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Peng Xu, John J Gildea, Chi Zhang, Prasad Konkalmatt, Santiago Cuevas, Dora Bigler Wang, Hanh T Tran, Pedro A Jose, and Robin A Felder

stained with DAPI (blue). Scale bar = 10 µm. Effect of PPAR-α agonist, fenofibrate (FFB), D 1 -like receptor antagonist, LE300, and high NaCl concentration on gastrin expression in human stomach antrum As aforementioned, PPAR

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D Pasquali, GM Pierantoni, A Fusco, S Staibano, V Colantuoni, A De Bellis, A Bellastella, and AA Sinisi

Expansion of adipose tissue in the orbits is a key feature of Graves' ophthalmopathy. Recent evidence shows that orbital fibroblasts are committed to differentiate into adipocytes under appropriate stimuli. Rosiglitazone, an agonist of the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARgamma) is able to induce both differentiation of orbital fibroblasts into mature adipocytes and expression of the TSH receptor (TSHr) gene. Several studies have suggested an important role of the high mobility group AT-hook 2 (HMGA2) gene in adipocytic cell growth and development. To investigate further the association between adipogenesis-related genes and orbital fibroblasts, we treated fibroblasts from Graves' ophthalmopathy (FGOs) and from normal orbital tissues with fenofibrate, a specific agonist for PPARalpha. We then evaluated the expression of the PPARalpha, PPARgamma2, HMGA2, leptin and TSHr genes before and after 24 h of fenofibrate treatment, using semiquantitative and real-time PCR. For up to 96 h after exposure to fenofibrate, FGOs differentiated into adipocytes. PPARalpha and PPARgamma2 were expressed more in FGOs than in normal cultures, whereas TSHr mRNA was detected only in FGOs. Expression of HMGA2 mRNA and protein was significantly increased in FGOs from 6 to 24 h after fenofibrate, confirming its role in the early phase of adipocyte differentiation. Treatment with fenofibrate for 24 h significantly increased the expression of leptin and TSHr genes. Moreover, TSH treatment significantly increased the accumulation of cAMP, demonstrating that FGOs express functional TSHr. The high level of expression of PPARalpha other than PPARgamma2 transcripts and the stimulating effect of fenofibrate on adipogenesis and on HMGA2, leptin and TSHr genes also indicate that the PPARalpha pathway plays an important part in the adipocyte differentiation of FGOs. These findings suggest that novel drugs to antagonize PPARalpha, other than the PPARgamma signalling system, may also need to be considered in the treatment or prevention of Graves' ophthalmopathy.

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KS Frederiksen, EM Wulf, K Wassermann, P Sauerberg, and J Fleckner

Peroxisome proliferator activated receptor (PPAR)-alpha controls the expression of multiple genes involved in lipid metabolism, and activators of PPAR-alpha, such as fibrates, are commonly used drugs in the treatment of hypertriglyceridemia and other dyslipidemic states. Recent data have also suggested a role for PPAR-alpha in insulin resistance and glucose homeostasis. In the present study, we have assessed the transcriptional and physiological responses to PPAR-alpha activation in a diet-induced rat model of insulin resistance. The two PPAR-alpha activators, fenofibrate and Wy-14643, were dosed at different concentrations in high-fat fed Sprague-Dawley rats, and the transcriptional responses were examined in liver using cDNA microarrays. In these analyses, 98 genes were identified as being regulated by both compounds. From this pool of genes, 27 correlated to the observed effect on plasma insulin, including PPAR-alpha itself and the leukocyte antigen-related protein tyrosine phosphatase (PTP-LAR). PTP-LAR was downregulated by both compounds, and showed upregulation as a result of the high-fat feeding. This regulation was also observed at the protein level. Furthermore, downregulation of PTP-LAR by fenofibric acid was demonstrated in rat FaO hepatoma cells in vitro, indicating that the observed regulation of PTP-LAR by fenofibrate and Wy-14643 in vivo is mediated as a direct effect of the PPAR agonists on the hepatocytes. PTP-LAR is one of the first genes involved in insulin receptor signaling to be shown to be regulated by PPAR-alpha agonists. These data suggest that factors apart from skeletal muscle lipid supply may influence PPAR-alpha-mediated amelioration of insulin resistance.

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You-Hong Cheng, Hiroki Utsunomiya, Mary Ellen Pavone, Ping Yin, and Serdar E Bulun

2000 , Carter 2003 ). Saidi et al . (2006) have recently reported that PPARα agonist (Fenofibrate) inhibits proliferation and induces apoptosis in endometrial cancer cells in vitro , and these effects are potentiated by RA. However, the molecular

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Pabitra B Pal, Himangshu Sonowal, Kirtikar Shukla, Satish K Srivastava, and Kota V Ramana

approaches such as insulin therapy ( Franklin et al. 2008 ) and thiazolidine-2-4-diones (TZDs) ( Fujishima et al. 1998 , Freed et al. 2002 , Dandona & Aljada 2004 ). Fenofibrates which activate PPAR-α and adiponectin ( Goya et al. 2004 , Koh et al

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Penny Ahlstrom, Esther Rai, Suharto Chakma, Hee Ho Cho, Palanivel Rengasamy, and Gary Sweeney

852754. ( doi:10.1155/2013/852754 ) 23762877 Dai F Jiang T Bao YY Chen GJ Chen L Zhang Q Lu YX 2016 Fenofibrate improves high-fat diet-induced and palmitate-induced endoplasmic reticulum stress and inflammation in skeletal muscle

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Daniela Pasquali, Valentina Rossi, Giovanni Conzo, Giuseppe Pannone, Pantaleo Bufo, Annamaria De Bellis, Andrea Renzullo, Giuseppe Bellastella, Annamaria Colao, Gianfranco Vallone, Antonio Bellastella, and Antonio A Sinisi

Endocrinology 25 63 – 71 . Pasquali D Pierantoni GM Fusco A Staibano S Colantuoni V De Bellis A Bellastella A Sinisi AA 2004 Fenofibrate increases the expression of high mobility group AT-hook 2 (HMGA2) gene and induces adipocyte differentiation

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Jing Cen, Ernest Sargsyan, Anders Forslund, and Peter Bergsten

fenofibrate . Acta Pharmacologica Sinica 29 443 – 450 . ( ) 10.1111/j.1745-7254.2008.00717.x 18358090 Tucker GT Casey C Phillips PJ Connor H Ward JD Woods HF 1981 Metformin kinetics in healthy

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Changxue Lu and Sheue-Yann Cheng

) Endogenous ligands Synthetic ligands Receptors PPARα Polyunsaturated FAs, leukotriene B4 (LTB4), HETE ( Kliewer et al . 1997 ) Clofibrate, fenofibrate, bezafibrate, gemfibrozil, ciprofibrate, Wy14 643 ( Willson et al . 2000 ), BMS-687453, BMS-711939

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Nora Martínez, Melisa Kurtz, Evangelina Capobianco, Romina Higa, Verónica White, and Alicia Jawerbaum

.1155/2008/142082 . Belfort R Berria R Cornell J Cusi K 2010 Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome . Journal of Clinical Endocrinology and Metabolism