Effects of Exendin‐4 Alone and With Peptide YY3–36 on Food Intake and Body Weight in Diet‐Induced Obese Rats

Jun 19, 2010Obesity (Silver Spring, Md.)

How exendin-4 alone and with peptide YY(3-36) affect eating and weight in rats with diet-induced obesity

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Abstract

Exendin-4 infusion at 15-20 pmol/h resulted in a 24 ± 1% reduction in daily food intake over 17 days in diet-induced obese rats.

Significant weight loss following gastric bypass surgery is linked to increased levels of gut hormones that reduce appetite.
Different dosing strategies of exendin-4 were tested over 10 weeks in diet-induced obese rats.
A specific dosing regimen of exendin-4 led to a 7% decrease in body weight.
Co-infusion of exendin-4 with peptide YY(3-36) did not extend the reduction in food intake beyond 10 days.
Decreased effectiveness of treatments over time suggests potential receptor downregulation and tolerance.
After a break from treatment, daily food intake significantly increased, indicating a possible counteracting mechanism.

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Significant weight loss following Roux-en-Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY(3-36) (PYY(3-36)). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY(3-36) that produces a sustained reduction in daily food intake and body weight in diet-induced obese (DIO) rats. We tested 12 exendin-4 strategies over 10 weeks. Exendin-4 infused during the first and last 3 h of the dark period at 15-20 pmol/h (0.15 nmol/kg/day) produced a sustained 24 ± 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin-4 and PYY(3-36) produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY(3-36) on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin-4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co-infusion of exendin-4 and PYY(3-36) does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin-4 alone and with PYY(3-36) on food intake and body weight.

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Effects of Exendin‐4 Alone and With Peptide YY3–36 on Food Intake and Body Weight in Diet‐Induced Obese Rats

Abstract

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