title: Regulation of AMP-activated protein kinase by LKB1 and CaMKK in adipocytes.
abstract: 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.
authors.affiliation: Protein Phosphorylation Research Group, Department of Experimental Medical Science, Lund University, BMC C11, SE 221 84 Lund, Sweden.
authors.forename: Amélie
authors.initials: A
authors.lastname: Gormand
authors.forename: Emma
authors.initials: E
authors.lastname: Henriksson
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Ström
authors.forename: Thomas Elbenhardt
authors.initials: TE
authors.lastname: Jensen
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Olga
authors.initials: O
authors.lastname: Göransson
mesh_terms: D041721:3T3-L1 Cells; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000201:enzymology*; D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D053644:Naphthalimides / Q000494:pharmacology; D010629:Phenformin / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D001562:Benzimidazoles; D053644:Naphthalimides; C458525:STO 609; D005576:Colforsin; D010629:Phenformin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D002118:Calcium