Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduces liver steatosis and cardiometabolic risk (CMR). Only few data are available on lipid metabolism and no information on the postprandial lipidomic profile. Thus, we investigated how exenatide treatment changes lipid metabolism and composition during fasting and after a meal tolerance test (MTT) in adults with severe obesity without diabetes. Thirty individuals (26F/4M, 30-60 years old, BMI>40 kg/m2, HbA1c=5.76%) were assigned (1:1) to diet with exenatide treatment (EXE, n=15, 10 μg twice-daily) or without treatment as control (CT, n=15) for 3 months. Fasting and postprandial lipidomic profile (by LC/MS-QTOF) and fatty acid metabolism (following a 6-hour MTT/tracer study) and composition (by GC/MS) were evaluated before and after treatment. Both groups had slight weight loss (EXE: -5.5% vs CT: -1.9%, p=0.052). During fasting, exenatide, compared to CT, reduced some ceramides (CER) and lysophosphocholines (LPC) previously associated with CMR, while relatively increasing unsaturated phospholipid species (PC, LPC) with protective effects on CMR, although concentrations of total lipid species were unchanged. During MTT, both groups suppressed lipolysis equally to baseline, but EXE exenatide significantly lowered free fatty acid clearance and postprandial triacyclglycerols (TAG) concentrations, particularly saturated TAGs with 44-54 carbons. Exenatide also reduced some postprandial CERs, PCs, LPCs previously linked to cardiometabolic risk. These changes in lipidomic profile remained statistically significant after adjusting for weight loss. Exenatide improved fasting and postprandial lipidomic profile associated with CMR mainly by reducing saturated postprandial TAGs and CERs, independently of weight loss and diabetes.

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