Abstract 429: Central Glucagon-Like Peptide-1 Reduces Intestinal Chylomicron Production via Melanocortin-4-Receptor Signaling

Insulin resistance and the metabolic syndrome are associated with intestinal overproduction of chylomicrons, resulting in postprandial dyslipidemia and atherogenic remnants. It is increasingly clear that a reduction in chylomicrons is achieved by the action of glucagon-like peptide-1 (GLP-1) in the periphery. However, this peptide is also generated by central neurons and regulates activity in brain regions that affect sympathetic signaling. Indeed, through sympathetic pathways GLP-1 can modulate peripheral lipogenesis. Therefore, we examined the potential role of peripheral and central GLP-1 in regulating chylomicron production. Healthy hamsters received an oral fat load followed by an intraperitoneal (IP) or intracerebroventricular (ICV) injection of the GLP-1 receptor (GLP-1R) agonist exendin-4. Postprandial triglyceride (TG) and apolipoprotein B48 (apoB48) levels from plasma TG-rich lipoproteins (TRL) were found to be reduced over 6 h. The effects of central exendin-4 were mirrored by ICV MK-0626, an inhibitor of GLP-1 degradation, and reversed by the GLP-1R antagonist exendin9-39. Given a potential link between central GLP-1 and the melanocortin-4-receptor (MC4R) system, hamsters received an MC4R antagonist ICV alongside exendin-4 and this prevented a lowering in TRL-TG levels. To determine whether subsequent communication with the gut was through sympathetic pathways, α- and β-adrenergic receptor blockers were infused intravenously prior to ICV exendin-4 treatment and prevented exendin-4 from reducing TRL-TG. Finally, to examine the interplay between central and peripheral GLP-1R signaling, exendin-4 was given IP while exendin9-39 was given ICV and vice-versa. IP exendin-4 diminished TRL-TG levels during central antagonism, while IP exendin9-39 prevented the action of ICV exendin-4. This suggests that peripheral GLP-1Rs may be potentiated by central stimulation, but can also act independently. Overall, we demonstrate a GLP-1-sensitive brain-gut axis for regulating chylomicron production, involving the MC4R system and sympathetic pathways. Future studies will investigate whether central GLP-1 signals via pro-opiomelanocortin neurons and sympathetic neurotransmitters to affect enterocyte chylomicron output.