Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists.
Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8-C10) bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD) simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H) 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H) 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products.
São Carlos Physics Institute, University of São Paulo, São Carlos, Sao Paulo, Brazil.
Marcelo Vizoná
MV
Liberato
Alessandro S
AS
Nascimento
Steven D
SD
Ayers
Jean Z
JZ
Lin
Aleksandra
A
Cvoro
Rodrigo L
RL
Silveira
Leandro
L
Martínez
Paulo C T
PC
Souza
Daniel
D
Saidemberg
Tuo
T
Deng
Angela Angelica
AA
Amato
Marie
M
Togashi
Willa A
WA
Hsueh
Kevin
K
Phillips
Mário Sérgio
MS
Palma
Francisco A R
FA
Neves
Munir S
MS
Skaf
Paul
P
Webb
Igor
I
Polikarpov
D016475:3T3 Cells; D000818:Animals; D001391:Azo Compounds; D003460:Crystallization; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D045162:Thiazolidinediones / Q000378:metabolism*
D001391:Azo Compounds; D005227:Fatty Acids; D047495:PPAR gamma; D045162:Thiazolidinediones; C011049:oil red O