Grant: Travel Awards - Institute Community Support

Obesity, a major risk factor for metabolic disorders, is initiated from an imbalance between energy intake and expenditure that leads to the excessive accumulation of white fat. AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine protein kinase playing a key role in cellular and whole-body energy homeostasis. The tumor suppressor folliculin (FLCN) is a novel AMPK binding partner. Loss of FLCN constitutively activates AMPK in absence of metabolic stress, resulting in PGC-1-mediated mitochondrial biogenesis and increased production of reactive oxygen species (ROS) in mouse embryonic fibroblasts (MEFs). We generated an adipose-specific FLCN knockout mouse model to investigate the role of FLCN and its function associated with AMPK/PGC-1 axis in whole body energy metabolism. Here we show that female mice with an adipose-specific knockout of FLCN exhibit elevated energy expenditure with increased CO2 respiration and O2 consumption, and are protected from diet-induced obesity. Importantly, FLCN deletion in the adipose tissue enhances the expression and activity of estrogen-related receptor alpha (ERRa), which is recognized as a key regulator of mitochondrial biogenesis and is activated by PGC-1 alpha. Chromatin immunoprecipitation (ChIP) analysis of ERR alpha target genes in FLCN KO MEFs shows increased binding to Aco2, Idh3a and Cs in the tricarboxylic acid (TCA) cycle suggesting upregulation of mitochondria activity. Thus, we reveal that loss of FLCN is involved in AMPK-dependent PGC-1 alpha/ERR alpha activation, which leads to elevated mitochondria respiration conferring an anti-obesity advantage in female mice.