Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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.

In: Cell Reports, Vol. 41, No. 12, 111862, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Neopane, K, Kozlov, N, Negoita, F, Murray-Segal, L, Brink, R, Hoque, A, Ovens, AJ, Tjin, G, McAloon, LM, Yu, D, Ling, NXY, Sanders, MJ, Oakhill, JS, Scott, JW, Steinberg, GR, Loh, K, Kemp, BE, Sakamoto, K & Galic, S 2022, 'Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis', Cell Reports, vol. 41, no. 12, 111862. https://doi.org/10.1016/j.celrep.2022.111862

APA

Neopane, K., Kozlov, N., Negoita, F., Murray-Segal, L., Brink, R., Hoque, A., Ovens, A. J., Tjin, G., McAloon, L. M., Yu, D., Ling, N. X. Y., Sanders, M. J., Oakhill, J. S., Scott, J. W., Steinberg, G. R., Loh, K., Kemp, B. E., Sakamoto, K., & Galic, S. (2022). Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis. Cell Reports, 41(12), [111862]. https://doi.org/10.1016/j.celrep.2022.111862

Vancouver

Neopane K, Kozlov N, Negoita F, Murray-Segal L, Brink R, Hoque A et al. Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis. Cell Reports. 2022;41(12). 111862. https://doi.org/10.1016/j.celrep.2022.111862

Author

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. / Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis. In: Cell Reports. 2022 ; Vol. 41, No. 12.

Bibtex

@article{adeb471217f643ebb3f7497247c2c4b0,
title = "Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis",
abstract = "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.",
keywords = "adiposity, AMPK, CP: Metabolism, myristoylation, phosphatase, signal transduction, steatosis",
author = "Katyayanee Neopane and Natalie Kozlov and Florentina Negoita and Lisa Murray-Segal and Robert Brink and Ashfaqul Hoque and Ovens, {Ashley J.} and Gavin Tjin and McAloon, {Luke M.} and Dingyi Yu and Ling, {Naomi X.Y.} and Sanders, {Matthew J.} and Oakhill, {Jonathan S.} and Scott, {John W.} and Steinberg, {Gregory R.} and Kim Loh and Kemp, {Bruce E.} and Kei Sakamoto and Sandra Galic",
note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
doi = "10.1016/j.celrep.2022.111862",
language = "English",
volume = "41",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",

}

RIS

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