Adipose tissue-targeted 11β-hydroxysteroid dehydrogenase type 1 inhibitor protects against diet-induced obesity

Juan Liu; Long Wang; Aisen Zhang; Wenjuan Di; Xiao Zhang; Lin Wu; Jing Yu; Juanmin Zha; Shan Lv; Peng Cheng; Miao Hu; Yujie Li; Hanmei Qi; Guoxian Ding; Yi Zhong

doi:10.1507/endocrj.K10E-318

ORIGINALS

Adipose tissue-targeted 11β-hydroxysteroid dehydrogenase type 1 inhibitor protects against diet-induced obesity

Juan Liu, Long Wang, Aisen Zhang, Wenjuan Di, Xiao Zhang, Lin Wu, Jing Yu, Juanmin Zha, Shan Lv, Peng Cheng, Miao Hu, Yujie Li, Hanmei Qi, Guoxian Ding, Yi Zhong

Author information

Juan Liu
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Long Wang
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Aisen Zhang
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Wenjuan Di
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Xiao Zhang
Department of Preventive Medicine, Feinberg School of Medicine Northwestern University, Chicago, USA
Lin Wu
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Jing Yu
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Juanmin Zha
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Shan Lv
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Peng Cheng
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Miao Hu
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Yujie Li
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Hanmei Qi
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Guoxian Ding
Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China
Yi Zhong
Department of Pharmaceutical Chemistry, China Pharmaceutical University, Nanjing, P.R.China

Keywords: Adipose tissue, 11β-hydroxysteroid dehydrogenase type 1, Blood glucose, Metabolic syndrome

JOURNAL FREE ACCESS

2011 Volume 58 Issue 3 Pages 199-209

DOI https://doi.org/10.1507/endocrj.K10E-318

View "Advance Publication" version (February 17, 2011).

Details

Abstract

Current pharmacological treatments for obesity and metabolic syndrome have various limitations. Recently, adipose tissue 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been proposed as a novel therapeutic target for the treatment of obesity and metabolic syndrome. Nevertheless, there is no adipose tissue-targeted 11β-HSD1 inhibitor available now. We sought to develop a new 11β-HSD1 pharmacological inhibitor that homes specifically to the white adipose tissue and aimed to investigate whether adipose tissue-targeted 11β-HSD1 inhibitor might decrease body weight gain and improve glucose tolerance in diet-induced obesity mice. BVT.2733, an 11β-HSD1 selective inhibitor was connected with a peptide CKGGRAKDC that homes to white fat vasculature. CKGGRAKDC-BVT.2733 (T-BVT) or an equimolar mixture of CKGGRAKDC and BVT.2733 (NT-BVT) was given to diet-induced obesity mice for two weeks through subcutaneous injection. T-BVT decreased body weight gain, improved glucose tolerance and decreased adipocyte size compared with vehicle treated mice. In adipose tissue T-BVT administration significantly increased adiponectin, vaspin mRNA levels; In liver T-BVT administration decreased the mRNA level of phosphoenolpyruvate carboxykinase (PEPCK), increased the mRNA levels of mitochondrial carnitine palmi-toyltransferase-I (mCPT-I) and peroxisome proliferator-activated receptorα(PPARα). No significant differences in adipocyte size and hepatic gene expression were observed after treatment with NT-BVT compared with vehicle treated mice, though NT-BVT also decreased body weight gain, improved glucose tolerance, and increased uncoupling protein-2 (UCP-2) mRNA levels in muscle. These results suggest that an adipose tissue-targeted pharmacological inhibitor of 11β-HSD1 may prove to be a new approach for the treatment of obesity and metabolic syndrome.

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