title: Role of extracellular signal-regulated kinase 5 in adipocyte signaling.
abstract: Increased adiposity due to energy imbalance is a critical factor of the epidemic crisis of obesity and type II diabetes. In addition to the obvious role in energy storage, regulatory factors are secreted from adipose depots to control appetite and cellular homeostasis. Complex signaling cross-talks within adipocyte are also evident due to the metabolic and immune nature of adipose depots. Here, we uncover a role of extracellular signal-regulated kinase 5 (ERK5) in adipocyte signaling. We find that deletion of ERK5 in adipose depots (adipo-ERK5(-/-)) increases adiposity, in part, due to increased food intake. Dysregulated secretion of adipokines, leptin resistance, and impaired glucose handling are also found in adipo-ERK5(-/-) mice. Mechanistically, we show that ERK5 impinges on transcription factor NFATc4. Decreased phosphorylation at the conserved gate-keeping Ser residues and increased nuclear localization of NFATc4 are found in adipo-ERK5(-/-) mice. We also find attenuated PKA activation in adipo-ERK5(-/-) mice. In response to stimulation of β-adrenergic G-protein-coupled receptor, we find decreased NFATc4 phosphorylation and impaired PKA activation in adipo-ERK5(-/-) mice. Reduced cAMP accumulation and increased phosphodiesterase activity are also found. Together, these results demonstrate integration of ERK5 with NFATc4 nucleo-cytoplasmic shuttling and PKA activation in adipocyte signaling.
authors.affiliation: From the Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Sara
authors.initials: S
authors.lastname: Guariglia
authors.forename: Wenjing
authors.initials: W
authors.lastname: Li
authors.forename: Deborah
authors.initials: D
authors.lastname: Brancho
authors.forename: Zhao V
authors.initials: ZV
authors.lastname: Wang
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Chi-Wing
authors.initials: CW
authors.lastname: Chow
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000201:enzymology*; D054392:Adipokines / Q000235:genetics / Q000378:metabolism; D050154:Adiposity / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism
chemical_list: D054392:Adipokines; D050778:NFATC Transcription Factors; C467907:Nfatc4 protein, mouse; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048054:Mitogen-Activated Protein Kinase 7
keywords: Adipose tissue; MAP Kinases (MAPKs); Metabolic Regulation; NFAT Transcription Factor; Protein Kinase A (PKA)