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Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 μM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.

This article is available online at http://www.jlr.org Triglycerides (TGs) are the chief route of transport of dietary fat within chylomicrons and VLDLs, as well as the main form of fuel storage in adipose tissue. TGs are synthesized from one glycerol and three FA molecules, which are attached via ester bonds to the hydroxyl groups of the glycerol backbone. Two major diacylglycerol acyltransferase (DGAT) isozymes, DGAT1 and DGAT2, have been identifi ed. Although both enzymes convert diacylglycerol to TG, they do not share similarity in either their nucleotide or amino acid sequences and have most probably arisen by convergent evolution ( 1, 2 ). Although there are some differences in their tissue distributions, both DGAT1 and DGAT2 are highly expressed in organs that synthesize large amounts of TG, such as the liver, adipose tissue, and small intestine ( 3 ).Studies with genetically altered mice, as well as in vivo suppression of DGAT expression, indicate that both DGAT1 and DGAT2 play important roles in TG synthesis. DGAT1 knockout mice (DGAT1 Ϫ / Ϫ ) have reduced tissue TG levels and exhibit increased sensitivity to insulin and leptin ( 4 ). In addition, they are resistant to high-fat dietinduced obesity as a result of an increase in their metabolic rates ( 4 ). In contrast, knockout mice lacking DGAT2 (DGAT2 Ϫ / Ϫ ) are lipopenic and die soon after birth as a result of profound reductions in substrates for energy metabolism and impaired skin permeability ( 5 ). Hepatic suppression of DGAT2 with antisense oligonucleotides (ASOs) reduced hepatic TG content in rodents ( 6, 7 ), and reversed diet-induced hepatic steatosis and insulin resistance Abstract Diacylglycerol acyltransferase (DGAT) catalyzes the fi nal step in triglyceride (TG) synthesis. There are two isoforms, DGAT1 and DGAT2, with distinct protein sequences and potentially different physiological functions. To date, the ability to determine clear functional differences between DGAT1 and DGAT2, especially with respect to hepatic TG synthesis, has been elusive. To dissect the roles of these two key enzymes, we pretreated HepG2 hepatoma cells with