The BATOFF project aims to uncover the fundamental principles governing the negative regulation of brown adipose tissue (BAT) thermogenesis by identifying intrinsic molecular “brake” systems that limit its energy-dissipating capacity and ensure precise control of heat production. In the past two years, we have conducted extensive work across all three aims (AIM1-3) of the project.
For AIM1, we have investigated the molecular regulation and functional significance of compartmentalized cAMP signaling mediated by phase separation processes in brown adipocyte thermogenesis, thereby providing mechanistic insight into how localized signaling controls thermogenic activation.
For AIM2, we have completed the in vitro experiments and successfully established genetically modified mouse models, including adipocyte-specific conditional knockouts and whole-body knockout models, enabling the extension of our studies into physiologically relevant in vivo systems.
For AIM3, we have performed both loss- and gain-of-function analyses of key purine nucleotide metabolic pathways to investigate their roles in constraining UCP1 activity. In parallel, we have developed a UCP1 functional analysis system that enables ectopic expression of mutant UCP1 in UCP1-deficient adipocytes, allowing systematic screening of variants to define structure–function relationships and their impact on thermogenic activity.
Building on these three synergistic mechanisms—a phase separation–mediated process, a lipolysis-driven feedforward circuit with embedded negative feedback, and a purinergic nucleotide–dependent inhibitory pathway—this work defines a coordinated regulatory framework that constrains BAT activity.
