Cell autonomous lipin 1 function is essential for development and maintenance of white and brown adipose tissue

Authors
Karim Nadra, Jean-Jacques Médard, Joram D. Mul, Gil-Soo Han, Sandra Grès, Mario Pende, Daniel Metzger, Pierre Chambon et al.

Lab
Department of Medical Genetics, University of Lausanne, Switzerland / INSERM, Strasbourg, France

Journal
MCB - Molecular and Cellular Biology

Abstract
Through analysis of mice with spatially and temporally restricted inactivation of Lpin1 we characterized its cell autonomous function in both white (WAT) and brown (BAT) adipocyte development and maintenance. We observed that the lipin 1 inactivation in adipocytes of aP2Cre/+/LpfEx2-3/fEx2-3 mice resulted in lipodystrophy and presence of adipocytes with multilocular lipid droplets. We further show that time-specific loss of lipin 1 in mature adipocytes in aP2Cre-ERT2/+/LpfEx2-3/fEx2-3 mice led to their replacement by newly formed Lpin1-positive adipocytes, thus establishing a role for lipin 1 in mature adipocyte maintenance. Importantly, we observed that the presence of newly formed Lpin1-positive adipocytes in aP2Cre-ERT2/+/LpfEx2-3/fEx2-3 mice protected these animals against WAT inflammation and hepatic steatosis induced by a high-fat diet. Loss of lipin 1 also affected BAT development and function as revealed by histological changes, defects in the expression of PPAR?, PGC-1? and UCP1 and functionally, by altered cold sensitivity. Finally, our data indicate that phosphatidic acid, which accumulates in WAT of animals lacking lipin 1 function, specifically inhibits differentiation of preadipocytes. Together, these observations firmly demonstrate a cell autonomous role of lipin 1 in WAT and BAT biology and indicate its potential as a therapeutical target for the treatment of obesity.