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Glucagon Activates the AMP‐Activated Protein Kinase/Acetyl‐CoA Carboxylase Pathway in Adipocytes
Author(s) -
Peng IChen,
Chen Zhen,
Hsu PangHung,
Su MeiI,
Tsai MingDaw,
Shyy John YJ.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.995.4
Subject(s) - ampk , glucagon , protein kinase a , amp activated protein kinase , chemistry , phosphorylation , acetyl coa carboxylase , kinase , medicine , endocrinology , pyruvate carboxylase , lipid metabolism , fatty acid synthesis , biochemistry , biology , fatty acid , enzyme , hormone
Glucagon is important in regulating lipid metabolism, in part through its inhibition of fatty acid (FA) synthesis in adipocytes. Given that acetyl‐CoA carboxylase (ACC) is the rate‐limiting enzyme for FA synthesis, the proposed mechanism is that glucagon activates PKA, which in turn phosphorylates ACC at Ser‐77 and Ser‐1200, thereby attenuates the lipogenic activity of ACC. Because AMPK also inhibits FA synthesis by phosphorylating ACC Ser‐79, we examined the involvement of AMPK in the glucagon‐elicited signaling in adipocytes. Western blot showed that glucagon treatment increased the phosphorylation of AMPK Thr‐172 and ACC Ser‐79 in adipocytes. LC/MS/MS revealed that ACC Ser‐79, but not Ser‐77 or Ser‐1200, was phosphorylated in these cells. The glucagon‐induced ACC Ser‐79 phosphorylation was blocked by pharmacological inhibition or genetic ablation of AMPK. In vitro kinase activity assay showed that Ca 2+ /calmodulin‐dependent protein kinase kinase β (CaMKKβ) is the upstream kinase phosphorylating AMPK responding to glucagon. As well, CaMKKβ inhibition reduced the AMPK activity with attenuated ACC Ser‐79 phosphorylation. Furthermore, CaMKKβ −/− mice receiving glucagon did not show an activation of the AMPK/ACC pathway in their adipose tissue. Our results suggest that AMPK is crucial in regulating the glucagon‐elicited lipid metabolism in adipocytes.