Original Article Halofenate Is a Selective Peroxisome Proliferator–Activated Receptor  Modulator With Antidiabetic Activity Tamara Allen, 1 Fang Zhang, 2 Shonna A. Moodie, 2 L. Edward Clemens, 2 Aaron Smith, 1 Francine Gregoire, 2 Andrea Bell, 2 George E.O. Muscat, 1 and Thomas A. Gustafson 2 Halofenate has been shown previously to lower triglycer- ides in dyslipidemic subjects. In addition, significant de- creases 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 prolifera- tor–activated receptor (PPAR)- modulator (SPPARM). 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 ago- nist rosiglitazone. The data suggest that the partial ago- nism 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-medi- ated adipogenic differentiation. Moreover, in 3T3-L1 adi- pocytes, 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 sensi- tization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPARM with promising therapeutic utility with the po- tential for less weight gain. Diabetes 55:2523–2533, 2006 H alofenate was tested clinically in the 1970s as a hypolipidemic and hypouricemic agent. In sub- sequent investigator-led studies, halofenate was shown to lower serum triglycerides and uric acid in patients with a variety of hyperlipidemias (1– 4). Treatment of dyslipidemic type 2 diabetic patients also showed triglyceride lowering and, surprisingly, signif- icant reductions in plasma glucose and insulin (3). Subse- quent studies in diabetic patients confirmed the glucose- and triglyceride-lowering effects of halofenate in combina- tion with oral hypoglycemic drugs and as monotherapy (4 –7). While the precise mechanism of halofenate’s poten- tiation of the glycemic effect of sulfonylureas was not understood, it was originally hypothesized that halofenate, being highly plasma protein bound, might dislodge oral hypoglycemic compounds from serum binding proteins, thus increasing their efficacy (8). However, significant decreases in glucose were also observed with halofenate monotherapy (5) showing that halofenate could function independently of sulfonylureas. In analyzing these histor- ical data, we noted that halofenate lowered glucose levels in diabetic, but not normoglycemic, subjects and that the time course of the beneficial glycemic effects was similar to that of the insulin-sensitizing thiazolidinediones (TZDs), which possesses glucose- and insulin-lowering properties mediated via activation of peroxisome proliferator–acti- vated receptor (PPAR)- (9). We hypothesized that the insulin-sensitizing effects of halofenate might similarly involve PPAR-; we carried out a series of experiments to test this hypothesis. PPAR- is a member of the NR1C subgroup, which includes PPAR- and -. These receptors form het- erodimers with the retinoid X receptor and modulate the transcription of genes. PPAR- is predominantly ex- pressed in white and brown adipose tissue, with lower expression in liver, muscle, and other tissues (10). PPAR- ligands include a surprisingly diverse set of natural ligands (11) such as linolenic, eicosapentaenoic, docohexaenoic, and arachidonic acid and synthetic ligands such as the TZDs, L-tyrosine– based compounds, several nonsteroidal anti-inflammatory drugs, and a variety of new chemical classes (12,13). Originally identified as a regulator of adipogenesis, PPAR- was thought to mediate the actions of TZDs solely through its actions in adipose tissue. However, subsequent studies utilizing tissue-specific PPAR- gene knockouts have demonstrated a complex role for PPAR- in whole-body insulin sensitivity involving multiple tissues, including liver and muscle (14 –16). Two TZDs, rosiglitazone and pioglitazone, are currently approved to treat type 2 diabetes. Despite their proven efficacy, a number of deleterious side effects have been noted, including increased weight gain and edema (17). Weight gain is likely due to both increased adiposity and fluid retention. Edema is particularly a problem in patients From the 1 Division of Molecular Genetics and Development, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Australia; and the 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@ metabolex.com. Received for publication 4 May 2006 and accepted in revised form 20 June 2006. T.A., F.Z., and S.A.M. contributed equally to this work. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org. AUC, area under the curve; HA, halofenic acid; ID, interaction domain; PPAR, peroxisome proliferator–activated receptor; SPPARM, selective PPAR- modulator; TZD, thiazolidinedione. DOI: 10.2337/db06-0618 © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. DIABETES, VOL. 55, SEPTEMBER 2006 2523