Endocrine Abstracts

Obesity caused by excess energy intake has been emerging as a major health concern in the world, with increased risk leading to diabetes, hypertension, nephropathy, and cardiovascular disease. A better understanding of the molecular mechanism on how obesity develops is of critically clinical importance. Accumulating data suggest that ER-stress is strongly related with development of obesity, implying that ER stress can be a therapeutically target of obesity. 4-Phenylbutyrate (PBA) which is known as a chemical chaperon has known to decrease ER-stress. However, the detailed molecular mechanism by which PBA decreases ER-stress remains elusive. To identify the effect of PBA on body weight gain, high fat diet (HFD) feeding mice were treated with PBA for 8weeks. As expected, HFD feeding dramatically induced body weight, but PBA treatment showed a resistance to HFD-induced weight gain. CT (computed tomography) scan image showed that abdominal and subcutaneous fat accumulation were dramatically decreased by PBA. Furthermore, fat composition analysis identified that whole body fat mass was decreased and lean body mass was increased by PBA as compared with control group. H&E staining showed that lipid accumulation in liver and fat tissues was decreased by PBA. To do further analysis the effect of PBA, we took advantage of genetic mouse model of obesity (ob/ob). Although we could not find significant difference in body weight by PBA, but blood glucose level was clearly decreased. Meanwhile, PBA improved glucose tolerance and insulin tolerance. Western analysis with Liver tissue samples from ob/ob mice showed that PBA decreased protein expression level of GRP78, ATF4 and CHOP as well as inhibited activities of protein pyruvate dehydrogenase kinase (PDK) which is an upstream kinase of pyruvate dehydrogenase complex (PDC) that is gatekeeper in pyruvate metabolism in mitochondria. These results suggest that PBA decrease diet induced obesity by alleviating ER-stress by modulating PDK activities.