Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice

Jun Shirakawa, Hideki Fujii, Kei Ohnuma, Koichiro Sato, Yuzuru Ito, Mitsuyo Kaji, Eri Sakamoto, Megumi Koganei, Hajime Sasaki, Yoji Nagashima, Kikuko Amo, Kazutaka Aoki, Chikao Morimoto, Eiji Takeda, Yasuo Terauchi

Research output: Contribution to journalArticlepeer-review

215 Citations (Scopus)


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. RESEARCH DESIGN AND METHODS-We investigated dietinduced 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.

Original languageEnglish
Pages (from-to)1246-1257
Number of pages12
Issue number4
Publication statusPublished - 2011 Apr

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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