Dyslipidemia is a common co-morbidity of insulin resistance, where chronic elevations in hepatic and intestinal lipoproteins are linked to cardiovascular disease. Postprandial production is regulated in-part by gut-derived hormones such as glucagon-like peptide (GLP) -1. Although degradation-resistant analogs of GLP-1 continue to work in diabetic individuals, none have examined whether GLP-1s endogenous neuroendocrine signalling pathways are affected by diet-induced dyslipidemia. Thus, we sought to test whether native GLP-1 could modulate postprandial lipids in a fructose-fed hamster model.Hamsters were fed either a chow or fructose-enriched (FF) diet for 14 days, then received a portal vein injection of either GLP-1 (7-36) or vehicle control to examine if they remained responsive to portal GLP-1. Separately, in hamsters fed either chow or a fat/fructose/cholesterol enriched (FFC) diet we performed nodose ganglia (NG) injections with GLP-1 (7-36) or vehicle. To recapitulate the loss of vagal GLP-1R signalling in the absence of dietary intervention we selectively deafferented GLP-1R containing NG neurons via injection of the cytotoxin saporin conjugated to exendin-4. After treatment, animals received a gavage of olive oil and an intraperitoneal injection of poloxamer to prevent lipoprotein clearance. Postprandial triglyceride-rich lipoproteins isolated via density ultracentrifugation were assessed via blood draws over a 6-hour period.Chow-fed hamsters saw significant reductions in post-prandial lipids after portal GLP-1 injection, whereas FF-fed hamsters were unaffected. Chow-fed hamsters were similarly responsive to GLP-1 (7-36) injection into the NG, displaying reduced postprandial lipids; however, FFC-fed hamsters showed no reduction in plasma lipids. Finally, selective deafferentation of NG GLP-1R-containing neurons caused significant rises in postprandial TG and TRL, underscoring the importance of GLP-1R insensitivity in states of metabolic disease.
S.S.Hoffman: None. D.C.Alvares: None. K.Adeli: None.
CIHR Foundation Grant