Turning off the furnace: the intracellular brake systems for brown fat thermogenesis

Free-ranging animals are continuously exposed to fluctuating ambient temperature, therefore rapid fine-tuning of thermogenesis to maintain core temperature homeostasis is critical for survival.

Brown adipose tissue (BAT) evolves as a thermogenic organ, the rapid switching on and off is essential for thermal regulation. Of note, thermogenesis inevitably comes at high energetic cost and BAT ultimately is an energy-wasting organ.

A constrained strategy that minimizes BAT activity unless obligate will have been favored during natural selection to safeguard metabolic thriftiness.

However, this tenet and the molecular basis that constrain BAT activity remain unappreciated, unexplored and unexploited.

Filling this fundamental knowledge gap will unlock endogenous constraints and allow efficiently and fully harness the energy-consuming potential of BAT for therapeutic interventions.

To this end, I identify that a phase separation-aided molecular event, a lipolysis-stimulated feedforward regulatory circuit with negative feedback loop, and a purinergic nucleotides flux-based inhibitory mechanism, are synergistically involved in rapidly terminating heat production.

BATOFF aims to study: 1) how these previously unappreciated mechanisms allow mammals to effectively orchestrate dynamics of BAT activity; 2) whether these constraining brake systems are malfunction under pathophysiological conditions; and 3) the translational potential of targeting these brakes.

I will address these questions using state-of-the-art gain and loss-of-function in vitro and in vivo studies, newly-generated mouse models, high-resolution cellular respirometry, live cell imaging, and cutting-edge 'omics'.

Results of BATOFF will not only provide a transformative molecular understanding of the cellular processes enabling physiological adaptation to thermogenic demand, but also with translational potential for prevention and treatment of obesity and diabetes by harnessing the calorie-burning potential of BAT.