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Halofenate Is a Selective Peroxisome Proliferator–Activated Receptor Modulator With Antidiabetic Activity

¹ Division of Molecular Genetics and Development, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Australia
² Department of Biology, Metabolex, Hayward, California

Address correspondence and reprint requests to Thomas A. Gustafson, Metabolex, 3876 Bay Center Pl., Hayward, CA 94545. E-mail: gus{at}metabolex.com

Abbreviations: AUC, area under the curve; HA, halofenic acid; ID, interaction domain; PPAR, peroxisome proliferator–activated receptor; SPPARM, selective PPAR- modulator; TZD, thiazolidinedione

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)- modulator (SPPARM). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-. Reporter assays show that HA is a partial PPAR- 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-–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 SPPARM with promising therapeutic utility with the potential for less weight gain.

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