Glucagon-like Peptide-2 Acts through Central GLP-2R and MC4R in Mobilizing Stored Lipids from the Intestine

Dysregulated gut lipid handling contributes to atherogenic dyslipidemia, a cardiovascular disease risk factor for patients with diabetes. The gut hormone glucagon-like peptide-2 (GLP-2) plays significant roles in intestinal lipid handling. In post-absorptive state, GLP-2 mobilizes pre-formed chylomicrons that are stored in the intestine from previous meals, the mechanisms of which are not fully understood. Our previous study demonstrated the involvement of a gut-brain neural pathway in this effect, but the key components of this pathway remain unknown. Here, we evaluated central GLP-2 receptor (GLP-2R) and melanocortin 4 receptor (MC4R) as important players in the pathway. Mesenteric lymph duct cannulated rats received intracerebroventricular infusion of a GLP-2R antagonist (GLP-2(11-33)), an MC4R antagonist (SHU9119), or saline as control. Post-absorptive lipid output from the intestine in response to peripheral GLP-2 was assessed. Spatial transcriptomics analysis was performed to determine the changes in mRNA expression among treatment groups. Blockade of central GLP-2R or MC4R attenuated the effects of GLP-2 in stimulating lymph triglyceride output. Treatments differentially affected key genes in jejunal endothelial cells, smooth muscle cells and neuronal cells. These results support the critical roles of central GLP-2R and MC4R in a neural pathway for peripheral GLP-2 in mobilizing lipids stored in the intestine during post-absorptive state. Overall design: Jejunum samples collected from peripherally GLP-2-treated sprague dawley rats with MC4R antagonist icv infusion (n=3; MG) or GLP-2R antagonist icv infusion (n=3; GG) or saline icv infusion (n=4; SG) were used for the analysis: MG or GG were compared to SG. MG was compared to GG.