Serum- and glucocorticoid-inducible kinase 1 promotes insulin resistance in adipocytes via degradation of insulin receptor substrate 1.

Abstract

AIMS:

Accumulating evidence indicates that serum- and glucocorticoid-inducible kinase 1 (SGK1) plays a role in the development of metabolic syndrome via a poorly understood mechanism. This study aimed to investigate the direct effect of SGK1 on insulin sensitivity in adipose tissue.

MATERIALS AND METHODS:

We ectopically expressed or silenced SGK1 in adipocytes via lentiviral transfection, measured glucose uptake and evaluated insulin signalling using western blotting. In vivo insulin resistance was measured at the whole-body and adipose tissue levels in db/db mice treated with an inhibitor of SGK1.

RESULTS:

After 8 weeks of SGK1 inhibitor treatment, the serum insulin level and homeostasis model assessment of insulin resistance index were significantly decreased, and AKT phosphorylation in adipose tissue was enhanced in db/db mice. Overexpression of constitutively active SGK1 in adipocytes in vitro decreased AKT phosphorylation and insulin-stimulated glucose uptake. Dexamethasone and oleic acid increased SGK1 expression and decreased AKT phosphorylation and insulin receptor substrate expression in adipocytes. Administration of an inhibitor of SGK1 or Lv-shSGK1 reversed the suppression of insulin signalling induced by dexamethasone and oleic acid. SGK1 overexpression increased FoxO1 phosphorylation, and administration of Lv-shSGK1 reversed an increase in FoxO1 phosphorylation induced by dexamethasone and oleic acid.

CONCLUSIONS:

Thus, SGK1 mediates the effect of glucocorticoids and high-fat feeding and induces insulin resistance in adipocytes. Our data suggest that SGK1 is a possible therapeutic target for metabolic syndrome and related complications.

• Authors: Min Zhang, Huan Chen, Meng-Si Liu, Ke-Ying Zhu, Yan Hao, Da-Long Zhu, Ping Li
• Journal: Diabetes/metabolism research and reviews (Diabetes Metab Res Rev) Vol. 37 Issue 4 Pg. e3451 (05 2021) ISSN: 1520-7560 [Electronic] England
• PMID: 33724645 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 John Wiley & Sons Ltd.

Chemical References

• Immediate-Early Proteins
• Insulin Receptor Substrate Proteins
• Protein Serine-Threonine Kinases
• serum-glucocorticoid regulated kinase

Topics

• Adipocytes (metabolism)
• Animals
• Immediate-Early Proteins (metabolism)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance
• Mice
• Protein Serine-Threonine Kinases (metabolism)