Cao et al. identify the fatty acid palmitoleate as a hormone (lipokine) that coordinates changes in fatty acid metabolism in adipose tissue with systemic control of metabolism. The authors studied knockout mice that lack the fatty acid binding proteins aP2 and mal1 (FABP4 and FABP5), which act primarily in adipose tissue. Such mice are resistant to metabolic syndrome, a common disease cluster characterized by metabolic dysfunction in humans. The authors therefore explored how changes in fatty acids in adipose tissue could alter systemic metabolic function. Unsupervised cluster analysis of high-resolution lipidomic analysis of some 400 lipid species in the major insulin-responsive tissues showed that the mice lacking FABPs had a lipid profile in adipose tissue similar to that of lean, insulin-sensitive, wild-type animals, even when they were fed a diet high in fat. The adipose tissue in the knockout animals showed increased production of palmitoleate, which is a marker of de novo lipogenesis (conversion of glucose to fatty acids). Application of plasma lipids from the FABP–/– or control animals or of palmitoleate alone to cultured cells or tissues showed that palmitoleate could reproduce the systemic effects on liver and muscle and adipose cells seen in the knockout animals. Further lipidomic analysis supported movement of palmitoleate from adipose tissue to muscle in the FABP–/– animals. This single fatty acid also appeared to substantially influence insulin sensitivity. Intralipid infusion of triglycerides composed only of the fatty acid palmitate caused decreased insulin signaling (phosphorylation of insulin receptor substrates 1 and 2 and of the kinase AKT) in liver, whereas triglyceride composed only of palmitoleate potentiated insulin signaling and caused improved glucose metabolism in the whole animal. The authors note that if humans have similar regulatory mechanisms, analysis of lipid composition could provide biomarkers of metabolic disease and alteration of lipid composition might provide a new avenue for clinical intervention in metabolic disease.
H. Cao, K. Gerhold, J. R. Mayers, M. M. Wiest, S. M. Watkins, G. S. Hotamisligil, Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933-944 (2008). [PubMed]