title: Glucagon regulates ACC activity in adipocytes through the CAMKKβ/AMPK pathway.
abstract: Glucagon is important for regulating lipid metabolism in part through its inhibition of fatty acid synthesis in adipocytes. Acetyl-CoA carboxylase 1 (ACC1) is the rate-limiting enzyme for fatty acid synthesis. Glucagon has been proposed to activate cAMP-dependent protein kinase A (PKA), which phosphorylates ACC1 to attenuate the lipogenic activity of ACC1. Because AMP-activated protein kinase (AMPK) also inhibits fatty acid synthesis by phosphorylation of ACC1, we examined the involvement of AMPK and its upstream kinase in the glucagon-elicited signaling in adipocytes in vitro and in vivo. LC-MS-MS analysis suggested that ACC1 was phosphorylated only at Ser(79), an AMPK-specific site, in glucagon-treated adipocytes. Pharmacological inhibitors and siRNA knockdown of AMPK or PKA in adipocytes demonstrate that glucagon regulates ACC1 and ACC2 activity through AMPK but not PKA. By using Ca(2+)/calmodulin-dependent protein kinase kinase-β knockout (CaMKKβ(-/-)) mice and cultured adipocytes, we further show that glucagon activates the CaMKKβ/AMPK/ACC cascade. Additionally, fasting increases the phosphorylation of AMPK and ACC in CaMKKβ(+/+) but not CaMKKβ(-/-) mice. These results indicate that CaMKKβ/AMPK signaling is an important molecular component in regulating lipid metabolism in adipocytes responding to glucagon and could be a therapeutic target for the dysregulation of energy storage.
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, 92521, USA.
authors.forename: I-Chen
authors.initials: IC
authors.lastname: Peng
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Ying-Shiuan
authors.initials: YS
authors.lastname: Li
authors.forename: Traci LaNai
authors.initials: TL
authors.lastname: Marin
authors.forename: Pang-Hung
authors.initials: PH
authors.lastname: Hsu
authors.forename: Mei-I
authors.initials: MI
authors.lastname: Su
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Cui
authors.forename: Songqin
authors.initials: S
authors.lastname: Pan
authors.forename: Christian Y
authors.initials: CY
authors.lastname: Lytle
authors.forename: David A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Frank
authors.initials: F
authors.lastname: Blaeser
authors.forename: Talal
authors.initials: T
authors.lastname: Chatila
authors.forename: John Y-J
authors.initials: JY
authors.lastname: Shyy
mesh_terms: D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology*; D052436:Adipose Tissue, White / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D005934:Glucagon / Q000494:pharmacology*; D007202:Indicators and Reagents; D050155:Lipogenesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013268:Stimulation, Chemical; D053719:Tandem Mass Spectrometry; D014162:Transfection
chemical_list: D007202:Indicators and Reagents; D005934:Glucagon; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C033288:(acetyl-CoA carboxylase) kinase; D055372:AMP-Activated Protein Kinases