title: Pharmacological evaluation of adipose dysfunction via 11β-hydroxysteroid dehydrogenase type 1 in the development of diabetes in diet-induced obese mice with cortisone pellet implantation.
abstract: Signals from intracellular glucocorticoids (GCs) via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissues have been reported to serve as amplifiers leading to deterioration of glucose metabolism associated with obesity. To elucidate adipose dysfunction via 11β-HSD1 activation in the development of obesity-related diabetes, we established novel diabetic mice by implanting a cortisone pellet (CP) in diet-induced obesity (DIO) mice. Cortisone pellet-implanted DIO mice (DIO/CP mice) showed hyperglycemia, insulin resistance, hyperlipidemia, and ectopic fat accumulation, whereas cortisone pellet implantation in lean mice did not induce hyperglycemia. In DIO/CP mice, indexes of lipolysis such as plasma glycerol and nonesterified fatty acids (NEFAs) increased before hyperglycemia appeared. Furthermore, the adipose mRNA level of 11β-HSD1 was up-regulated in DIO/CP mice compared with sham-operated DIO mice. RU486 (mifepristone, 11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one), a glucocorticoid receptor antagonist, decreased adipose mRNA levels of 11β-HSD1 as well as adipose triglyceride lipase. RU486 also improved plasma NEFA, glycerol, and glucose levels in DIO/CP mice. These results demonstrate that lipolysis in adipose tissues caused by GC activation via 11β-HSD1 serves as a trigger for diabetes with ectopic fat accumulation. Our findings also indicate the possibility of a vicious circle of GC signals via 11β-HSD1 up-regulation in adipose tissues, contributing to deterioration of glucose metabolism to result in diabetes. Our DIO/CP mouse could be a suitable model of type 2 diabetes to evaluate adipose dysfunction via 11β-HSD1.
authors: Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan (N.A., Y.A., H.K., T.K., T.O., K.I., K.A., T.S., K.H.); and Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (N.A., T.M.).
authors: Nobuteru
authors: N
authors: Akiyama
authors: Yuko
authors: Y
authors: Akiyama
authors: Hideaki
authors: H
authors: Kato
authors: Takayuki
authors: T
authors: Kuroda
authors: Takashi
authors: T
authors: Ono
authors: Keiichi
authors: K
authors: Imagawa
authors: Kenji
authors: K
authors: Asakura
authors: Toshihiro
authors: T
authors: Shinosaki
authors: Toshihiko
authors: T
authors: Murayama
authors: Kohji
authors: K
authors: Hanasaki
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D000818:Animals; D003348:Cortisone / Q000008:administration & dosage / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005938:Glucocorticoids / Q000097:blood / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D009765:Obesity / Q000139:chemically induced / Q000150:complications / Q000201:enzymology / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D015854:Up-Regulation
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005947:Glucose; D003348:Cortisone