Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα

Abstract

The tumor suppressor folliculin (FLCN) forms a repressor complex with AMP-activated protein kinase (AMPK). Given that AMPK is a master regulator of cellular energy homeostasis, we generated an adipose-specific Flcn (Adipoq-FLCN) knockout mouse model to investigate the role of FLCN in energy metabolism. We show that loss of FLCN results in a complete metabolic reprogramming of adipose tissues, resulting in enhanced oxidative metabolism. Adipoq-FLCN knockout mice exhibit increased energy expenditure and are protected from high-fat diet (HFD)-induced obesity. Importantly, FLCN ablation leads to chronic hyperactivation of AMPK, which in turns induces and activates two key transcriptional regulators of cellular metabolism, proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) and estrogen-related receptor α (ERRα). Together, the AMPK/PGC-1α/ERRα molecular axis positively modulates the expression of metabolic genes to promote mitochondrial biogenesis and activity. In addition, mitochondrial uncoupling proteins as well as other markers of brown fat are up-regulated in both white and brown FLCN-null adipose tissues, underlying the increased resistance of Adipoq-FLCN knockout mice to cold exposure. These findings identify a key role of FLCN as a negative regulator of mitochondrial function and identify a novel molecular pathway involved in the browning of white adipocytes and the activity of brown fat.

The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue

“…A recent study (Yan et al 2016) also reported on the phenotype of adipose-specific deletion of FLCN using the same genetic model of adiponectin-Cre to delete FLCN in adipose cells. The study reported that FLCN deletion in fat leads to browning of adipose tissue, cold resistance, obesity resistance upon high-fat diet challenge, and improved glucose metabolism.…”

“…5,6). It is possible that the FLCN-AMPK pathway proposed by Yan et al (2016) superimposes on this pathway by modulating mTOR/TFE3. A recent report (Young et al 2016) showed in embryoid bodies that AMPK promotes the activity of TFEB, a molecule highly homologous to TFE3, and that this regulation of TFEB by AMPK occurs at least partly through mTOR.…”

Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1α in female mice

“…Adipose tissue function is controlled by several processes including mitochondrial biogenesis, adaptive thermogenesis, mitochondrial fatty acid oxidation, oxygen consumption and oxidative phosphorylation that are regulated by PGC-1α [23], [24], [25]. Adipocytes store fat and excess energy, however, beige and brown adipocytes are regarded as the major source of mitochondrial and thermogenic function to combat obesity and metabolic syndrome [23], [26].…”

“…Adipocytes store fat and excess energy, however, beige and brown adipocytes are regarded as the major source of mitochondrial and thermogenic function to combat obesity and metabolic syndrome [23], [26]. Several transcriptional factors regulate the levels of signaling molecules that are involved in the expression of thermogenic and mitochondrial function in beige and visceral fat [23], [25], [26], [27], [28], [29].…”

Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis

“…Cold and energy stress also induce the stress-activated protein kinase AMP-activated protein kinase (AMPK), which enhances EE and thus is a major target in obesity and T2D (19)(20)(21)(22)(23)(24). β-ARmediated AMPK activation augments insulin sensitivity in a UCP1-dependent manner (22).…”