Regulation of AMP-activated protein kinase by LKB1 and CaMKK in adipocytes
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
AMP-activated protein kinase (AMPK) is a serine/threonine kinase that regulates cellular and whole body energy homeostasis. In adipose tissue, activation of AMPK has been demonstrated in response to a variety of extracellular stimuli. However, the upstream kinase that activates AMPK in adipocytes remains elusive. Previous studies have identified LKB1 as a major AMPK kinase in muscle, liver, and other tissues. In certain cell types, Ca(2+) /calmodulin-dependent protein kinase kinase β (CaMKKβ) has been shown to activate AMPK in response to increases of intracellular Ca(2+) levels. Our aim was to investigate if LKB1 and/or CaMKK function as AMPK kinases in adipocytes. We used adipose tissue and isolated adipocytes from mice in which the expression of LKB1 was reduced to 10-20% of that of wild-type (LKB1 hypomorphic mice). We show that adipocytes from LKB1 hypomorphic mice display a 40% decrease in basal AMPK activity and a decrease of AMPK activity in the presence of the AMPK activator phenformin. We also demonstrate that stimulation of 3T3L1 adipocytes with intracellular [Ca(2+) ]-raising agents results in an activation of the AMPK pathway. The inhibition of CaMKK isoforms, particularly CaMKKβ, by the inhibitor STO-609 or by siRNAs, blocked Ca(2+) -, but not phenformin-, AICAR-, or forskolin-induced activation of AMPK, indicating that CaMKK activated AMPK in response to Ca(2+) . Collectively, we show that LKB1 is required to maintain normal AMPK-signaling in non-stimulated adipocytes and in the presence of phenformin. In addition, we demonstrate the existence of a Ca(2+) /CaMKK signaling pathway that can also regulate the activity of AMPK in adipocytes.
Originalsprog | Engelsk |
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Tidsskrift | Journal of Cellular Biochemistry |
Vol/bind | 112 |
Udgave nummer | 5 |
Sider (fra-til) | 1364-1375 |
Antal sider | 12 |
ISSN | 0730-2312 |
DOI | |
Status | Udgivet - 2011 |
Bibliografisk note
CURIS 2011 5200 169
- 3T3-L1 Cells, AMP-Activated Protein Kinases, Adipocytes, Adipose Tissue, Animals, Benzimidazoles, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Colforsin, Mice, Mice, Knockout, Naphthalimides, Phenformin, Protein-Serine-Threonine Kinases, Signal Transduction
Forskningsområder
ID: 142185069