Glucagon regulates ACC activity in adipocytes through the CAMKK β/AMPK pathway

I. Chen Peng, Zhen Chen, Wei Sun, Ying Shiuan Li, Traci Lanai Marin, Pang Hung Hsu, Mei I. Su, Xiaopei Cui, Songqin Pan, Christian Y. Lytle, David A. Johnson, Frank Blaeser, Talal Chatila, John Y.J. Shyy

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

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 (CaMKK β -/-) mice and cultured adipocytes, we further show that glucagon activates the CaMKK β / AMPK/ACC cascade. Additionally, fasting increases the phosphorylation of AMPK and ACC in CaMKK β +/+ but not CaMKK β -/- mice. These results indicate that CaMKKf/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.

Original languageEnglish
Pages (from-to)E1560-E1568
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume302
Issue number12
DOIs
Publication statusPublished - 2012 Jun 15

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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