Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα
Autor: | Ming Yan, Masaya Baba, Benjamin Walker, Sanaz Manteghi, Vincent Giguère, Arnim Pause, Julie St-Pierre, Catherine R. Dufour, Étienne Audet-Walsh |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
medicine.medical_specialty Adipose tissue AMP-Activated Protein Kinases Biology Mice 03 medical and health sciences 0302 clinical medicine AMP-activated protein kinase Proto-Oncogene Proteins Internal medicine Genetics medicine Animals Obesity Folliculin Mice Knockout Tumor Suppressor Proteins AMPK Adipose Tissue Beige Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Cell biology Cold Temperature Enzyme Activation 030104 developmental biology Endocrinology Gene Expression Regulation Receptors Estrogen Nuclear receptor Mitochondrial biogenesis 030220 oncology & carcinogenesis Knockout mouse biology.protein Signal transduction Energy Metabolism Oxidation-Reduction Research Paper Signal Transduction Developmental Biology |
Zdroj: | Genes & Development. 30:1034-1046 |
ISSN: | 1549-5477 0890-9369 |
Popis: | 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. |
Databáze: | OpenAIRE |
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