FXR liver-adipose axis

Obesity and obesity-related disorders such as non-alcoholic fatty liver disease (NAFLD) are a dramatically increasing health and economic burden in the Western World. In obese patients, up to 70% have fatty liver disease. Lifestyle interventions and bariatric surgery are effective treatments for NAFLD but there is no established pharmacological treatment, yet. Pharmacological treatment of NAFLD ideally not only focuses on the reduction of fat in the liver but also on the underlying metabolic syndrome. The hepatic bile acid receptor FXR is one of the most promising pharmacological drug targets to achieve these goals. FXR activation in the liver by endogenous as well as exogenous pharmacological activators reduces plasma glucose levels as well as intrahepatic lipid storage and it has inhibitory effect on proinflammatory mediators. However, not only hepatic effects contribute to the metabolically beneficial events of FXR activation, but also extrahepatic events. In a previous research project in obese human subjects treated with FXR activators we identified signaling pathways and molecules in the liver, which are known to further act on the adipose tissue. In particular, these pathways and molecules are able to induce browning of white adipose tissue (WAT) and subsequently thermogenesis. Brown adipose tissue and browning of WAT has attracted significant interest as a target in metabolic diseases, as it is able to dissipate energy as heat, a process called adaptive thermogenesis. In rodent models of obesity with NAFLD, activation of brown adipose tissue and browning of WAT results in improved the metabolic syndrome including weight reduction, improved insulin sensitivity and lipid profiles as well as amelioration of NAFLD. However, most of the signals resulting in browning have only been studied in mice and a robust human correlation is missing. A preliminary experiment in visceral and subcutaneous WAT samples of our human study population showed induced surrogate markers of browning in subcutaneous WAT after treatment with FXR activators. Therefore, we herein propose that FXR activation in the liver produces signaling factors, which results in browning of WAT in obese patients. To answer our hypothesis we will study different WAT depots in human subjects which are either morbidly obese or non-obese and which have received a clinical approved FXR agonist or placebo. We speculate that part of the WAT turn brown by application of the FXR activator. Results of this study will not only reveal a new inter-organ and disease specific FXR signaling axis in obese patients with NAFLD, but will also shed more light on the browning capacities in human adipose tissue.