SPMs, linoleic acid, and antibody levels in obesity

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PROJECT SUMMARY Numerous studies have defined how obesity impairs chronic inflammation. In contrast, far less is known about how obesity impairs humoral immunity, which is responsible for antibody production. Establishing underlying factors that link obesity with impaired antibody production is critical given that obese individuals have increased susceptibility to viral/bacterial infections and poor responses to differing vaccinations. At a molecular level, antibody production is regulated, in part, by specialized pro-resolving mediators (SPMs). SPMs are potent immunoresolvants synthesized from polyunsaturated fatty acids such as docosahexaenoic acid (DHA). We and others have found that SPMs synthesized from DHA boost antibody production upon influenza infection and vaccination. Furthermore, DHA-derived SPMs are deficient in obesity and associated with an elevation in linoleic acid in obese mice. Linoleic acid is extremely abundant in the western diet and may be a major reason why SPMs are deficient in the obese. Collectively, our data lead us to test the central hypothesis that obese subjects that do not effectively produce antibodies upon influenza vaccination have decreased circulating levels of DHA-derived SPMs and increased levels of linoleic acid. To address this hypothesis, we will rely on analyses of blood samples stored from a large clinical study in which subjects were stratified as responders (i.e. lean and obese individuals that produced antibody) and non-responders (i.e. lean and obese subjects that did not effectively produce antibody) upon the seasonal trivalent inactivated influenza vaccine. The approach will rely on mass spectrometry based metabololipidomic analyses, gas chromatography with flame ionization detection, and ELISAs. Impact: This proposal will establish key links between impaired antibody production and obesity at the human level. This will set the basis for future mechanistic studies and investigation of SPMs and linoleic acid as potential modifiable variables in humans to improve outcomes in response to viral infections/vaccinations. Completion of this proposal will had provided insight into a major public health burden, which is the convergence of an infectious disease (influenza) with a noncommunicable disease (obesity).