Diet-Induced Adipose Tissue Inflammation and Liver Steatosis Are Prevented by DPP-4 Inhibition in Diabetic Mice
- Jun Shirakawa1,
- Hideki Fujii2,
- Kei Ohnuma3,
- Koichiro Sato1,
- Yuzuru Ito1,
- Mitsuyo Kaji1,
- Eri Sakamoto1,
- Megumi Koganei4,
- Hajime Sasaki4,
- Yoji Nagashima5,
- Kikuko Amo6,
- Kazutaka Aoki1,
- Chikao Morimoto3,
- Eiji Takeda6 and
- Yasuo Terauchi1⇓
- 1Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
- 2Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
- 3Division of Clinical Immunology, Institute of Medical Sciences, University of Tokyo, Tokyo, Japan
- 4Food Science Institute, Division of Research and Development, Meiji Dairies Corporation, Odawara, Japan
- 5Department of Molecular Pathology, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan
- 6Department of Clinical Nutrition, Institute of Health Biosciences, Tokushima University, Tokushima, Japan
- Corresponding author: Yasuo Terauchi, .
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 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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1338/-/DC1.
- Received September 20, 2010.
- Accepted December 27, 2010.
- © 2011 by the American Diabetes Association.
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