•GLP-1R agonist caused equal suppression of eating in wildtype and Brattleboro rats.•Brattleboro rats were hyperresponsive to the drinking suppression by GLP-1R agonist.•There were sex and genotype ...differences in GLP-1R antagonist response.•Female Brattleboro rats had wildtype-like cycle-associated changes in food intake.•Estrous cycle had no effect on fluid intake in Brattleboro rats.
Eating and drinking co-occur and many of the same mechanisms that control one are involved in the control of the other, making it difficult to isolate specific mechanisms for the control of fluid intake. Glucagon-like peptide-1 (GLP-1) is a peptide that seems to be involved in the endogenous control of both ingestive behaviors, but we lack a thorough understanding of how and where GLP-1 is acting to control fluid intake. Vasopressin-deficient Brattleboro rats are a model of hereditary hypothalamic diabetes insipidus that have been used extensively for the study of vasopressin actions in behavior and physiology. Here, we propose that these rats, that eat normally but drink excessively, provide a useful model to dissociate central controls of food and fluid intakes. As an initial step toward establishing this model for these purposes, we focused on GLP-1. Similar to the effect observed after treatment with a GLP-1 receptor (GLP-1R) agonist, the intake difference between wildtype and Brattleboro rats was largely a function in the number of licking bursts, indicating differences in post-ingestive feedback (e.g., satiation). When given central injections of a GLP-1R agonist, the effect on feeding was comparable between wildtype and Brattleboro rats, but the effect of drug on fluid intake was markedly exaggerated in Brattleboro rats. Additionally, Brattleboro rats did not respond to GLP-1R antagonism, whereas wildtype rats did. Taken together, these results suggest that Brattleboro rats exhibit a selective disruption to GLP-1′s control of water intake. Overall, these experiments provide foundational studies of the ingestive behavior of Brattleboro rats and demonstrate the potential to use these rats to disentangle the effects of GLP-1 on food and fluid intakes.
•High-fat diet was associated with less drinking.•Drinking effects of a central or peripheral GLP-1 agonist were unaffected by diet.•Hypophagia caused by a peripheral injection of GLP-1 agonist was ...reduced in HFD rats.•Hypophagia caused by a central injection of GLP-1 agonist was unaffected by diet.
Rats that are maintained on a high-fat diet (HFD) differ from controls in many ways, but how HFD maintenance affects water intake and drinking behavior has not been well studied. This is unfortunate because diet and obesity may influence fluid balance in humans through a mechanism that is poorly understood. We therefore tested the hypothesis that HFD maintenance affects water intake in rats. Water intake and drinking behavior are, in part, controlled by the actions of glucagon-like peptide-1 (GLP-1), a peptide which is well studied for its hypophagic effects. Previous studies have shown that HFD maintenance impairs the ability of GLP-1 receptor agonists to suppress food intake when the drug is administered peripherally, but not centrally. The effects of GLP-1 on fluid intake are thought to rely more on central receptor activation; therefore, a secondary aim of these experiments was to shed additional light on the location of GLP-1 responsive cells that mediate feeding vs drinking behavior. We maintained male Sprague–Dawley rats on HFD or low-fat diet (LFD) for six weeks and measured body weight, food intake, water intake, and drinking behavior. We then tested the relative contributions of diet and body weight on food intake and water intake after peripheral and central injections of GLP-1 receptor agonist Exendin-4 (Ex4). We found that HFD maintenance reduced the amount of water consumed, when intake was corrected for body weight. Consistent with other reports, rats on HFD showed a smaller suppression of food intake when given Ex4 peripherally, but not centrally. Water intake suppression when given Ex4 did not differ by diet or body weight regardless of injection site, however, adding support to the hypothesis that only central GLP-1 receptors are involved in water intake.
Proper fluid balance is critical for life. Learning plays an important role in shaping the appetitive behaviors required for drinking. Children often forego drinking plain water and instead consume ...beverages such as milk or juice. What effect this may have on adult thirst responses remains an open question. To model aspects of the human condition, we bred Sprague-Dawley rats and prevented the pups from obtaining fluid other than from nursing. Pups were weaned onto either tap water, 5% sucrose, or 0.45% saline, and given access to only that fluid for at least 7 weeks. We then measured intake of water or sucrose/saline in one-bottle tests after mild hypertonic saline (HS) injection, or overnight fluid deprivation, and in two-bottle tests after HS injection while rats were maintained on their respective fluids, and after all subjects had only water to drink for a week. We found that sucrose- and saline-maintained rats drank less water than did controls after the HS challenge. After overnight fluid deprivation, rats maintained on saline drank less water and more saline, but there was no difference in intake between water-maintained and sucrose-maintained rats. Differences in licking patterns, including more licks/burst for sucrose by sucrose-maintained rats were detected, even in cases when total intake was not different. These data provide evidence that adult rat water intake can be reduced by exclusively drinking sucrose or saline early in life.
Fluid imbalance is a pervasive and costly problem. One way that the nervous system controls fluid intake is through the central actions of glucagon-like peptide-1 (GLP-1); however, it is not yet ...known where or how GLP-1 is acting in the brain to control fluid intake. One problem in furthering our understanding of GLP-1’s role in the control of fluid intake is that GLP-1 affects both drinking and feeding and these behaviors are intertwined. This dissertation uses a rat model that has a genetic mutation leading to extremely high water intake, but normal food intake, to dissociate these normally intertwined behaviors in order to better understand the neural substrates underlying the behaviors. We have previously shown that there are differences in these rats’ pharmacological response to a GLP-1 receptor (GLP-1R) agonist, and the experiments in this dissertation tested if these findings reflect differences in the endogenous GLP-1 system. To this end, the experiments used immunohistochemistry for markers of activation within the GLP-1 system to evaluate the nucleus of the solitary tract (NTS), which is involved in the control of water intake and food intake, in response to pharmacological and physiological stimuli. We found that there was more cellular activation, as measured by Fos immunohistochemistry, after a pharmacological stimulus in both genotypes. When examining the NTS as a whole, only wildtype rats had elevated Fos associated with the act of drinking. Additionally, we evaluated pCREB as a measure of GLP-1 specific activation and there were no differences between any of the groups, suggesting that pCREB may not be a valuable measure in these circumstances. Overall, these results suggest that the NTS may be a key brain region that is both involved in the Brattleboro rat’s hypersensitive response to exogenous GLP-1 and the Brattleboro rat’s lack of water intake satiety.
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