Liraglutide, a Long-Acting Glucagon-Like Peptide-1 Analog, Reduces Body Weight and Food Intake in Obese Candy-Fed Rats, Whereas a Dipeptidyl Peptidase-IV Inhibitor, Vildagliptin, Does Not

Abstract

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

Effects of liraglutide and sibutramine on food intake, palatability, body weight and glucose tolerance in the gubra DIO-rats

“…Six-week-old Sprague-Dawley rats were offered a two-choice diet consisting of standard rodent chow diet or the gubra diet, a highly palatable high-fat, high-sugar diet. After a six-month feeding period, body weight changes, ingestive responses and feeding behaviors were examined following daily administration of sibutramine and liraglutide for 23 d. Compared to the vehicle control, chronic administration of either sibutramine or liraglutide to high-fat/sugar-fed DIO-rats caused significant reductions in body weight gain, which is in agreement with previously reported data using other rodent DIO models [14,15,[31][32][33][34] . The body weight loss observed in both groups was mainly caused by decreasing levels of total fat mass as revealed by the weekly measurements of whole body composition.…”

“…Since then, numerous DIO models have been published using the general approach whereby diets composed of alternating components of fat and carbohydrates are administered to normal, lean rats or mice over long periods [8,10,20] . The so-called cafeteria diets, where animals have a choice of various palatable foods such as chocolate, peanuts etc, encourages overeating and hence provides highly relevant models for examining human diets in rodents [15,[21][22][23] .…”

“…The rats also have access to standard pelleted chow, and hence the model allows for assessment of diet preference. Compared to other cafeteria diets, the gubra diet is easy to dispense and measure, and does not change from day-to-day [15] . The diet promotes voluntary hyperphagia that results in rapid weight gain and increases fat pad mass.…”

Reversal of visceral adiposity in candy-diet fed female Wistar rats by the CB1 receptor antagonist rimonabant

“…24,25 In female rats, the candy-diet caused a body weight plateau, which was about 10% above that of the control rats receiving standard rat chow solely. 32 Therefore, this candy-diet animal model represented a model of just mild obesity compared with the genetic ones of, for example, fa/fa Zucker rats. 21,24,25 The control candy-diet rats had significantly elevated fat stores after 6 weeks on diet, which was maintained until the end of the study.…”

Serotonin controlling feeding and satiety

“…It remains to be investigated, if mCPP or other 5-HT agonists activate central GLP-1 neurons at all, as this would be a prerequisite for true interactions between GLP-1 and 5-HT. Due to the short half-life of GLP-1 itself, GLP-1 receptor agonists have been developed which are, due to their longer half-life, pharmacologically more feasible to suppress feeding [300,308,309] .…”