Hindbrain leptin and glucagon-like-peptide-1 receptor signaling interact to suppress food intake in an additive manner

Jan 18, 2012International journal of obesity (2005)

Combined signals in the lower brain area add up to reduce eating

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Abstract

The maximum food intake suppression achievable by hindbrain leptin alone in non-obese rats is approximately 33%.

Hindbrain leptin receptor (LepR) and glucagon-like-peptide-1 receptor (GLP-1R) signaling interact to control food intake and body weight in an additive manner.
Co-administration of the GLP-1R agonist exendin-4 enhances the intake suppressive effects of leptin beyond what leptin can achieve alone.
Blockade of hindbrain GLP-1R signaling reduces the intake inhibitory effects of leptin, indicating the relevance of GLP-1R in endogenous food intake control.
These findings suggest that combined activation of LepR and GLP-1R may be a promising target for obesity treatment.

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BACKGROUND: The physiological control of feeding behavior involves modulation of the intake inhibitory effects of gastrointestinal satiation signaling via endogenous hindbrain leptin receptor (LepR) and glucagon-like-peptide-1 receptor (GLP-1R) activation.

DESIGN AND RESULTS: Using a variety of dose-combinations of hindbrain delivered (4th intracerebroventricular; i.c.v.) leptin and the GLP-1R agonist exendin-4, experiments demonstrate that hindbrain LepR and GLP-1R signaling interact to control food intake and body weight in an additive manner. In addition, the maximum intake suppressive response that could be achieved by 4th i.c.v. leptin alone in non-obese rats (∼33%) was shown to be further suppressed when exendin-4 was co-administered. Importantly, it was determined that the interaction between hindbrain LepR signaling and GLP-1R signaling is relevant to endogenous food intake control, as hindbrain GLP-1R blockade by the selective antagonist exendin-(9-39) attenuated the intake inhibitory effects of hindbrain leptin delivery.

CONCLUSIONS: Collectively, the findings reported here show that hindbrain LepR and GLP-1R activation interact in at least an additive manner to control food intake and body weight. As evidence is accumulating that combination pharmacotherapies offer greater sustained food intake and body weight suppression in obese individuals when compared with mono-drug therapies or lifestyle modifications alone, these findings highlight the need for further examination of combined central nervous system GLP-1R and LepR signaling as a potential drug target for obesity treatment.

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Hindbrain leptin and glucagon-like-peptide-1 receptor signaling interact to suppress food intake in an additive manner

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