Peripheral Exendin-4 and Peptide YY3–36 Synergistically Reduce Food Intake through Different Mechanisms in Mice

Abstract

Glucagon-like peptide-1(7-36NH2) (GLP-1) and peptide YY(3-36NH2) (PYY(3-36NH2)) are cosecreted from the intestine in response to nutrient ingestion. Peripheral administration of GLP-1 or PYY(3-36NH2) decreases food intake (FI) in rodents and humans; however, the exact mechanisms by which these peptides regulate FI remain unclear. Male C57BL/6 mice were injected (ip) with exendin-4(1-39) (Ex4, a GLP-1 receptor agonist) and/or PYY(3-36NH2) (0.03-3 microg), and FI was determined for up to 24 h. Ex4 and PYY(3-36NH2) alone decreased FI by up to 83 and 26%, respectively (P < 0.05-0.001), whereas a combination of the two peptides (0.06 microg Ex4 plus 3 microg PYY(3-36NH2)) further reduced FI for up to 8 h in a synergistic manner (P < 0.05-0.001). Ex4 and/or PYY(3-36NH2) delayed gastric emptying by a maximum of 19% (P < 0.01-0.001); however, there was no significant effect on locomotor activity nor was there induction of taste aversion. Capsaicin pretreatment prevented the inhibitory effect of Ex4 on FI (P < 0.05), but had no effect on the anorexigenic actions of PYY(3-36NH2). Similarly, exendin-4(9-39) (a GLP-1 receptor antagonist) partially abolished Ex4-induced anorexia (P < 0.05), but did not affect the satiation produced by PYY(3-36NH2). Conversely, BIIE0246 (a Y2 receptor antagonist) completely blocked the anorexigenic effects of PYY(3-36NH2) (P < 0.001), but had no effect on Ex4-induced satiety. Thus, Ex4 and PYY(3-36NH2) suppress FI via independent mechanisms involving a GLP-1 receptor-dependent, sensory afferent pathway (Ex4) and a Y2-receptor mediated pathway (PYY(3-36NH2)). These findings suggest that administration of low doses of Ex4 together with PYY(3-36NH2) may increase the suppression of FI without inducing significant side effects.

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

“…), 5 the effect of exenatide, at the ED 50 dose, was sustained for 5 h post-injection. Although dose dependent, this effect has shown to be durable in normal mice for 24 h. 31 Sustained exenatide exposure produced a persistent reduction in body weight in both mice and rats, with a maximal weight loss at 4 weeks of 16 and 11%, respectively. The demonstrated action of peripheral exenatide to reduce weight in monogenic models of obesity 6,18,27,28 can now be Exenatide reduces body weight in high-fat-fed rats CM Mack et al extended to normal rats consuming an HF diet.…”

“…Acutely, peripherally administered exenatide potently inhibited 60 min food intake in fasted mice with an ED 50 of B2 mg/kg, consistent with previous reports. 31 In rats, the potency of exenatide to reduce food intake following i.p. or i.c.v.…”

“…35 We therefore examined the potential of exenatide to induce kaolin consumption in rats. As exenatide has also been shown to decrease locomotor activity, 31 we also examined exenatide's acute effect on general activity levels in rats. In both models, our goal was to discern doses at which food intake effects may be dissociated from potentially adverse actions of exenatide.…”

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

“…9,10 Endogenous release or intraperitoneal GLP-1R agonist delivery triggers a set of responses that include reduced food intake, [11][12][13][14] inhibition of gastric emptying, 9,14 stimulation of glucosedependent insulin secretion 15,16 and tachycardia. [17][18][19][20][21] GLP-1R ligand is also supplied by proglucagon-expressing neurons of the caudal brainstem that project to GLP-1Rs, which are distributed throughout the brain.…”

“…33 Hypothalamic processing had been hypothesized to mediate the profile of responses evoked by peripheral GLP-1R ligand delivery. 11,30,42 Peripheral administration of GLP-1R agonists induces central neuronal activation, as indicated by Fos-like immunoreactivity 10,11,18,42 and a magnetic resonance imaging signal, 30 in the paraventricular nucleus and, in some reports, the arcuate nucleus and ventral medial hypothalamus nuclei. The neural mediation of the intake inhibition resulting from peripheral GLP-1R stimulation was examined earlier 11 by interrupting connections between the caudal brainstem and hypothalamus with midbrain knife-cuts.…”