Cellular mechanobiology and engineering of active brown adipose tissue

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PROJECT SUMMARY/ABSTRACT There is a dire need for new technologies to address the obesity epidemic and its associated sequellae, including Type II Diabetes. Increasing caloric output through expansion and activation of brown adipose tissue (BAT), which “burns” metabolic fuels to produce heat, is garnering increasing interest as a novel mechanism to trigger weight loss in adults. However, the technological translation of this approach, including the engineering of biomaterial platforms to support BAT in vitro and in vivo, has been limited by a poor understanding of how cues from the physical microenvironment regulate BAT activation. Our preliminary data hint at a novel and unexpected model in which beta-adrenergic (ß-AR) stimulation triggers BAT activation through a myosin- and YAP/TAZ-dependent mechanotransductive signaling network, ultimately enhancing expression of the heat- generating mitochondrial protein UCP1. This model has profound implications, because it would suggest that incorporation of mechanical cues within the microenvironment could be leveraged to activate BAT and promote caloric output as a strategy to combat obesity. Thus, the goal of this proposal is to critically test the hypothesis that ß-AR and mechanotransductive signaling collude to stimulate BAT activation and enhanced cellular respiration. We have three aims: (1) To dissect the mechanisms through which actomyosin tension acutely activates BAT; (2) To determine how mechanical activation of YAP/TAZ regulates expression of UCP1; and (3) To investigate the role of mechanosensitive YAP/TAZ-dependent signals in white/beige adipose fate determination. In addition to detailed dissection of signaling events, our approach features an innovative combination of engineered materials, mechanical stimulation, advanced mouse genetic models, inducible expression of myosin-activating proteins, and measurements of cell and tissue mechanics. Successful completion of this work would substantially advance our mechanistic understanding of BAT activation while informing the design of materials technologies to stimulate BAT activation to reduce obesity.