Exenatide reduces food intake and activates the enteric nervous system of the gastrointestinal tract and the dorsal vagal complex of the hindbrain in the rat by a GLP-1 receptor

Washington, Martha C.; Raboin, Shannon J.; Thompson, William E.; Larsen, Christina J.; Sayegh, Ayman I.

doi:10.1016/j.brainres.2010.05.002

Cited by 47 publications

(29 citation statements)

References 34 publications

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“…11,13,32). Systemic administration of the GLP-1-receptor agonist exendin-4 (Ex4) decreases intake of food and sucrose solution (3,5,6,35,68,72,74), and this effect is blocked by the GLP-1-receptor antagonist exendin-3(9 -39) (Ex9) (3,68,73,74), which, under certain conditions, independently increases food intake (Refs. 73, 74; although see Refs.…”

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confidence: 99%

Roux-en-Y gastric bypass in rats increases sucrose taste-related motivated behavior independent of pharmacological GLP-1-receptor modulation

Mathes

Bueter

Smith

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Roux-en-Y gastric bypass (RYGB) surgery has been shown to decrease consummatory responsiveness of rats to high sucrose concentrations, and genetic deletion of glucagon-like peptide-1 receptors (GLP-1R) has been shown to decrease consummatory responsiveness of mice to low-sucrose concentrations. Here we assessed the effects of RYGB and pharmacological GLP-1R modulation on sucrose licking by chow-fed rats in a brief-access test that assessed consummatory and appetitive behaviors. Rats were tested while fasted presurgically and postsurgically and while nondeprived postsurgically and 5 h after intraperitoneal injections with the GLP-1R antagonist exendin-3(9-39) (30 μg/kg), agonist exendin-4 (1 μg/kg), and vehicle in 30-min sessions during which a sucrose concentration series (0.01-1.0 M) was presented in 10-s trials. Other rats were tested postsurgically or 15 min after peptide or vehicle injection while fasted and while nondeprived. Independent of food-deprivation state, sucrose experience, or GLP-1R modulation, RYGB rats took 1.5-3× as many trials as sham-operated rats, indicating increased appetitive behavior. Under nondeprived conditions, RYGB rats with presurgical sucrose experience licked more to sucrose relative to water compared with sham-operated rats. Exendin-4 and exendin-3(9-39) impacted 0.3 M sucrose intake in a one-bottle test, but never interacted with surgical group to affect brief-access responding. Unlike prior reports in both clearly obese and relatively leaner rats given RYGB and in GLP-1R knockout mice, we found that neither RYGB nor GLP-1R blockade decreased consummatory responsiveness to sucrose in our less obese chow-fed rats. Collectively, these results highlight the fact that changes in taste-driven motivated behavior to sucrose after RYGB and/or GLP-1R modulation are very model and measure dependent.

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mentioning

confidence: 99%

Roux-en-Y gastric bypass in rats increases sucrose taste-related motivated behavior independent of pharmacological GLP-1-receptor modulation

Mathes

Bueter

Smith

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Given that rats predominantly feed during the dark cycle, it is not necessary to administer a second dose of the peptide for the reduction of food intake as would be necessary if using the drug for glycemic control. Additionally, dosages needed to produce a sustained weight loss were based on previous studies and were significantly higher in rats than in humans [26,44,45,46,47,48]. …”

Section: Discussionmentioning

confidence: 99%

Glucagon-Like Peptide-1 Agonist Exendin-4 Leads to Reduction of Weight and Caloric Intake in a Rat Model of Hypothalamic Obesity

Elfers¹,

Simmons

Roth

2012

Horm Res Paediatr

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Background: Hypothalamic obesity caused by damage of medial hypothalamic nuclei presents a therapeutic challenge. Glucagon-like peptide-1 agonist exenatide (synthetic version of exendin-4 (Ex4)), used for treatment of diabetes, causes weight loss via hindbrain signaling. Methods: We tested Ex4 in an established rat model of medial hypothalamic lesions. Lesion and control animals were administered either daily intraperitoneal injections of 1 µg·kg^–1 Ex4 or saline for 9 days. Results: In our rat model, a significant difference in percent baseline food intake (lesion –20.8%, control –13.6%; p < 0.001) and percent change in body weight (lesion –4.9%/9 days, control –3.2%/9 days; p < 0.05) was observed during Ex4 treatment compared with saline. Conclusion: Ex4 resulted in reduction of food intake and body weight. Follow-up studies are required to further elucidate its effects on energy homeostasis and to establish Ex4 as a potential drug for treatment of hypothalamic obesity.

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“…Thereby, the vagus nerve transmits the metabolic information to the NTS in the brainstem [59][60][61][62][63], which relays the glucose signal to hypothalamic nuclei [59,64]. The brain centralizes the metabolic information and generates new signals to guide the energetic flux towards tissues, either for energy use or storage.…”

Section: The Gut-to-brain Glp-1-dependent Axismentioning

confidence: 99%

“…Exenatide is a synthetic version of exendin-4 recently approved for clinical use in type 2 diabetic patients [90][91][92]. These peripheral effects are also associated with brain neuronal activations in the brainstem (area postrema, NTS, and dorsal motor nucleus of the vagus), and can be prevented by an intraperitoneal injection of exendin-9 [63]. Thus, the satiating effect of peripherally administered GLP-1 at least requires an activation of peripheral GLP-1 receptors, which metabolically transmits the signal of satiety to the brain using the vagus nerve.…”

Section: The Gut-to-brain Glp-1-dependent Axismentioning

confidence: 99%

GLP-1, the Gut-Brain, and Brain-Periphery Axes

Cabou¹,

Burcelin²

2011

Rev Diabet Stud

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■ AbstractGlucagon-like peptide 1 (GLP-1) is a gut hormone which directly binds to the GLP-1 receptor located at the surface of the pancreatic β-cells to enhance glucose-induced insulin secretion. In addition to its pancreatic effects, GLP-1 can induce metabolic actions by interacting with its receptors expressed on nerve cells in the gut and the brain. GLP-1 can also be considered as a neuropeptide synthesized by neuronal cells in the brain stem that release the peptide directly into the hypothalamus. In this environment, GLP-1 is assumed to control numerous metabolic and cardiovascular functions such as insulin secretion, glucose production and utilization, and arterial blood flow. However, the exact roles of these two locations in the regulation of glucose homeostasis are not well understood. In this review, we highlight the latest experimental data supporting the role of the gutbrain and brain-periphery axes in the control of glucose homeostasis. We also focus our attention on the relevance of β-cell and brain cell targeting by gut GLP-1 for the regulation of glucose homeostasis. In addition to its action on β-cells, we find that understanding the physiological role of GLP-1 will help to develop GLP-1-based therapies to control glycemia in type 2 diabetes by triggering the gut-brain axis or the brain directly. This pleiotropic action of GLP-1 is an important concept that may help to explain the observation that, during their treatment, type 2 diabetic patients can be identified as 'responders' and 'non-responders'.

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Exenatide reduces food intake and activates the enteric nervous system of the gastrointestinal tract and the dorsal vagal complex of the hindbrain in the rat by a GLP-1 receptor

Cited by 47 publications

References 34 publications

Roux-en-Y gastric bypass in rats increases sucrose taste-related motivated behavior independent of pharmacological GLP-1-receptor modulation

Roux-en-Y gastric bypass in rats increases sucrose taste-related motivated behavior independent of pharmacological GLP-1-receptor modulation

Glucagon-Like Peptide-1 Agonist Exendin-4 Leads to Reduction of Weight and Caloric Intake in a Rat Model of Hypothalamic Obesity

GLP-1, the Gut-Brain, and Brain-Periphery Axes

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