The plasma free fatty acid carrier proteome is altered in diet induced and genetically obese mice

Background: Plasma free fatty acid (FFA) turnover is known to be elevated in obesity, suggesting that the proteins carrying FFAs may also be altered. However, the effect of obesity on the plasma FFA carrier proteome is unknown. Methods: Starting at 6 weeks of age, male and female C57BL/6J wildtype mice were fed either a low-fat diet (10% of energy from fat) or a high-fat diet (60% of energy from fat), and genetic obesity was studied in leptin-deficient ob/ob mice on the low-fat diet. At 20 weeks of age, plasma and liver samples were collected. Plasma FFA carrier proteins were isolated using a fatty acid pulldown assay and detected by proteomics. Plasma proteins and lipoprotein particles were separated by fast protein liquid chromatography (FPLC), and FFA, cholesterol, and triacylglycerol levels were measured in these fractions. Hepatic gene expressions were quantified by qPCR. Results: The fatty acid pulldown assay isolated 284 proteins in each sex, with dozens of differentially abundant proteins between lean and obese groups. We identified eight proteins that exhibited altered abundance in both models of obesity for both sexes. Six of these proteins (three higher and three lower in obese groups) are known to be transcribed in the liver, and thus hepatic mRNA expression for these genes was measured. Interestingly, proteins with lower or higher abundance in the plasma FFA carrier proteome in obesity showed correspondingly lower or higher gene expressions in the liver. Furthermore, FFAs coeluted with lipoprotein particles in FPLC fractions, with accentuated FFA levels in the low-density lipoprotein (LDL) fractions in obesity, corresponding to increased LDL abundance. Conclusion: Obesity remodels the spectrum of plasma FFA carriers, potentially via changes in gene expression and lipoprotein abundance. Funding: Diabetes Action Research and Education Foundation. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.