Lipocalin prostaglandin D synthase and PPARγ2 coordinate to regulate carbohydrate and lipid metabolism in vivo.
Mice lacking Peroxisome Proliferator-Activated Receptor γ2 (PPARγ2) have unexpectedly normal glucose tolerance and mild insulin resistance. Mice lacking PPARγ2 were found to have elevated levels of Lipocalin prostaglandin D synthase (L-PGDS) expression in BAT and subcutaneous white adipose tissue (WAT). To determine if induction of L-PGDS was compensating for a lack of PPARγ2, we crossed L-PGDS KO mice to PPARγ2 KO mice to generate Double Knock Out mice (DKO). Using DKO mice we demonstrated a requirement of L-PGDS for maintenance of subcutaneous WAT (scWAT) function. In scWAT, DKO mice had reduced expression of thermogenic genes, the de novo lipogenic program and the lipases ATGL and HSL. Despite the reduction in markers of lipolysis in scWAT, DKO mice had a normal metabolic rate and elevated serum FFA levels compared to L-PGDS KO alone. Analysis of intra-abdominal white adipose tissue (epididymal WAT) showed elevated expression of mRNA and protein markers of lipolysis in DKO mice, suggesting that DKO mice may become more reliant on intra-abdominal WAT to supply lipid for oxidation. This switch in depot utilisation from subcutaneous to epididymal white adipose tissue was associated with a worsening of whole organism metabolic function, with DKO mice being glucose intolerant, and having elevated serum triglyceride levels compared to any other genotype. Overall, L-PGDS and PPARγ2 coordinate to regulate carbohydrate and lipid metabolism.
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge, United Kingdom. sv234@medschl.cam.ac.uk
Sam
S
Virtue
Mojgan
M
Masoodi
Vidya
V
Velagapudi
Chong Yew
CY
Tan
Martin
M
Dale
Tapani
T
Suorti
Marc
M
Slawik
Margaret
M
Blount
Keith
K
Burling
Mark
M
Campbell
Naomi
N
Eguchi
Gema
G
Medina-Gomez
Jaswinder K
JK
Sethi
Matej
M
Orešič
Yoshihiro
Y
Urade
Julian L
JL
Griffin
Antonio
A
Vidal-Puig
D017667:Adipocytes / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D050260:Carbohydrate Metabolism / Q000235:genetics; D015777:Eicosanoids / Q000378:metabolism; D005786:Gene Expression Regulation; D007333:Insulin Resistance / Q000235:genetics; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism
D015415:Biomarkers; D015777:Eicosanoids; D054834:Lipocalins; D047495:PPAR gamma; D012333:RNA, Messenger; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase