title: Dehydroepiandrosterone-enhanced dual specificity protein phosphatase (DDSP) prevents diet-induced and genetic obesity.
abstract: Dehydroepiandrosterone (DHEA) exerts a wide variety of therapeutic effects against medical disorders, such as diabetes and obesity. However, the molecular basis of DHEA action remains to be clarified. Previously, we reported that DHEA-enhanced dual specificity protein phosphatase, designated DDSP, is one of the target molecules of DHEA. To examine the role of DDSP in DHEA signaling, we generated mice that carry a DDSP transgene in which expression is driven by the CAG promoter (DDSP-Tg). DDSP-Tg mice weighed significantly less than wild-type (WT) control mice when a high fat diet was supplied (p < 0.01). No difference in food-intake or locomotor activity was found between DDSP-Tg and WT mice. Oxygen consumption of DDSP-Tg mice was higher than that of WT mice (p < 0.01), which suggested an increase in basal metabolism in DDSP-Tg mice. To further investigate the role of DDSP in genetic obese mice, DDSP-Tg mice with a db/db background were generated (DDSP-Tg db/db). We observed cancellation of obesity by the db/db mutation and development of a cachexic phenotype in DDSP-Tg db/db mice. In conclusion, our study shows that expression of DDSP leads to prevention of diet-induced and genetic (db/db) obesity. Anti-obese effects of DHEA might be mediated through DDSP, which might be a therapeutic target for intervention of obesity.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ashida
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 Japan.
authors.forename: Kiminobu
authors.initials: K
authors.lastname: Goto
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Nawata
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
authors.affiliation: Department of Endocrinoloty and Diabetes Mellitus, School of Medicine, Fukuoka University, Fukuoka, 814-0180 Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yanase
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 Japan. Electronic address: nomura@med.kyushu-u.ac.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D015870:Gene Expression; D020738:Leptin / Q000378:metabolism; D050155:Lipogenesis; D008820:Mice, Obese; D008822:Mice, Transgenic; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D022722:Thermogenesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020738:Leptin; D048051:p38 Mitogen-Activated Protein Kinases; C500554:DDSP protein, human; D017027:Protein Tyrosine Phosphatases
keywords: DHEA-enhanced dual specificity protein phosphatase; Dehydroepiandrosterone; Leptin; Obesity; p38 MAPK