title: Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice.
abstract: OBJECTIVE
  Diet composition alters the metabolic states of adipocytes and hepatocytes in diabetes. The effects of dipeptidyl peptidase-4 (DPP-4) inhibition on adipose tissue inflammation and fatty liver have been obscure. We investigated the extrapancreatic effects of DPP-4 inhibition on visceral fat and the liver.
  
  
  METHODS
  We investigated diet-induced metabolic changes in β-cell-specific glucokinase haploinsufficient (Gck(+/-)) diabetic mice. We challenged animals with a diet containing a combination of sucrose and oleic acid (SO) or sucrose and linoleic acid (SL). Next, we assessed the effects of a DPP-4 inhibitor, des-fluoro-sitagliptin, on adipose tissue inflammation and hepatic steatosis.
  
  
  RESULTS
  The epididymal fat weight and serum leptin level were significantly higher in Gck(+/-) mice fed SL than in mice fed SO, although no significant differences in body weight or adipocyte size were noted. Compared with SO, SL increased the numbers of CD11c(+) M1 macrophages and CD8(+) T-cells in visceral adipose tissue and the expression of E-selectin, P-selectin, and plasminogen activator inhibitor-1 (PAI-1). DPP-4 inhibition significantly prevented adipose tissue infiltration by CD8(+) T-cells and M1 macrophages and decreased the expression of PAI-1. The production of cytokines by activated T-cells was not affected by DPP-4 inhibition. Furthermore, DPP-4 inhibition prevented fatty liver in both wild-type and Gck(+/-) mice. DPP-4 inhibition also decreased the expressions of sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase-1, and fatty acid synthase, and increased the expression of peroxisome proliferator-activated receptor-α in the liver.
  
  
  CONCLUSIONS
  Our findings indicated that DPP-4 inhibition has extrapancreatic protective effects against diet-induced adipose tissue inflammation and hepatic steatosis.
authors.affiliation: Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Shirakawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Kei
authors.initials: K
authors.lastname: Ohnuma
authors.forename: Koichiro
authors.initials: K
authors.lastname: Sato
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Ito
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Kaji
authors.forename: Eri
authors.initials: E
authors.lastname: Sakamoto
authors.forename: Megumi
authors.initials: M
authors.lastname: Koganei
authors.forename: Hajime
authors.initials: H
authors.lastname: Sasaki
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Kikuko
authors.initials: K
authors.lastname: Amo
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Aoki
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
authors.forename: Eiji
authors.initials: E
authors.lastname: Takeda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D019422:Dietary Sucrose / Q000009:adverse effects*; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D000077270:Exenatide; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D006984:Hypertrophy / Q000139:chemically induced; D007328:Insulin / Q000097:blood*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D018932:Chemokine CCL2; D004041:Dietary Fats; D019422:Dietary Sucrose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D010455:Peptides; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D014688:Venoms; D016753:Interleukin-10; D007371:Interferon-gamma; D000077270:Exenatide; D005941:Glucokinase; D018819:Dipeptidyl Peptidase 4