title: 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.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, Quebec H3G 1Y6, Canada;
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, Quebec H3G 1Y6, Canada;
authors.forename: Étienne
authors.initials: É
authors.lastname: Audet-Walsh
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, Quebec H3G 1Y6, Canada;
authors.forename: Sanaz
authors.initials: S
authors.lastname: Manteghi
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec H3A 1A3, Canada;
authors.forename: Catherine Rosa
authors.initials: CR
authors.lastname: Dufour
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, Quebec H3G 1Y6, Canada;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Walker
authors.affiliation: International Research Centre for Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan;
authors.forename: Masaya
authors.initials: M
authors.lastname: Baba
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, Quebec H3G 1Y6, Canada;
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, Quebec H3G 1Y6, Canada; International Research Centre for Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan; Department of Oncology, McGill University, Montréal, Quebec H3G 1Y6, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Quebec H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, Quebec H3G 1Y6, Canada;
authors.forename: Arnim
authors.initials: A
authors.lastname: Pause
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics; D000069796:Adipose Tissue, Beige / Q000378:metabolism*; D000818:Animals; D003080:Cold Temperature; D004734:Energy Metabolism / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology / Q000235:genetics; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D055372:AMP-Activated Protein Kinases; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D025521:Tumor Suppressor Proteins; D000097983:ERRalpha Estrogen-Related Receptor; C526060:Bhd protein, mouse; C485290:Ppargc1a protein, mouse
keywords: brown fat; high-fat diet; metabolic reprogramming; nuclear receptors; obesity; thermogenesis