title: Adipose tissue-targeted 11β-hydroxysteroid dehydrogenase type 1 inhibitor protects against diet-induced obesity.
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.
authors.affiliation: Department of Geratology, the First Hospital Affiliated to Nanjing Medical University, Nanjing, P.R.China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: Aisen
authors.initials: A
authors.lastname: Zhang
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Di
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.forename: Juanmin
authors.initials: J
authors.lastname: Zha
authors.forename: Shan
authors.initials: S
authors.lastname: Lv
authors.forename: Peng
authors.initials: P
authors.lastname: Cheng
authors.forename: Miao
authors.initials: M
authors.lastname: Hu
authors.forename: Yujie
authors.initials: Y
authors.lastname: Li
authors.forename: Hanmei
authors.initials: H
authors.lastname: Qi
authors.forename: Guoxian
authors.initials: G
authors.lastname: Ding
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D017667:Adipocytes / Q000473:pathology; D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018149:Glucose Intolerance / Q000188:drug therapy; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D009765:Obesity / Q000209:etiology* / Q000517:prevention & control*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000096926:Benzenesulfonamides
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D052242:Adiponectin; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D054409:Nicotinamide Phosphoribosyltransferase; D010879:Piperazines; D013449:Sulfonamides; D013844:Thiazoles; C474501:3-chloro-2-methyl-N-(4-(2-(4-methyl-1-piperazinyl)-2-oxoethyl)-1,3-thiazol-2-yl)benzenesulfonamide; D000096926:Benzenesulfonamides