11β-Hydroxysteroid dehydrogenase type 1 shRNA ameliorates glucocorticoid-induced insulin resistance and lipolysis in mouse abdominal adipose tissue.
Long-term glucocorticoid exposure increases the risk for developing type 2 diabetes. Prereceptor activation of glucocorticoid availability in target tissue by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) coupled with hexose-6-phosphate dehydrogenase (H6PDH) is an important mediator of the metabolic syndrome. We explored whether the tissue-specific modulation of 11β-HSD1 and H6PDH in adipose tissue mediates glucocorticoid-induced insulin resistance and lipolysis and analyzed the effects of 11β-HSD1 inhibition on the key lipid metabolism genes and insulin-signaling cascade. We observed that corticosterone (CORT) treatment increased expression of 11β-HSD1 and H6PDH and induced lipase HSL and ATGL with suppression of p-Thr(172) AMPK in adipose tissue of C57BL/6J mice. In contrast, CORT induced adipose insulin resistance, as reflected by a marked decrease in IR and IRS-1 gene expression with a reduction in p-Thr(308) Akt/PKB. Furthermore, 11β-HSD1 shRNA attenuated CORT-induced 11β-HSD1 and lipase expression and improved insulin sensitivity with a concomitant stimulation of pThr(308) Akt/PKB and p-Thr(172) AMPK within adipose tissue. Addition of CORT to 3T3-L1 adipocytes enhanced 11β-HSD1 and H6PDH and impaired p-Thr(308) Akt/PKB, leading to lipolysis. Knockdown of 11β-HSD1 by shRNA attenuated CORT-induced lipolysis and reversed CORT-mediated inhibition of pThr(172) AMPK, which was accompanied by a parallel improvement of insulin signaling response in these cells. These findings suggest that elevated adipose 11β-HSD1 expression may contribute to glucocorticoid-induced insulin resistance and adipolysis.
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Sciences, University of California Los Angeles (UCLA) School of Medicine, Los Angeles, California;
Ying
Y
Wang
Department of Pediatrics, First Hospital, Jilin University, ChangChun, China;
Chaoying
C
Yan
Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai Diabetes Institute, Shanghai, China;
Limei
L
Liu
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Sciences, University of California Los Angeles (UCLA) School of Medicine, Los Angeles, California;
Wei
W
Wang
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Sciences, University of California Los Angeles (UCLA) School of Medicine, Los Angeles, California;
Hanze
H
Du
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Sciences, University of California Los Angeles (UCLA) School of Medicine, Los Angeles, California;
Winnie
W
Fan
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Sciences, University of California Los Angeles (UCLA) School of Medicine, Los Angeles, California; Department of Pharmaceutical Sciences, Western University of Health Sciences, Pomona, California; and.
Kabirullah
K
Lutfy
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California.
Meisheng
M
Jiang
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Sciences, University of California Los Angeles (UCLA) School of Medicine, Los Angeles, California;
Theodore C
TC
Friedman
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Sciences, University of California Los Angeles (UCLA) School of Medicine, Los Angeles, California; dryanjunliu@hotmail.com.
Yanjun
Y
Liu
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D041721:3T3-L1 Cells; D050153:Abdominal Fat / Q000187:drug effects* / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000502:physiology; D000818:Animals; D003345:Corticosterone / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008066:Lipolysis / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*
D005938:Glucocorticoids; D034741:RNA, Small Interfering; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone
11β-hydroxysteroid dehydrogenase type 1; adipose tissue; glucocorticoid; hexose-6-phosphate dehydrogenase; insulin signaling; lipolysis; short-hairpin RNA