Influence of obesity and insulin resistance with hepatic steatosis on the human plasma lipidome

Insulin resistance accompanied by hepatic steatosis is a common complication of obesity. In an effort to identify plasma lipids that could be biomarkers or causes of insulin resistance with steatosis in people with obesity, we evaluated the plasma lipidome in three distinct groups separated by adiposity, hepatic steatosis, and insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure: i) insulin-sensitive lean (ISL, n = 13); ii) insulin-sensitive obese (ISO, n = 14); and iii) insulin-resistant obese with hepatic steatosis (IROS, n = 13). We evaluated 759 complex lipid species in 16 subclasses (including phospholipids, glycerolipids, sphingolipids, acylcarnitines, and cholesteryl esters) and 84 eicosanoids in fasting plasma samples. Total abundances of each lipid subclass (sum of species) in the ISO group were not different from values in the ISL group, whereas phosphatidylethanolamines, triglycerides, and diacylglycerols were more abundant in the IROS than in the ISO group. The abundances of only 5 individual complex lipid species were different between the ISL and ISO groups, whereas the abundances of 23 lipids were different between the ISO and IROS groups. More complex lipids were associated with insulin sensitivity (n = 124) than obesity per se (n = 7). In contrast, plasma eicosanoids were not different between the ISO and IROS groups but were greater in both groups with obesity than in the ISL group. We conclude that insulin resistance with hepatic steatosis is associated with alterations in the plasma complex lipidome, independent of adiposity, in people with obesity, whereas adiposity has a greater impact than insulin resistance on plasma eicosanoid concentrations.