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

Cell Reports (Oct 2021)

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

Affiliations

Ben Zhou: 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; Corresponding author
Yuyao Zhang: 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
Sainan Li: 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
Lianfeng Wu: Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, School of Life Sciences, Westlake University, Hangzhou, 310024, China
Geza Fejes-Toth: Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA
Aniko Naray-Fejes-Toth: Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA
Alexander A. Soukas: 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; Corresponding author

Journal volume & issue: Vol. 37, no. 1
p. 109785

Abstract

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Summary: 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 (Sgk1Lko) 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 AMPKαSer485/491. 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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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