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A common genetic variant in the methylenetetrahydrofolate reductase (MTHFR) gene involving a cytosine to thymidine (C-->T) transition at nucleotide 677 is associated with reduced enzyme activity, altered folate status and potentially higher folate requirements. The objectives of this study were to investigate the effect of the MTHFR 677 T allele on folate status variables in Mexican women (n = 43; 18-45 y) and to assess the adequacy of the 1998 folate U.S. Recommended Dietary Allowance (RDA), 400 micro g/d as dietary folate equivalents (DFE). Subjects (14 CC, 12 CT, 17 TT genotypes) consumed a low folate diet (135 micro g/d DFE) for 7 wk followed by repletion with 400 micro g/d DFE (7 CC, 6 CT, 9 TT) or 800 micro g/d DFE (7 CC, 6 CT, 8 TT) for 7 wk. Throughout repletion with 400 micro g/d DFE, the TT genotype had lower (P 0.05) in their response relative to the CC genotype. Throughout repletion with 800 micro g/d DFE, the CT genotype had lower (P 0.05) in the measured variables between the TT and CC genotypes. Repletion with 400 micro g/d DFE led to normal blood folate and desirable plasma tHcy concentrations, regardless of MTHFR C677T genotype. Collectively, these data demonstrate that the MTHFR C-->T variant modulates folate status response to controlled folate intakes and support the adequacy of the 1998 folate U.S. RDA for all three MTHFR C677T genotypes.

Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety as a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship (SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists. While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement of PPAR alpha and gamma activity required the introduction of new heterocyclic substituents that were not known in the PPAR literature. Systematic optimization led to the discovery of 4-thiazolyl-phenyl derivatives with potent PPAR alpha/gamma/delta pan agonistic activity. The lead candidate from this series was found to exhibit excellent ADME properties and superior therapeutic potential compared to known PPAR gamma activating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, while normalizing glucose levels in diabetic rodent models.

A third p-adrenoceptor subtype has been cloned from the rat, mouse, and human genornes. The presence of these receptors primarily on adipose tissue has raised the possibility that p,-adrenoceptor selective agonists may be useful antiobesity agents. CL 316,243 is a highly selective P,-agonist; it has a >30,000 to 1 p,-to-p,-adrenoceptor selectivity ratio and a 10,030 to 1 p3-to-pzadrenoceptor selectivity ratio in in vitro functional assays. In vivo, animals were treated with CL 314,698, a diester prodrug of CL 316,243, which i s rapidly converted to CL 316,243. In obese (ob/ob) and diabetic (db/db) mice, treatment with CL 314,698 reduced their hyperglycemia to the euglycemia of their lean littermates, and decreased plasma insulin levels. In obese mice, the compound also caused decreased weight gain despite increased food consumption, and the decreased weight was due to loss of fat while lean body mass was spared. CL 314,698 treatment also improved both glucose and insulin tolerance in obese mice, suggesting that it decreased insulin resistance. CL 314,698 also prevented further weight gain, without affecting food consumption, in rats previously made obese by feeding a high fat diet. The compound reduced plasma insulin and triglyceride levels, and reduced fat pad weights, while having no effect on plasma glucose, cholesterol, thyroxine, or T, levels or on skeletal muscle weight. Decreased weight gain without decreased food consumption suggested that CL 316,243 stimulated thermogenesis. Treatment of obese mice for 3 weeks with CL 316,243 increased thermogenesis by 45% as measured by indirect calorimetry. Thus, CL 316,243 is a potent, 6,-adrenoceptor selective agonist with thermogenic, antidiabetic, and antiobesity properties in several models of non-insulin dependent diabetes and obesity.