title: Halofenate is a selective peroxisome proliferator-activated receptor gamma modulator with antidiabetic activity.
abstract: Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-gamma modulator (SPPARgammaM). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-gamma. Reporter assays show that HA is a partial PPAR-gamma agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-gamma-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPARgammaM with promising therapeutic utility with the potential for less weight gain.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Australia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Allen
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Shonna A
authors.initials: SA
authors.lastname: Moodie
authors.forename: L Edward
authors.initials: LE
authors.lastname: Clemens
authors.forename: Aaron
authors.initials: A
authors.lastname: Smith
authors.forename: Francine
authors.initials: F
authors.lastname: Gregoire
authors.forename: Andrea
authors.initials: A
authors.lastname: Bell
authors.forename: George E O
authors.initials: GE
authors.lastname: Muscat
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gustafson
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003920:Diabetes Mellitus / Q000188:drug therapy; D005786:Gene Expression Regulation / Q000187:drug effects; D006218:Halofenate / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008024:Ligands; D051379:Mice; D008820:Mice, Obese; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D020798:Two-Hybrid System Techniques
chemical_list: D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D006218:Halofenate