Glucagon-like eptide-1 mediates hedonic intake and food reward
Open Access
- Author:
- Pritchett, Carolyn Elisabeth
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- November 15, 2012
- Committee Members:
- Andras Hajnal, Dissertation Advisor/Co-Advisor
Andras Hajnal, Committee Chair/Co-Chair
Ralph Norgren, Committee Member
Robert G Levenson, Committee Member
Christopher J Lynch, Committee Member
Kirsteen Nairn Browning, Committee Member - Keywords:
- GLP-1
reward
dopamine
obesity
high fat diets
hedonic
food intake
mesolimbic - Abstract:
- Current theories on the cause and prevention of obesity highlight the importance of the reward system in feeding, food choices, and hyperphagia. Palatable foods, commonly high in fat and sugar content, can engage the reward system and increase motivation to procure and consume such foods, independent of caloric need or nutritional value. Excessive consumption of highly palatable foods is believed to be a key environmental factor in obesity rates. Of major concern are the complex and long-lasting changes to various neural systems following obesity. Among these include changes to mesolimbic dopamine signaling along the central reward pathway; altered dopamine signaling has been linked with both a genetic predisposition for obesity and dietary induced obesity. Recently, more attention has been given to alterations in the gut-brain system that occur with obesity, such as notable differences in the incretin hormone glucagon-like-peptide-1 (GLP-1). Interestingly, obesity-induced GLP-1 deficits appear to be reversed following Roux-en-Y gastric bypass surgery, and changes to GLP-1 and similar peptides have been theorized as critical factors in the success of this surgical procedure. While GLP-1 has been clearly defined as both an incretin and a satiety hormone, less is known about the influence of GLP-1 on systems driving hedonic intake and food reward. Furthermore, the debate continues as to the role of GLP-1 in obesity, and its precise impact in Roux-en-Y gastric bypass surgery. To investigate the role of GLP-1 on the dopamine reward system, and how GLP-1 is influenced in obesity, we investigated how temporarily altering the dopamine and GLP-1 systems of lean and dietary induced obese (DIO) rats influenced hedonic intake of palatable solutions using the synthetic GLP-1 agonist Exendin-4 and receptor specific dopamine antagonists. Peripherally administered dopamine antagonists led to significant reductions in the intake of palatable carbohydrates, with notable differences between the two dietary obese groups despite similar body weight gain; one group was fed a high fat-high energy diet and one fed a fat-carbohydrate high energy combination diet. Furthermore, these differences were dependent upon the receptor subtype targeted, with D1 receptor antagonism producing more potent reductions than D2 receptor antagonism, and upon the type of carbohydrate, with sucrose intake more susceptible to dopamine antagonism than fructose intake. These data indicate dopamine signals do change in obesity, and the type of diet leading to obesity can influence the extent and perhaps nature of such changes. This data implies that differential responses may occur to different palatable foods, and indicates why individuals may respond to different treatment regimens with various success rates. Using an identical animal model of two DIO groups, we again compared responses to sucrose and fructose in chow-fed lean and DIO rats after activation of the GLP-1 receptor by the synthetic analog Exendin-4. Exendin-4 (ip) reduced both sucrose and fructose intake, and the magnitude of the effect varied with respect to the obesogenic diet and the type of carbohydrate being tested. As in the dopamine receptor inhibition tests, all groups reduced sucrose intake following treatment, but the reduction in carbohydrate intake, particularly to fructose, was attenuated in animals made obese on the high-fat compared to the fat-carbohydrate combination diet. Upon establishing similar effects to dopamine receptor antagonism and GLP-1 receptor activation peripherally, we then explored the central GLP-1 system, localizing the effects of GLP-1 on both hedonic intake and food-reward. After establishing a role for GLP-1 within the ventral tegmental area (VTA) using behavioral methods, we then examined the anatomical and neural relationship between GLP-1 and the dopamine system using immunohistochemistry and electrophysiology. Our findings are the first to directly demonstrate that GLP-1 in the VTA is not only behaviorally important, altering both hedonic intake and the motivation to procure sucrose, but may also have powerful influence on the dopaminergic system through the presence of GLP-1 receptors throughout the VTA. GLP-1 receptors were not only found on VTA dopaminergic neurons, but microiontophoretic application of GLP-1 directly upon dopamine neurons also resulted in significantly altered firing. These novel findings represent a powerful new potential role for GLP-1 in the control of intake unrelated to hunger. Finally, using an animal model of Roux-en-Y gastric bypass surgery, we investigated whether differences would occur between surgical subjects and their dietary obese Sham-operated counterparts in their willingness to work for a sucrose reward, and how GLP-1 receptor activation changed operant responses. When administered peripherally, the long-lasting GLP-1 agonist Exendin-4 did not alter behaviors. When applied centrally, Exendin-4 attenuated the willingness of GBS and Sham rats to work for and consume a sucrose reward, and the GLP-1 receptor antagonist Exendin-9 blocked this effect. Furthermore, when looking at levels of GLP-1 receptor mRNA within the midbrain in our surgical and sham cohorts compared to naïve chow-fed lean controls, we found when comparing Roux-en-Y and Sham animals to our chow controls, the surgical procedure seemed to return receptor levels to a state more congruent with that observed in lean controls. Taken together, these data clearly demonstrate a role for GLP-1 in the control of intake related to palatable, hedonic foods. We described how activation of the peripheral GLP-1 system influences hedonic intake of palatable carbohydrates in a manner similar to blocking peripheral dopamine signaling. Furthermore, we found that central GLP-1 may play a particularly important role in the seeking and consumption of highly palatable foods by acting directly on the mesolimbic dopamine system. These findings indicate GLP-1 may have further clinical potential in reducing hedonic appetite and food cravings.