Cell Autonomous Lipin 1 Function Is Essential for Development and Maintenance of White and Brown Adipose Tissue

Abstract

ABSTRACTThrough analysis of mice with spatially and temporally restricted inactivation ofLpin1, 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 ofaP2Cre/+/LpfEx2-3/fEx2-3mice resulted in lipodystrophy and the presence of adipocytes with multilocular lipid droplets. We further showed that time-specific loss of lipin 1 in mature adipocytes inaP2Cre-ERT2/+/LpfEx2-3/fEx2-3mice led to their replacement by newly formedLpin1-positive adipocytes, thus establishing a role for lipin 1 in mature adipocyte maintenance. Importantly, we observed that the presence of newly formedLpin1-positive adipocytes inaP2Cre-ERT2/+/LpfEx2-3/fEx2-3mice 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 peroxisome proliferator-activated receptor alpha (PPARα), PGC-1α, 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.