title: The novel dipeptidyl peptidase-4 inhibitor teneligliptin prevents high-fat diet-induced obesity accompanied with increased energy expenditure in mice.
abstract: Dipeptidyl peptidase-4 (DPP-4)-deficient mice exhibit prevention of obesity with increased energy expenditure, whereas currently available DPP-4 inhibitors do not induce similar changes. We investigated the impact of the novel DPP-4 inhibitor teneligliptin on body weight, energy expenditure, and obesity-related manifestations in diet-induced obese mice. Six-weeks-old C57BL/6N mice were fed a high-fat diet (60%kcal fat) ad libitum and administered teneligliptin (30 or 60mg/kg) via drinking water for 10 weeks. Mice fed a high-fat diet showed accelerated body weight gain. In contrast, compared with the vehicle group, the administration of teneligliptin reduced body weight to 88% and 71% at dose of 30mg/kg/day and 60mg/kg/day, respectively. Although there was no change in locomotor activity, indirect calorimetry studies showed that teneligliptin (60mg/kg) increased oxygen consumption by 22%. Adipocyte hypertrophy and hepatic steatosis induced by a high-fat diet were suppressed by teneligliptin. The mean adipocyte size in the 60-mg/kg treatment group was 44% and hepatic triglyceride levels were 34% of the levels in the vehicle group. Furthermore, treatment with teneligliptin (60mg/kg) reduced plasma levels of insulin to 40% and increased the glucose infusion rate to 39%, as measured in the euglycemic clamp study, indicating its beneficial effect on insulin resistance. We showed for the first time that the DPP-4 inhibitor prevents obesity and obesity-related manifestations with increased energy expenditure. Our findings suggest the potential utility of teneligliptin for the treatment of a broad spectrum of metabolic disorders related to obesity beyond glycemic control.
authors.affiliation: Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan. Electronic address: fukuda.sayaka@mu.mt-pharma.co.jp.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Fukuda-Tsuru
authors.affiliation: Department I, Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Kakimoto
authors.affiliation: Department I, Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Utsumi
authors.affiliation: Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Kiuchi
authors.affiliation: Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ishii
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D052436:Adipose Tissue, White / Q000187:drug effects / Q000473:pathology; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use*; D059305:Diet, High-Fat; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004734:Energy Metabolism / Q000187:drug effects*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy*; D009929:Organ Size / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D053778:Thiazolidines / Q000494:pharmacology / Q000627:therapeutic use*; D015430:Weight Gain / Q000187:drug effects
chemical_list: C579035:3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine; D019440:Anti-Obesity Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011720:Pyrazoles; D053778:Thiazolidines
keywords: Adipocyte hypertrophy; Dipeptidyl peptidase-4; Energy expenditure; Hepatic steatosis; Insulin resistance; Obesity