Medium Chain Fatty Acids Are Selective Peroxisome Proliferator Activated Receptor (PPAR) γ Activators and Pan-PPAR Partial Agonists

Abstract

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.

Lauric Acid Beneficially Modulates Apolipoprotein Secretion and Enhances Fatty Acid Oxidation via PPARα-dependent Pathways in Cultured Rat Hepatocytes

“…In addition, hepatocytes treated with laurate showed up-regulated mRNA expression and secretion of apolipoprotein A1, as well as increased fatty acid oxidation; the laurate treatment did not inhibit the effect of PPARα agonist on fatty acid oxidation. There are reports that medium chain fatty acids are natural ligands for PPAR, 45 and PPARα activation up-regulates fatty acid oxidation-related genes, such as acyl CoA oxidase and carnitine palmitoyl transferase I, which suppresses postprandial lipidemia and lipid accumulation in enterocytes. 50, 51 Our study clearly proved that lauric acid may act as ligand for PPARα, which mediates its effects partly via the PPARα pathway.…”

Effects of a Tricaprylin Emulsion on Anti-glomerular Basement Membrane Glomerulonephritis in Rats: <i>In Vivo</i> and <i>in Silico</i> Studies

“…Moreover, medium-chain triacyl glycerols or fatty acids were reported to interact with multiple proteins to affect various signaling pathways, such as G proteincoupled receptor GPR84 and peroxisome proliferator activated receptor γ. 34,35) Further study is needed to identify the critical signaling pathways that are stimulated by medium-chain triacylglycerols, particularly the tricaprylin emulsion or tricaprylin alone, to induce the antinephritic effect on anti-GBM GN. Given the current limited and insufficient pharmacotherapy for GN, the tricaprylin emulsion or even tricaprylin alone is of interest as a potentially effective treatment for GN.…”

Nutritional Genetics and Energy Metabolism in Human Obesity

“…The function of PPARγ in differentiation of adipoctyes and in insulinsensitization has been elucidated through the use of drugs known as thiazolidinediones, which serve as strong synthetic ligands [58]. Arachidonic acid and eicosapentaenoic acid are the natural fatty acid ligands that bind most readily, but elicit only weak activation, and many other small lipophilic molecules, medium chain fatty acids and eicosanoids also elicit weak activation [70][71][72]. Despite their efficacy in improving insulin sensitivity, thiazolidinediones have many side effects.…”