The stimulus effect of BMP7 and the inhibitory effect of TLR4 on adaptive thermogenesis

Adaptive thermogenesis is a cellular process that converts excess energy into heat via uncoupled respiration. Adaptive thermogenesis is mediated by an emergence of brown-like adipocytes (beige) within white adipose tissue (WAT), in a process called ‘WAT browning’. Adult humans retain a substantial amount of beige fat that increases energy expenditure upon various inducers such as cold exposure. Therefore, activation of brown/beige adipocytes is an attractive strategy to facilitate weight loss and improve metabolic health. However, obese subjects are less responsive to thermogenic signaling cues compared to lean subjects. To enhance WAT browning, either increasing brown stimulatory signaling cues, or decreasing inhibitory signaling is necessary. BMP7 stimulates brown adipocyte formation, especially in rodents. However, less is known about its role in humans. In addition, the characteristic of the BMP7-induced brown adipocytes, whether they are beige or classical brown fat cells, is undetermined. In this dissertation, I aimed to investigate the effect of BMP7 on human brown adipocyte differentiation and metabolic activities. I found that BMP7 stimulates the differentiation of human stem cells to brown adipocytes expressing beige-specific markers. BMP7-derived beige adipocytes were metabolically active and their oxygen consumption rate was higher than non-BMP7 treated cells. These findings can facilitate the discovery of new compounds that can affect thermogenesis as BMP7-derived beige cells can be used as a human model of beige adipocytes. TLR4 activation, in response to elevated endotoxins and/or free fatty acids, is well documented in obese subjects and can lead to chronic inflammation. However, whether TLR4 activation plays a role in the adaptive thermogenesis impairment observed in obesity has not been established yet. In the second part of my dissertation, I aimed to identify the role of TLR4-induced inflammation on WAT browning. TLR4 activation by a high-fat diet or LPS, a TLR4 ligand, attenuated adaptive thermogenesis in mice, whereas adaptive thermogenesis in TLR4 knockout mice was protected. Chronic TLR4 activation increased ROS production and ER stress. Blunting ER stress by pharmacological inhibitors or genetic deletion of upstream regulator CHOP protected from TLR4-induced WAT browning inhibition. These results indicate that 1) TLR4 activation is a pivotal contributor in thermogenic impairment observed in obesity, and 2) targeted inhibition of TLR4/ER stress signaling axis might be efficacious in promoting adaptive thermogenesis