title: Anti-obesity effects of KR-66195, a synthetic DPP-IV inhibitor, in diet-induced obese mice and obese-diabetic ob/ob mice.
abstract: OBJECTIVE
  We investigated whether KR-66195, a new synthetic dipeptidyl dipeptidase IV inhibitor, could prevent weight gain, as well as improving glycemic control in diet-induced obese (DIO) and ob/ob mice.
  
  
  METHODS
  Male C57BL/6 mice were randomly assigned to the following groups: chow diet, high-fat diet, and high-fat diet with KR-66195. After KR-66195 treatment for eight weeks, intraperitoneal glucose tolerance tests were performed. A pair-feeding study was performed to investigate the mechanisms of the anti-obesity effects of KR-66195 in DIO mice. Female ob/ob mice were treated with KR-66195 for three weeks and compared to the vehicle-treated group.
  
  
  RESULTS
  In DIO mice, KR-66195 treatment increased the plasma glucagon-like peptide (GLP)-1 levels and improved glucose tolerance. This treatment also reduced body weight gain (5.38±0.94 g vs. 12.08±0.55 g, P<0.01) and food intake (2.41±0.09 g vs. 2.79±0.11 g, P<0.05). In ob/ob mice, KR-66195 treatment for three weeks resulted in comparable effects in DIO mice. In the pair-feeding study, KR-66195-treated mice exhibited a 16% increase in energy expenditure (kcal/h/kg lean body mass) without significant differences in body weight or activities compared with pair-fed mice. These results suggest that KR-66195 prevented weight gain in DIO mice by decreasing food intake, as well as increasing energy expenditure.
  
  
  CONCLUSIONS
  KR-66195 markedly increased plasma levels of GLP-1, resulting in the probable improvement in glucose tolerance and reduced body weight and food intake. Thus, KR-66195 might be further developed as a therapeutic drug to treat obesity, as well as diabetes.
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Lee
authors.affiliation: Graduate School, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Yeon Wook
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gil Medical Center, Gachon University, Incheon, Republic of Korea.
authors.forename: Hyunhee
authors.initials: H
authors.lastname: Oh
authors.affiliation: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gil Medical Center, Gachon University, Incheon, Republic of Korea.
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.affiliation: Drug Discovery Division, Korea Research Institute of Chemical Technology, Yusong-Gu, Daejeon 305-600, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Byung-Wan
authors.initials: BW
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Eun Seok
authors.initials: ES
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Bong Soo
authors.initials: BS
authors.lastname: Cha
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Electronic address: endohclee@yuhs.ac.
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Lee
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition / Q000187:drug effects; D003920:Diabetes Mellitus / Q000517:prevention & control; D059305:Diet, High-Fat; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005951:Glucose Tolerance Test / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D011897:Random Allocation; D053778:Thiazolidines / Q000494:pharmacology*; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; D004791:Enzyme Inhibitors; C000589463:KR-66195; D053778:Thiazolidines; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; D014633:Valine
keywords: Diabetes; Dipeptidyl peptidase (DPP)-IV; Glucagon-like peptide (GLP)-1; KR-66195; Obesity