GLP-1 Receptor Agonist Treatment Improves Fasting and Postprandial Lipidomic Profiles Independently of Diabetes and Weight Loss

Treatment with glucagon-like peptide 1 receptor agonists reduces liver steatosis and cardiometabolic risk (CMR). Few data are available on lipid metabolism, and no information is available on the postprandial lipidomic profile. Thus, we investigated how exenatide treatment changes lipid metabolism and composition during fasting and after a mixed-meal tolerance test (MMTT) in adults with severe obesity without diabetes. Thirty individuals (26 females and 4 males, 30–60 years old, BMI >40 kg/m2, HbA1c 5.76%) were as-signed (1:1) to diet with exenatide 10 lg twice daily treatment (n = 15) or without treatment as control (n = 15) for 3 months. Fasting and postprandial lipidomic profile (by liquid chromatography quadrupole time-of-flight mass spec-trometry) and fatty acid metabolism (following a 6-h MMTT/ tracer study) and composition (by gas chromatography-mass spectrometry) were evaluated before and after treat-ment. Both groups had slight weight loss (25.5% vs. 21.9%, exenatide vs. control; P = 0.052). During fasting, ex-enatide, compared with control, reduced some ceramides (CERs) and lysophosphatidylcholines (LPCs) previously associated with CMR, while relatively increasing unsaturated phospholipid species (phosphatidylcholine [PC], LPC) with protective effects on CMR, although concentrations of total lipid species were unchanged. During MMTT, both groups showed suppressed lipolysis equal to baseline, but exena-tide significantly lowered free fatty acid clearance and post-prandial triacyclglycerol (TAG) concentrations, particularly saturated TAGs with 44–54 carbons. Exenatide also reduced some postprandial CERs, PCs, and LPCs previously linked to CMR. These changes in lipidomic profile remained statistically significant after adjusting for weight loss. Exe-natide improved fasting and postprandial lipidomic profiles associated with CMR mainly by reducing saturated postprandial TAGs and CERs independently of weight loss and diabetes.