Ether Lipids and Adipocyte-Derived 1-Deoxyceramides as Hallmarks for Lean and Obese Type 2 Diabetic Patients

Background: The worldwide increase in obesity and type 2 diabetes (T2D) represents a major health challenge. Chronically altered lipids induced by obesity further promote the development of T2D, and the accumulation of toxic lipid metabolites in serum and peripheral organs may contribute to the diabetic phenotype. Methods: To better understand the complex metabolic pattern of lean and obese T2D and non-T2D individuals, we analysed the lipid profile of human serum, skeletal muscle and visceral adipose tissue of two cohorts by systematic mass spectrometry-based lipid analysis. Findings: Lipid homeostasis was strongly altered in a disease and tissue-specific manner, allowing us to define T2D signatures associated with obesity from those that were obesity-independent. Lipid changes encompassed lyso-, diacyl- and ether-phospholipids. Moreover, strong changes in sphingolipids included cytotoxic 1-deoxyceramide accumulation in a disease-specific manner in serum and visceral adipose tissue. Increased production of non-canonical 1-deoxyceramides in human adipose tissue was confirmed in adipocytes cell culture experiments. Interpretation: Taken together, the observed lipidome changes in obesity and T2D will facilitate the identification of T2D patient subgroups and represent an important step towards personalized medicine in diabetes. Funding Statement: This study was supported by the SNSF grants 31003A_166700/1 and 310030-184708, the Vontobel Foundation, the Olga Mayenfisch Foundation, the Novartis Foundation for Medical-Biological Research, the Fondation Ernst et Lucie Schmidheiny, the Jubilaumsstiftung Swiss Life Foundation, and the Fondation pour la Recherche sur le Cancer (C.D.); by SNSF grant CRSII3_154405 (H.R., C.D., E.L.); SNSF grant CRSII3_160741 (S.A.B., J.P, E.T.D); SNSF grant 310030B_166686 (H.R.), the NCCR Chemical Biology funded by the SNSF (H.R.), by the Bo & Kerstin Hjelt diabetes Foundation (U.L.-M.), and by the Young Independent Investigator Grant SGED/SSED (F. S.). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study had ethics committee approval (CER11-015). The study conformed to the Declaration of Helsinki and the experimental protocol (‘DIOMEDE’) was approved by the Ethical Committee SUD EST IV (Agreement 12/111) and performed according to the French legislation (Huriet’s law).