Critical role for cytosolic group IVA phospholipase A2 in early adipocyte differentiation and obesity

Adipogenesis is the process of differentiation of immature mesenchymal stem cells into adipocytes. Elucidation of the mechanisms that regulate adipocyte differentiation is key for the development of novel therapies for the control of obesity and related comorbidities. Cytosolic group IVA phospholipase A (cPLAα) is the pivotal enzyme in receptor-mediated arachidonic acid (AA) mobilization and attendant eicosanoid production. Using primary multipotent cells and cell lines predetermined to become adipocytes, we show here that cPLAα displays a proadipogenic function that occurs very early in the adipogenic process. Interestingly, cPLAα levels decrease during adipogenesis, but cPLAα-deficient preadipocytes exhibit a reduced capacity to differentiate into adipocytes, which affects early and terminal adipogenic transcription factors. Additionally, the absence of the phospholipase alters proliferation and cell-cycle progression that takes place during adipogenesis. Preconditioning of preadipocytes with AA increases the adipogenic capacity of these cells. Moreover, animals deficient in cPLAα show resistance to obesity when fed a high fat diet that parallels changes in the expression of adipogenic transcription factors of the adipose tissue. Collectively, these results show that preadipocyte cPLAα activation is a hitherto unrecognized factor for adipogenesis in vitro and in vivo.This work was supported by the Spanish Ministry of Science and Innovation (Grants SAF2010-18831, BFU2010-18826 and SAF2013-48201-R), the Regional Government of Castile and Leon (Grants BIO39/VA04/10, CSI168A12-1 and BIO/VA03/14) and by grants-in aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and AMED-CREST from the Japan Agency for Medical Research and Development (MM and HS). L.P. and G.L. were supported by predoctoral fellowships from the Spanish Ministry of Science and Innovation (Plan de Formación de Personal Investigador and Plan de Formación de Profesorado Universitario programs, respectively). M.V. was supported by a predoctoral fellowship from the Regional Government of Castile and Leon. CIBERDEM is an initiative of Instituto de Salud Carlos III.Peer Reviewe