Coordinate functional regulation between microsomal prostaglandin E synthase-1 (mPGES-1) and peroxisome proliferator-activated receptor γ (PPARγ) in the conversion of white-to-brown adipocytes.
Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor and a master regulator of adipogenesis. Microsomal prostaglandin E (PGE) synthase-1 (mPGES-1) is an inducible enzyme that couples with cyclooxygenase-2 for the biosynthesis of PGE2. In this study we demonstrate the existence of a coordinate functional interaction between PPARγ and mPGES-1 in controlling the process of pre-adipocyte differentiation in white adipose tissue (WAT). Adipocyte-specific PPARγ knock-out mice carrying an aP2 promoter-driven Cre recombinase transgene showed a blunted response to the adipogenic effects of a high fat diet. Pre-adipocytes from these knock-out mice showed loss of PPARγ and were resistant to rosiglitazone-induced WAT differentiation. In parallel, WAT from these mice showed increased expression of uncoupling protein 1, a mitochondrial enzyme that dissipates chemical energy as heat. Adipose tissue from mice lacking PPARγ also showed mPGES-1 up-regulation and increased PGE2 levels. In turn, PGE2 suppressed PPARγ expression and blocked rosiglitazone-induced pre-adipocyte differentiation toward white adipocytes while directly elevating uncoupling protein 1 expression and pre-adipocyte differentiation into mature beige/brite adipocytes. Consistently, pharmacological mPGES-1 inhibition directed pre-adipocyte differentiation toward white adipocytes while suppressing differentiation into beige/brite adipocytes. This browning effect was reproduced in knockdown experiments using a siRNA directed against mPGES-1. The effects of PGE2 on pre-adipocyte differentiation were not seen in mice lacking PPARγ in adipose tissue and were not mirrored by other eicosanoids (i.e. leukotriene B4). Taken together, these findings identify PGE2 as a key regulator of white-to-brown adipogenesis and suggest the existence of a coordinate regulation of adipogenesis between PPARγ and mPGES-1.
From the Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS-Esther Koplowitz Center, Barcelona 08036, Spain.
Verónica
V
García-Alonso
Cristina
C
López-Vicario
Esther
E
Titos
Eva
E
Morán-Salvador
Ana
A
González-Périz
Bibiana
B
Rius
Marcelina
M
Párrizas
Oliver
O
Werz
Vicente
V
Arroyo
Joan
J
Clària
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology; D052437:Adipocytes, Brown / Q000378:metabolism*; D052438:Adipocytes, White / Q000378:metabolism*; D050156:Adipogenesis; D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D002454:Cell Differentiation; D015777:Eicosanoids / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis; D007249:Inflammation / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008861:Microsomes / Q000201:enzymology*; D009765:Obesity / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism
D015777:Eicosanoids; D047495:PPAR gamma; D011453:Prostaglandins; D020033:Protein Isoforms; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse
Adipose Tissue; Beige Adipocytes; Cyclooxygenase (COX) Pathway; Eicosanoid; Metabolic Diseases; PPARγ; Pre-adipocytes; Prostaglandins; mPGES-1