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

Introduction

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, and the rapid switching on and off is essential for thermal regulation.

Energetic Cost of Thermogenesis

Of note, thermogenesis inevitably comes at a 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.

Knowledge Gap

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.

Research Objectives

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

Specific Aims

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 malfunction under pathophysiological conditions.
3. The translational potential of targeting these brakes.

Methodology

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'.

Expected Outcomes

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