Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis
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Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis. / Neopane, Katyayanee; Kozlov, Natalie; Negoita, Florentina; Murray-Segal, Lisa; Brink, Robert; Hoque, Ashfaqul; Ovens, Ashley J.; Tjin, Gavin; McAloon, Luke M.; Yu, Dingyi; Ling, Naomi X.Y.; Sanders, Matthew J.; Oakhill, Jonathan S.; Scott, John W.; Steinberg, Gregory R.; Loh, Kim; Kemp, Bruce E.; Sakamoto, Kei; Galic, Sandra.
I: Cell Reports, Bind 41, Nr. 12, 111862, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis
AU - Neopane, Katyayanee
AU - Kozlov, Natalie
AU - Negoita, Florentina
AU - Murray-Segal, Lisa
AU - Brink, Robert
AU - Hoque, Ashfaqul
AU - Ovens, Ashley J.
AU - Tjin, Gavin
AU - McAloon, Luke M.
AU - Yu, Dingyi
AU - Ling, Naomi X.Y.
AU - Sanders, Matthew J.
AU - Oakhill, Jonathan S.
AU - Scott, John W.
AU - Steinberg, Gregory R.
AU - Loh, Kim
AU - Kemp, Bruce E.
AU - Sakamoto, Kei
AU - Galic, Sandra
N1 - Publisher Copyright: © 2022 The Author(s)
PY - 2022
Y1 - 2022
N2 - AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis and a therapeutic target for metabolic diseases. Co/post-translational N-myristoylation of glycine-2 (Gly2) of the AMPK β subunit has been suggested to regulate the distribution of the kinase between the cytosol and membranes through a “myristoyl switch” mechanism. However, the relevance of AMPK myristoylation for metabolic signaling in cells and in vivo is unclear. Here, we generated knockin mice with a Gly2-to-alanine point mutation of AMPKβ1 (β1-G2A). We demonstrate that non-myristoylated AMPKβ1 has reduced stability but is associated with increased kinase activity and phosphorylation of the Thr172 activation site in the AMPK α subunit. Using proximity ligation assays, we show that loss of β1 myristoylation impedes colocalization of the phosphatase PPM1A/B with AMPK in cells. Mice carrying the β1-G2A mutation have improved metabolic health with reduced adiposity, hepatic lipid accumulation, and insulin resistance under conditions of high-fat diet-induced obesity.
AB - AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis and a therapeutic target for metabolic diseases. Co/post-translational N-myristoylation of glycine-2 (Gly2) of the AMPK β subunit has been suggested to regulate the distribution of the kinase between the cytosol and membranes through a “myristoyl switch” mechanism. However, the relevance of AMPK myristoylation for metabolic signaling in cells and in vivo is unclear. Here, we generated knockin mice with a Gly2-to-alanine point mutation of AMPKβ1 (β1-G2A). We demonstrate that non-myristoylated AMPKβ1 has reduced stability but is associated with increased kinase activity and phosphorylation of the Thr172 activation site in the AMPK α subunit. Using proximity ligation assays, we show that loss of β1 myristoylation impedes colocalization of the phosphatase PPM1A/B with AMPK in cells. Mice carrying the β1-G2A mutation have improved metabolic health with reduced adiposity, hepatic lipid accumulation, and insulin resistance under conditions of high-fat diet-induced obesity.
KW - adiposity
KW - AMPK
KW - CP: Metabolism
KW - myristoylation
KW - phosphatase
KW - signal transduction
KW - steatosis
U2 - 10.1016/j.celrep.2022.111862
DO - 10.1016/j.celrep.2022.111862
M3 - Journal article
C2 - 36543129
AN - SCOPUS:85144389434
VL - 41
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 12
M1 - 111862
ER -
ID: 331255154