Poster Session 1 - E7
1Melanie A Markovic, 1,2Patricia L Brubaker
1 Departments of Physiology; 2 Medicine, University of Toronto, 1 King’s College Circle, Toronto, Ontario, M5S 1A8 Canada,
Glucagon-like peptide 2 (GLP-2) is an intestinal-specific growth hormone secreted by the enteroendocrine L-cell. It is known to increase lipid uptake as well as chylomicron and triglyceride secretion in humans in the post-absorptive state. In mice, GLP-2 has been shown to increase postprandial lipid absorption and chylomicron production through CD36. The lack of expression of the GLP-2 receptor in enterocytes requires GLP-2 to elicit its effects via downstream mediators. We have previously shown that insulin-like growth factor-1 (IGF-1) is required for GLP-2 induced proliferation and enhanced barrier function, effects that are mediated via the intestinal epithelial IGF-1 receptor (IE-IGF-1R). It is unknown whether this pathway is required for the GLP-2 induced increase in fat absorption, or if other fat transporters are upregulated with GLP-2 treatment. It is also unknown whether the IE-IGF-1R itself plays a role in the lipid absorption pathway. To answer these questions, inducible IE-IGF-1R knockout (KO) and control (fl/fl and villin-cre ± tamoxifen, and fl/fl-cre - tamoxifen) mice were treated for 11 days with either long-acting h(GLY2)GLP-2 or vehicle. The IE-IGF-1R was found to be required for the 2.5-fold increase in CD36 protein levels after GLP-2 treatment (p-value < 0.05), as KO mice failed to respond to treatment (n=7-10). Protein expression of fatty acid transport protein 4, FATP4, increased over 4-fold with GLP-2 treatment (p < 0.05), an effect that was also abrogated in the IE-IGF-1R KO mice (n=7-10). The receptor itself may play a role in lipid absorption as KO mice, regardless of treatment, appeared to have an accumulation of fat in their enterocytes (n=2), as observed via transmission electron microscopy. Furthermore, FATP4 mRNA expression was reduced 40% in KO mice, as compared to the control animals (n=8-15; p < 0.05). When put on a Western diet for 18 weeks, the KO mice displayed similar changes in body weight, insulin tolerance, food intake, and small intestinal weight, as compared to controls (n=5-9). When given a duodenal fat tolerance test with radioactive triolein, control mice on the Western diet had significantly lower levels of plasma radioactivity as compared to chow controls (n=5-9, p<0.01). However, KO mice on the Western diet displayed no difference in plasma radioactivity compared to chow KO mice. Collectively, these results suggest a novel role for the IE-IGF-1R in lipid handling in mice, under homeostatic as well as GLP-2 treatment conditions.