ScreenDMT reveals linoleic acid diols replicably associate with BMI and stimulate adipocyte calcium fluxes

Abstract

Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. An activator of BAT is 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with body mass index (BMI) and which directly improves metabolism in other tissues. Here we profile plasma lipidomics from a cohort of 83 people and test which lipids' association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME both replicably inversely associate with BMI and mechanistically activate calcium fluxes in mouse brown and white adipocytes in vitro. ScreenDMT can be applied to test directional replication, directional mediation, and qualitative interactions, and our results identify 9,10-diHOME and the pathway stimulated by linoleic acid diols as candidate therapeutic targets to improve systemic metabolism.