TY - JOUR
T1 - Cell autonomous lipin 1 function is essential for development and maintenance of white and brown adipose tissue
AU - Nadra, Karim
AU - Médard, Jean Jacques
AU - Mul, Joram D.
AU - Han, Gil Soo
AU - Grès, Sandra
AU - Pende, Mario
AU - Metzger, Daniel
AU - Chambon, Pierre
AU - Cuppen, Edwin
AU - Saulnier-Blache, Jean Sébastien
AU - Carman, George M.
AU - Desvergne, Béatrice
AU - Chrast, Roman
PY - 2012/12
Y1 - 2012/12
N2 - 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 the presence of adipocytes with multilocular lipid droplets. We further showed that time-specific loss of lipin 1 in mature adipocytes in aP2Cre/+/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/+/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 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 forthe treatment of obesity.
AB - 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 the presence of adipocytes with multilocular lipid droplets. We further showed that time-specific loss of lipin 1 in mature adipocytes in aP2Cre/+/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/+/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 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 forthe treatment of obesity.
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U2 - 10.1128/MCB.00512-12
DO - 10.1128/MCB.00512-12
M3 - Article
C2 - 23028044
AN - SCOPUS:84871887974
SN - 0270-7306
VL - 32
SP - 4794
EP - 4810
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 23
ER -