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Metabolic effects of the glucagon-like peptide-1 analog liraglutide and the dipeptidyl peptidase-IV inhibitor vildagliptin were compared in rats made obese by supplementary candy feeding. Female Sprague-Dawley rats were randomized to 12-week diets of chow or chow plus candy. The latter were randomized for 12 further weeks to continue their diet while receiving 0.2 mg/kg liraglutide twice daily subcutaneously, 10 mg/kg vildagliptin twice daily orally, or vehicle or to revert to chow-only diet. Energy expenditure was measured, and oral glucose tolerance tests (OGTTs) were performed. Body composition was determined by dual-energy X-ray absorptiometry scanning, and pancreatic ␤-cell mass was determined by histology. Candy feeding increased weight, fat mass, and feedingassociated energy expenditure. Liraglutide or reversal to chow diet fully reversed weight and fat gains. Liraglutide was associated with decreased calorie intake and shifted food preference (increased chow/decreased candy consumption). Despite weight loss, liraglutide-treated rats did not decrease energy expenditure compared with candy-fed controls. Vildagliptin affected neither weight, food intake, nor energy expenditure. OGTTs, histology, and blood analyses indirectly suggested that both drugs increased insulin sensitivity. Liraglutide and vildagliptin inhibited obesityassociated increases in ␤-cell mass. This was associated with weight and fat mass normalization with liraglutide, but not vildagliptin, where the ratio of ␤-cell to body mass was low. Diabetes 56:8 -15, 2007

The data suggest that the 'gastric inhibitory' GLP-1 receptors in rats are subject to desensitization/tachyphylaxis but that this effect is dependent on full 24-h exposure as obtained by liraglutide. The body weight-lowering effects of GLP-1 receptor stimulation are not subject to desensitization. These data indicate that regulation of appetite signals in the brain, and not GE, is the main mechanism for liraglutide-induced weight loss.

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