title: Atrial natriuretic peptide regulates lipid mobilization and oxygen consumption in human adipocytes by activating AMPK.
abstract: Atrial natriuretic peptide (ANP) has been shown to regulate lipid and carbohydrate metabolism providing a possible link between cardiovascular function and metabolism by mediating the switch from carbohydrate to lipid mobilization and oxidation. ANP exerts a potent lipolytic effect via cGMP-dependent protein kinase (cGK)-I mediated-stimulation of AMP-activated protein kinase (AMPK). Activation of the ANP/cGK signaling cascade also promotes muscle mitochondrial biogenesis and fat oxidation. Here we demonstrate that ANP regulates lipid metabolism and oxygen utilization in differentiated human adipocytes by activating the alpha2 subunit of AMPK. ANP treatment increased lipolysis by seven fold and oxygen consumption by two fold, both of which were attenuated by inhibition of AMPK activity. ANP-induced lipolysis was shown to be mediated by the alpha2 subunit of AMPK as introduction of dominant-negative alpha2 subunit of AMPK attenuated ANP effects on lipolysis. ANP-induced activation of AMPK enhanced mitochondrial oxidative capacity as evidenced by a two fold increase in oxygen consumption and induction of mitochondrial genes, including carnitine palmitoyltransferase 1A (CPT1a) by 1.4-fold, cytochrome C (CytC) by 1.3-fold, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) by 1.4-fold. Treatment of human adipocytes with fatty acids and tumor necrosis factor α (TNFα) induced insulin resistance and down-regulation of mitochondrial genes, which was restored by ANP treatment. These results show that ANP regulates lipid catabolism and enhances energy dissipation through AMPK activation in human adipocytes.
authors.affiliation: Translational Sciences - Translational Medicine, Novartis Institutes for Biomedical Research, Inc., 220 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Souza
authors.forename: Mary D L
authors.initials: MD
authors.lastname: Chau
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.forename: Marie-Soleil
authors.initials: MS
authors.lastname: Gauthier
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Clairmont
authors.forename: Zhidan
authors.initials: Z
authors.lastname: Wu
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
authors.forename: William P
authors.initials: WP
authors.lastname: Dole
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009320:Atrial Natriuretic Factor / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D050259:Genes, Mitochondrial; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008066:Lipolysis; D010101:Oxygen Consumption
chemical_list: D009320:Atrial Natriuretic Factor; C526181:PRKAA2 protein, human; D055372:AMP-Activated Protein Kinases