Serum- and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMP-activated protein kinase

Ben Zhou; Yuyao Zhang; Sainan Li; Lianfeng Wu; Geza Fejes-Toth; Aniko Naray-Fejes-Toth; Alexander A Soukas

doi:10.1016/j.celrep.2021.109785

Serum- and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMP-activated protein kinase

Cell Rep. 2021 Oct 5;37(1):109785. doi: 10.1016/j.celrep.2021.109785.

Authors

Ben Zhou¹, Yuyao Zhang², Sainan Li², Lianfeng Wu³, Geza Fejes-Toth⁴, Aniko Naray-Fejes-Toth⁴, Alexander A Soukas⁵

Affiliations

¹ Department of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China. Electronic address: benzhou@sibs.ac.cn.
² Department of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, School of Life Sciences, Westlake University, Hangzhou, 310024, China.
⁴ Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA.
⁵ Department of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: asoukas@mgh.harvard.edu.

Abstract

A hallmark of type 2 diabetes (T2D) is hepatic resistance to insulin's glucose-lowering effects. The serum- and glucocorticoid-regulated family of protein kinases (SGK) is activated downstream of mechanistic target of rapamycin complex 2 (mTORC2) in response to insulin in parallel to AKT. Surprisingly, despite an identical substrate recognition motif to AKT, which drives insulin sensitivity, pathological accumulation of SGK1 drives insulin resistance. Liver-specific Sgk1-knockout (Sgk1^Lko) mice display improved glucose tolerance and insulin sensitivity and are protected from hepatic steatosis when fed a high-fat diet. Sgk1 promotes insulin resistance by inactivating AMP-activated protein kinase (AMPK) via phosphorylation on inhibitory site AMPKα^Ser485/491. We demonstrate that SGK1 is dominant among SGK family kinases in regulation of insulin sensitivity, as Sgk1, Sgk2, and Sgk3 triple-knockout mice have similar increases in hepatic insulin sensitivity. In aggregate, these data suggest that targeting hepatic SGK1 may have therapeutic potential in T2D.

Keywords: AMPK; SGK; glucose homeostasis; hepatic insulin resistance; lipid homeostasis; mTORC1; mTORC2; obesity; type 2 diabetes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / antagonists & inhibitors
AMP-Activated Protein Kinases / metabolism*
Animals
Diabetes Mellitus, Type 2 / pathology
Diet, High-Fat
Forkhead Box Protein O1 / metabolism
Glucose / metabolism
Immediate-Early Proteins / deficiency
Immediate-Early Proteins / genetics
Immediate-Early Proteins / metabolism*
Insulin / metabolism
Insulin Resistance
Liver / metabolism*
Mechanistic Target of Rapamycin Complex 2 / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation
Protein Serine-Threonine Kinases / deficiency
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Proto-Oncogene Proteins c-akt / metabolism
RNA, Guide, CRISPR-Cas Systems
Signal Transduction

Substances

Forkhead Box Protein O1
Foxo1 protein, mouse
Immediate-Early Proteins
Insulin
Mechanistic Target of Rapamycin Complex 2
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
Sgk2 protein, mouse
Sgk3 protein, mouse
serum-glucocorticoid regulated kinase
AMP-Activated Protein Kinases
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding