Regulation of AMP-activated protein kinase by LKB1 and CaMKK in adipocytes
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Regulation of AMP-activated protein kinase by LKB1 and CaMKK in adipocytes. / Gormand, Amélie; Henriksson, Emma; Ström, Kristoffer; Jensen, Thomas Elbenhardt; Sakamoto, Kei; Göransson, Olga.
I: Journal of Cellular Biochemistry, Bind 112, Nr. 5, 2011, s. 1364-1375.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Regulation of AMP-activated protein kinase by LKB1 and CaMKK in adipocytes
AU - Gormand, Amélie
AU - Henriksson, Emma
AU - Ström, Kristoffer
AU - Jensen, Thomas Elbenhardt
AU - Sakamoto, Kei
AU - Göransson, Olga
N1 - CURIS 2011 5200 169
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - 3T3-L1 Cells
KW - AMP-Activated Protein Kinases
KW - Adipocytes
KW - Adipose Tissue
KW - Animals
KW - Benzimidazoles
KW - Calcium
KW - Calcium-Calmodulin-Dependent Protein Kinase Kinase
KW - Colforsin
KW - Mice
KW - Mice, Knockout
KW - Naphthalimides
KW - Phenformin
KW - Protein-Serine-Threonine Kinases
KW - Signal Transduction
U2 - 10.1002/jcb.23053
DO - 10.1002/jcb.23053
M3 - Journal article
C2 - 21312243
VL - 112
SP - 1364
EP - 1375
JO - Journal of cellular biochemistry. Supplement
JF - Journal of cellular biochemistry. Supplement
SN - 0733-1959
IS - 5
ER -
ID: 142185069