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

Abstract

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.

Figure 1

A–B: Neither 4^th icv administration of leptin 0.4μg nor Ex-4 0.05μg influenced food intake, whereas the combination of two drugs produced significant suppression of 24h food intake. The degree of intake suppression of drug combination was equivalent to the predicted additive suppression (showed as dotted line). C–D: Co-administration of leptin 0.4μg and Ex-4 0.05μg induced a moderate but non-significant 24h body weight loss. However, the suppression of body weight by the drug combination was equivalent to the predicted additive suppression (showed as dotted line). Bars with different letters are considered significantly different (P< 0.05).

Figure 2

4^th icv leptin 3μg or Ex-4 0.1μg alone significantly reduced 3h, 6h and 24h food intake and decreased 24h body weight (A, C). Co-administration of leptin 3μg and Ex-4 0.1μg produced a significantly greater degree of intake suppression at 6h and 24h (A), as well as greater degree of 24h body weight loss (C) relative to each drug administered alone. The magnitude of 6h and 24h intake suppression and 24h body weight loss produced by the drug combination was equivalent to the predicted additive suppression (B, D, showed as dotted line). Bars with different letters are considered significantly different (P< 0.05).

Figure 3

Three very high doses (20μg, 30μg and 40μg) of leptin were administered 4^th icv to determine the maximum intake suppression that could be achieved by hindbrain leptin delivery. Each dose significantly suppressed 6h and 24h food intake and 24h body weight gain (A, B). However, no significant difference was achieved between each dose. Bars with different letters are considered significantly different (P< 0.05).

Figure 4

Leptin 20μg and Ex-4 (4^th icv) alone significantly reduced 6h and 24h food intake, as well as 24h body weight. Co-administration of leptin and Ex-4 produced a greater degree of intake suppression at 6h and 24h, as well as 24h body weight loss relative to each drug alone (A, C). The intake and body weight gain suppressions are also illustrated by the combination of Ex-4 and leptin (B, D). Bars with different letters are considered significantly different (P< 0.05).

Figure 5

A–B: Leptin (8μg; 4^th icv) significantly reduced 1h, 3h, 6h and 24h food intake and 24h body weight. GLP-1 receptor antagonist Ex-9 (10μg; 4^th icv) had no effect on food intake when administered alone. However, Ex-9 attenuated leptin induced intake suppression at 1h and 3h, as well as 24h body weight loss. Bars with different letters are considered significantly different (P< 0.05).