The role of prostaglandin E2 receptor EP4 subtype in energy balance and obesity

Abstract

Obesity features increased accumulation of fat in the body and results in adverse health consequences, including type II diabetes mellitus and cardiovascular diseases. The global epidemic of obesity and lack of effective treatments call for the search of new anti-obesity medication. Activation of prostaglandin receptor subtype 4 (EP4) had been shown to produce potent anti-inflammatory effect and possibly induce brite adipocytes to increase energy expenditure, both of which can potentially ameliorate obesity. The purpose of this dissertation is to characterize the metabolic phenotypes of EP4 receptor in mice and to elucidate whether administration of CAY10580, a selective EP4 agonist, could protect against obesity and its related complications. The experiments were carried out on diet-induced obese mice and EP4 knockout mice. Anthropometric measurement, glucose and insulin tolerance test, indirect calorimetry, quantitative real-time PCR, plasma analytes measurement and histological studies were performed. The findings revealed that EP4 activation by CAY10580 prevented high-fat diet fed mice from becoming obese, but it did not exhibit a curative effect in reversing obesity in mice. Activation of EP4 by CAY10580 suppressed body weight gain and adiposity in high-fat diet fed mice by reducing the weight of epididymal, subcutaneous and peri-renal white adipose tissues, inter-scapular brown adipose tissue and liver. The lower adiposity resulted in improved glucose and insulin sensitivity and lower plasma leptin level. The cause of reduced adiposity by EP4 activation is not due to changes in energy intake, obligatory energy expenditure, locomotor activities, adaptive thermogenesis and lipolysis. EP4- mediated reduction in adiposity was characterized by smaller adipocyte size and greater proportion of small adipocytes in subcutaneous white adipose tissue. Furthermore, mice deficient in EP4 also showed reduced adiposity at epididymal, subcutaneous and peri-renal white adipose tissues, and inter-scapular brown adipose tissue. The reduced adiposity in EP4 deficient mice was associated with impaired cold intolerance. Taken together, EP4 activation is effective in preventing obesity and relieving obesity-associated glucose and insulin tolerance, and EP4 might play an essential role in adiposity maintenance through the modulation on adipocyte development.