NAc core injection of GLP-1 significantly increased c-Fos expression in the NAc core. We conclude that that GLP-1Rs in the NAc play a physiologic role in food intake control, and suggest that the GLP-1 projection to NAc core may link satiation signal processing in the hindbrain with forebrain processing of food reward.
Brain oxytocin is known to play a role in the control of food intake, and recent studies suggest that stimulation of central oxytocin receptors selectively suppresses carbohydrate intake. The specific oxytocin projection sites and receptor populations involved in this response are as yet unidentified. We hypothesized that oxytocin receptors in the ventral tegmental area (VTA) may play a role in limiting sucrose intake, because the VTA is known to influence palatable food intake. We first performed a dose response study in which we observed that intra-VTA oxytocin injection significantly suppressed intake of a 10% sucrose solution during a 30-min test session by 13.35% - 20.5% relative to vehicle treatment. Doses of intra-VTA oxytocin that suppressed sucrose intake had no effect on water intake. Next we examined the effects of two oxytocin receptor antagonists, (d(CH2)51,Tyr(Me)2,Orn8)-Oxytocin (OVT) and L-368,899. Each of these antagonists significantly increased 10% sucrose intake by 17% - 20.5% relative to vehicle when delivered directly into the VTA, at doses subthreshold for effect if injected into the cerebral ventricles. Finally, we observed that the effect of intra-VTA oxytocin to suppress 10% sucrose intake was significantly attenuated by pretreatment with L-368,899, supporting the suggestion that the VTA oxytocin treatment suppresses intake through action at oxytocin receptors. These findings support the suggestion that endogenous oxytocin action within the VTA suppresses sucrose intake. We conclude that oxytocin receptors in the VTA play a physiologic role in the control of sucrose ingestion.
Recent evidence suggests that the glucagon-like peptide-1 (GLP-1) neuronal projection to the nucleus accumbens core (NAcC) contributes to food intake control. To investigate the role of endogenous stimulation of GLP-1 receptors (GLP-1R) in NAcC, we examined the effects of the GLP-1R antagonist exendin-(9 -39) (Ex9) on meal pattern and microstructure of ingestive behavior in rats. Intra-NAcC Ex9 treatment selectively increased meal size relative to vehicle in rats consuming 0.25 M sucrose solution or sweetened condensed milk. Microstructural analysis revealed effects of NAcC Ex9 on initial lick rate and the size and duration of licking bursts in rats consuming 0.1 or 0.25 M sucrose, suggesting that blockade of NAcC GLP-1R increases palatability. Because NAcC Ex9 did not affect licking for nonnutritive saccharin (0.1%), we suggest that the presence of nutrients in the gut may be required for endogenous stimulation of NAcC GLP-1R. Consistent with this, we also found that the meal sizesuppressive effects of intragastric nutrient infusion were attenuated by NAcC delivery of Ex9 at a dose that had no effect when delivered alone. Analysis of licking patterns revealed that NAcC Ex9 did not reverse intragastric nutrient-induced suppression of burst number but rather blunted the effect of nutrient infusion on meal size primarily by increasing the size and duration of licking bursts. Together, our results suggest that NAcC Ex9 influences taste evaluation. We conclude that GLP-1 released in NAcC in response to gastrointestinal nutrients reduces the hedonic value of food. licking microstructure; palatability; satiation; glucagon-like peptide-1; nucleus accumbens GLUCAGON-LIKE PEPTIDE-1 (GLP-1) NEURONS in the hindbrain nucleus of the solitary tract (NTS) have been hypothesized to play a role in the control of food intake since it was first shown that intracerebroventricular injection of GLP-1 potently suppresses feeding (22). These neurons are activated by meal-related signals such as gastric distention (23) and receive direct vagal afferent input (13). A physiological role for brain GLP-1 is suggested by studies showing that either pharmacological blockade of GLP-1 receptors (GLP-1R) or siRNA-mediated knockdown of NTS GLP-1 expression increases food intake and body weight (16, 3). NTS GLP-1 cells project widely throughout the brain to nuclei traditionally considered important for energy homeostasis (e.g., the paraventricular nucleus of the hypothalamus) but also to nuclei associated with reward and motivation such as the ventral tegmental area and the nucleus accumbens (NAc) (1, 10, 18). Here, we focus on the role of GLP-1R in the NAc core (NAcC) subregion. We targeted the NAcC because our previous research suggests that GLP-1R in core, but not shell, affect feeding (10). Recent studies have shown that stimulation of GLP-1R in this nucleus suppresses food intake, whereas site-specific blockade of GLP-1R increases intake (1, 10). Importantly, NAcC GLP-1R stimulation does not condition a taste aversion (10), nor does it induce...
Previous data suggests that the adiposity signal leptin reduces food intake in part by enhancing sensitivity to short-term signals that promote meal termination, including glucagon-like peptide 1 (GLP-1). We hypothesized that maintenance on a high-fat (HF) diet, which causes resistance to leptin, would impair GLP-1′s ability to reduce food intake. To test this hypothesis, we examined the anorexic responses to intraperitoneal injection of 100 μg/kg GLP-1 and 1 μg/kg exendin-4 (Ex-4), the potent, degradation resistant GLP-1 receptor agonist, in Wistar rats maintained on a low-fat (10%; LF) or HF (60%) diet for 4-6 weeks. Rats maintained on each of these diets were tested twice, once while consuming LF food and once while consuming HF food, to distinguish between effects of acute vs. chronic consumption of HF food. LF-maintained rats tested on LF diet reduced 60-min dark phase intake in response to GLP-1, but HF-maintained rats failed to respond to GLP-1 whether they were tested on HF or LF diet. LF-maintained rats tested on HF diet also showed no response, suggesting that even brief exposure to HF diet can impair sensitivity to GLP-1 receptor activation. Both LF- and HF-maintained rats showed significant anorexic responses to Ex4 at 4 h post-treatment, but only LF-maintained rats had significantly reduced intake and body weight 24 h after injections. To determine whether the ability of endogenous GLP-1 to promote satiation is impaired by HF maintenance, we examined the response to exendin 3 (9-39) (Ex9), a GLP-1 receptor antagonist. In LF-maintained rats, Ex9 increased intake significantly, but HF-maintained rats reduced food intake in response to Ex9. These data support the suggestion that maintenance on HF diet reduces the anorexic effects of GLP-1 receptor activation, and this phenomenon may contribute to overconsumption of high-fat foods.
Rationale Brain orexin 1 receptors (OX1Rs) are involved in food-motivated behavior. Most research has focused on fore-brain OX1R populations, but hindbrain OX1Rs affect feeding. We hypothesized that hindbrain OX1Rs affect the reward value of food. Objectives We examined the effects of hindbrain OX1R stimulation or blockade on motivation for food, palatable high-fat (HF) food intake, and food-conditioned place preference. Methods Rats trained to lever press for sucrose on a progressive ratio (PR) schedule received fourth intracerebroventricular (icv) injections of vehicle, orexin-A (0.1–1 nmol), or the OX1R antagonist SB334867 (10–20 nmol) before operant test sessions. Effects of these treatments on HF food intake during daily 1-h tests were assessed with fourth icv and nucleus of the solitary tract (NTS) injections. We conditioned a place preference by pairing HF food with one side of a two-sided chamber and then examined the effect of 20 nmol fourth icv SB334867 on the expression of that preference. Results In ad lib fed rats on the PR schedule, fourth icv orexin-A significantly increased responding and breakpoint relative to the vehicle. In 24-h food-deprived rats, fourth icv SB334867 significantly decreased responding and breakpoint. Orexin-A delivered to the fourth ventricle (0.1 nmol) or NTS (0.01 nmol) increased HF diet intake. Fourth icv SB334867 did not affect HF food intake, but SB334867 delivered either fourth icv (20 nmol) or intra-NTS (5–10 nmol) suppressed chow intake. Expression of HF food-conditioned place preference was inhibited by fourth icv SB334867. Conclusions Hindbrain OX1R activity affects food-motivated operant behavior and may play a role in responding to cues that predict palatable food.
Hypothalamic orexin neurons project to the hindbrain, and 4th-ventricle intracerebroventricular (4th-icv) injection of orexin-A treatment increases food intake. We assessed the effects of hindbrain orexin-A and the orexin-1-receptor antagonist SB334867 on meal pattern in rats consuming standard chow. When injected 4th-icv shortly before dark onset, lower doses of orexin-A increased food intake over a 2-h period by increasing the size of the first meal relative to vehicle, whereas the highest dose increased food intake by causing the second meal to be taken sooner. Conversely, hindbrain SB334867 reduced food intake by decreasing the size of the first meal of the dark phase. We also examined the effects of 4th-icv orexin-A and SB334867 on locomotor activity. Only the highest dose of orexin-A increased activity, and SB334867 had no effect. In addition, hindbrain SB334867 induced c-Fos in the nucleus of the solitary tract. These data support the suggestion that endogenous hindbrain orexin-A acts to limit satiation. Both orexin-A and the pancreatic satiation hormone amylin require an intact area postrema to affect food intake, so we asked whether 4th-icv orexin-A impairs the satiating effect of peripheral amylin treatment. Amylin reduced the size of the first meal of the dark cycle when rats were pretreated with 4th-icv saline, yet amylin was ineffective after 4th-icv orexin-A pretreatment. Using double-label immunohistochemistry, we determined that some orexin-A fibers in the area postrema are located in proximity to amylin-responsive neurons. Therefore, hindbrain orexin-A may increase food intake, in part, by reducing the ability of rats to respond to amylin during a meal.
Taste stimuli are normally dissolved in saliva prior to interacting with their respective receptor targets. There are hundreds of proteins in saliva, and it has been hypothesized that these proteins could interact with either taste stimuli or taste receptors to alter taste signaling and diet acceptance. However, the impact of these proteins on feeding has been relatively unexplored using rodent models. We have developed a novel technique for saliva collection that allows us to link salivary protein expression with feeding behavior. First, we monitored the microstructure of rats' feeding patterns on a 0.375% quinine diet (Q-diet) while tracking changes in salivary protein expression. We found 5 protein bands were upregulated by diet exposure to Q-diet and upregulation of a subset of these bands were statistically related to increased diet acceptance, including changes in behavioral measures that are thought to represent both orosensory and postingestive signaling. In a second experiment, we measured the licking to a range of quinine solutions (0.01-1.0mM) before and after the animals were exposed to a tannic acid diet that altered salivary protein expression. Rats found the quinine solutions less aversive after salivary protein altering diets. In a third experiment we recorded the response of the chorda tympani (CT) nerve while delivering quinine solutions (0.3-30mM) to the front of the tongue dissolved in either "donor saliva" containing salivary proteins or donor saliva which has had the salivary proteins removed. Donor saliva was collected from a separate group of animals using isoproterenol and pilocarpine. The samples containing salivary proteins resulted in lower nerve responses than those without salivary proteins. Together these data suggest that salivary proteins are capable of altering taste-guided behaviors and taste nerve signaling.
Hypothalamic orexin neurons project to numerous brain areas, including the ventral tegmental area (VTA), which is involved in motivation and food-seeking behavior. Here we address how exogenously administered orexin-A and endogenous orexin 1 receptor (OX1R) activation in the VTA affects feeding behavior. We hypothesized that orexin-A and OX1R antagonist SB334867 delivered to the VTA, at doses that were subthreshold for effect when injected into the ventricle, would affect intake of palatable foods in multiple test situations. We first used a hedonic feeding model in which satiated rats selectively consume a high-fat diet (HFD). Intra-VTA orexin-A stimulated additional consumption of chow and increased HFD intake in this model. In ad libitum-fed rats given daily 30-min test sessions, intra-VTA orexin-A also increased intake of HFD and 0.1 M sucrose. Further analysis of licking patterns revealed that that VTA orexin-A increased meal size and licking burst size only toward the end of the meal. Consistent with this finding, a subthreshold dose of VTA orexin-A prevented intake suppression induced by gastrointestinal nutrient infusion. Surprisingly, intra-VTA orexin-A had no effect on operant responding for sucrose pellets on a progressive ratio schedule of reinforcement. A role for endogenous VTA OX1R stimulation is supported by our finding that bilateral VTA injection of the selective OX1R antagonist SB334867 suppressed 0.1 M sucrose intake. Together, our data suggest that OX1R activity in the VTA facilitates food intake, potentially by counteracting postingestive negative feedback that would normally suppress feeding later in a meal.
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