Mechanisms for regulation of a novel class of anti-diabetic lipids

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The growing epidemic of obesity and Type 2 diabetes requires new strategies for prevention and treatment. We discovered a structurally novel, family of endogenous bioactive lipids, branched fatty Acid esters of Hydroxy fatty Acids (FAHFAs). A subfamily, Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), has anti-diabetic and anti-inflammatory effects. PAHSA levels are low in serum and adipose tissue of insulin-resistant versus insulin-sensitive people, and levels correlate highly with insulin sensitivity. In insulin-resistant mice, PAHSA administration improves glucose tolerance and insulin sensitivity, in part by enhancing insulin action to suppress hepatic glucose production which results from improved lipolysis suppression. PAHSAs are anti-inflammatory and reduce colitis severity and the incidence of auto-immune Type 1 diabetes in mice. We have made tremendous strides in discovering new activities for PAHSAs, identifying additional families of bioactive and storage forms of FAHFAs, and uncovering biochemical pathways and enzymes that control tissue FAHFA levels. These studies underscore that FAHFAs are a highly-regulated class of lipids with tremendous translational potential. The overall objective of this proposal is to determine the mechanisms that regulate tissue and serum FAHFA levels in physiologic and disease states by identifying enzymes and pathways that regulate FAHFA biosynthesis, degradation and incorporation into other lipids. We will use innovative and robust assays we developed with isotopically-labeled FAHFAs and their precursors to measure FAHFA synthesis and degradation in vivo, target specific pathways of FAHFA regulation, and identify additional, missing enzymes and other factors that regulate FAHFA biosynthesis, degradation, transport and storage. We have already made terrific progress by identifying 3 FAHFA hydrolases and the first FAHFA biosynthetic transacylase. We will delineate this new biosynthetic pathway using novel mechanistic studies. We also propose a highly complementary, innovative, systems analyses that will integrate transcriptomic data with targeted FAHFA measurements. First, we will take advantage of the large, reciprocal regulation of FAHFAs in our unique mouse models with altered expression of Glut4 and ChREBP, to find unknown factors mediating this regulation. Since Glut4 and ChREBP expression in adipose tissue from humans correlates with insulin sensitivity and adipose FAHFA levels, genes identified with these experiments could have clinical relevance. The second approach exploits the natural genetic variation in the diversity outbred (DO) mice, which have as much natural genetic variation as the human population. We will perform targeted measurements of ~300 different FAHFA isomers in adipose tissue, liver and plasma of ~500 DO mice and leverage the existing genetic and transcriptomic data from DO mice to find new "drivers"/regulators of tissue FAHFA levels. These studies will advance our understanding of FAHFA biology in health and disease and potentially uncover novel enzymes and pathways in lipid metabolism that can be targeted for clinical benefit.