Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to antagonize the activity of PPARgamma full agonists. nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPARgamma conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPARgamma full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia. However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPARgamma target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPARgamma modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome.

No abstract

SUMMARYLipaemia retinalis is a rarely described condition which occurs in certain types of both primary and secondary hyperlipidaemia. It presents with a striking fundal appearance. We report 7 cases of lipaemia retinalis and ocular manifestations in hyperlipidaemia which presented over a 12 year period to our hospitals. These illustrate the different presentations and stages of the disease, and other fundal abnormalities seen in hyperlipidaemia.Lipaemia retinalis, which was first described in 1880 by Heyll, occurs in certain types of both primary and secondary hyperlipidaemia. The principal fundal abnormality in lipaemia retinalis is a milky disco 1-ouration of retinal vessels. This can vary in degree from barely detectable peripheral vessel changes to cream colouration of all retinal vessels with a 'salmon' -coloured fundus. The grading system used to describe the stages of the disease is given in Table I Lipaemia retinalis has been described in both

No abstract