期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 302, 期 12, 页码 E1560-E1568出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00504.2011
关键词
acetyl-coenzyme A carboxylase; Ca2+/calmodulin-dependent protein kinase kinase-beta; adenosine 5 '-monophosphate-activated protein kinase; lipid metabolism; fatty acid synthesis; energy mobilization
资金
- National Institutes of Health [R01-HL-89940, R01-HL-105318, R01-AI-085090, R01-AI-073731]
- UCR Biomedical Sciences Program for Innovative Collaborative Research
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 Ca2+/calmodulin-dependent protein kinase kinase-beta knockout (CaMKK beta(-/-)) mice and cultured adipocytes, we further show that glucagon activates the CaMKK beta/AMPK/ACC cascade. Additionally, fasting increases the phosphorylation of AMPK and ACC in CaMKK beta(+/+) but not CaMKK beta(-/-) mice. These results indicate that CaMKK beta/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.
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