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Stimulation of the G protein coupled receptor GPR120 has been shown to have anti-inflammatory and insulin-sensitizing effects, to promote glucagon like peptide-1 (GLP-1) secretion, and to play a key role in sensing dietary fat and control energy balance. In a search for differentially expressed genes potentially involved in food intake and body-weight regulation we identified GPR120 to be differentially regulated in the intestine of selectively bred diet induced obese (DIO) and diet resistant (DR) rats. Subsequently we investigated the effect of GPR120 receptor stimulation with the long chain fatty acid alpha linolenic acid (ALA) on GLP-1 secretion in rats. Independent of diet (high or low fat), GPR120 expression showed a two-fold increase in the intestine of DIO compared to DR rats. In situ hybridization revealed a broad expression of GPR120 in the gut mucosa in both intestinal epithelial and endocrine cells. Using double in situ hybridization GPR120 mRNA did not appear to be enriched in preproglucagon expressing L-cells. In line with the anatomical data, ALA administration did not increase circulating GLP-1 levels. Our data shows a widespread expression of GPR120 in the gut epithelium and can not confirm a major role for GPR120 in the regulation of GLP-1 secretion. The broad expression of GPR120 in the gut epithelium supports reports indicating a putative role of GPR120 as a sensor of dietary fat.

The availability of useful animal models reflecting the human obesity syndrome is crucial in the search for novel compounds for the pharmacological treatment of obesity. In the current study, we have performed an extensive characterization of the obesity syndrome in a polygenetic animal model, namely the selectively bred diet-induced obese (DIO) and diet-resistant (DR) rat strains. We show that they constitute useful models of the human obesity syndrome. DIO and DR rats were fed either a high-energy (HE) or a standard chow (Chow) diet from weaning to 9 months of age. Metabolic characterization including blood biochemistry and glucose homeostasis was examined at 2, 3, 6, and 9 months of age. Furthermore, in 6-month-old HE-fed DIO rats, the anti-obesity effects of liraglutide and sibutramine were examined in a 28-day study. Only HE-fed DIO rats developed visceral obesity, hyperleptinemia, hyperinsulinemia, and dyslipidemia, and showed a worsening of glucose tolerance over time. In line with the hyperlipidemic profile, a severe hepatic fat infiltration was observed in DIO rats at 6 months of age. The effects of liraglutide and sibutramine were tested in 6-month-old DIO rats. Both compounds effectively reduced food intake and body weight in DIO rats. Liraglutide furthermore improved glucose tolerance when compared with sibutramine. Our data highlights the usefulness of a polygenetic animal model for screening of compounds affecting food intake, body weight, and glucose homeostasis. Furthermore, the results underscore the effectiveness of GLP-1 mimetics both as anti-diabetes and anti-obesity agents.