Diet-Induced Adipose Tissue Inflammation and Liver Steatosis Are Prevented by DPP-4 Inhibition in Diabetic Mice

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

doi:10.2337/db10-1338

Cited by 239 publications

(204 citation statements)

References 49 publications

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“…Trials of weight loss improve liver function and liver histology in NAFLD (28). The improvement of liver histology by sitagliptin may originate from both weight-independent and weight-dependent effects (29,30).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob/ob male mice

Onoyama¹,

Koda²,

Okamoto³

et al. 2015

Molecular Medicine Reports

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Abstract. Non-alcoholic steatohepatitis is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The dipeptidyl peptidase-IV enzyme is important in glucose metabolism, as well as lipid accumulation, extracellular matrix metabolism and immune stimulation. Furthermore, the enzyme activity of dipeptidyl peptidase-IV is known to be increased in non-alcoholic steatohepatitis. Therefore, dipeptidyl peptidase-IV inhibitors are potential therapeutic agents for non-alcoholic steatohepatitis. The present study assessed the therapeutic effects of sitagliptin, a dipeptidyl peptidase-IV inhibitor, on non-alcoholic steatohepatitis using fatty liver Shionogi-ob/ob male mice. Sitagliptin (2 mg/kg/day; n=10) or placebo (control; n=10) was orally administered to fatty liver Shionogi-ob/ob mice for 12 weeks, and hepatic steatosis, fibrosis, inflammation and oxidative stress were assessed in comparison with the controls. Sitagliptin administration reduced body weight and blood glucose levels, and improved hepatic fibrosis. It also inhibited the gene expression levels of fatty acid synthase, transforming growth factor-β1, tissue inhibitor of metalloproteinases-1, procollagen-type 1, tumor necrosis factor-α, monocyte chemoattractant protein-1 and enhanced peroxisome proliferator activated receptor-α. Furthermore, a marked attenuation of hepatic stellate cell activation and Kupffer cells was observed in the sitagliptin group. A decrease in oxidative stress and apoptosis was also observed. Sitagliptin attenuated the progression of hepatic fibrosis by improving lipid metabolism, inflammation and oxidative stress in non-alcoholic steatohepatitis. IntroductionNon-alcoholic steatohepatitis (NASH) is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The central pathophysiological issue in patients afflicted with NASH is insulin resistance. Improvement of insulin resistance has therapeutic potential in preventing the progression of NASH (1). Previously, dipeptidyl peptidase (DPP)-IV inhibitors have been used as novel oral drugs for the treatment of type 2 diabetes. DPP-IV is an enzyme, which inactivates incretins, including glucagon-like peptide-1 and gastric inhibitory polypeptide, which regulates blood glucose primarily via stimulation of glucose-dependent insulin release. As a result, the activation of DPP-IV leads to the development of glucose intolerance and hepatic steatosis (2). DPP-IV enzyme has widespread organ distribution throughout the body and has pleiotropic biological functions (3-5). DPP-IV is involved in glucose metabolism and lipid accumulation, degradation of the extracellular matrix, appetite regulation and immune stimulation via its peptidase activities (6-10). The liver is one of the organs expressing DPP-IV to a high degree (11). The mRNA expression of DPP-IV is also increased in the liver of non-alcoholic fatty liver disease (NAFLD) (12). Serum DPP-IV activity and the expression of hepatic DPP-IV are correlated with hepatic steatosis and NAFLD s...

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Section: Discussionmentioning

confidence: 99%

Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob/ob male mice

Onoyama¹,

Koda²,

Okamoto³

et al. 2015

Molecular Medicine Reports

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“…Limited animal studies have also suggested that DPP-4 inhibition may reduce the number of inflammatory cells within visceral adipose tissue and halt the progression of atherosclerosis via immunomodulation. [20][21][22] …”

Section: Cardiovascular Effects Of Dpp-4 Inhibitionmentioning

confidence: 99%

Cardiovascular effects of the DPP-4 inhibitors

Jose

Inzucchi

2012

Diabetes and Vascular Disease Research

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Type 2 Diabetes continues to rise in prevalence throughout the globe, and cardiovascular diseases remain the most common cause of morbidity and mortality among patients. Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a newer class of oral anti-hyperglycemic agents whose effect is mediated through the incretin hormones, GLP-1 and GIP. In this review, we discuss the incretin system, DPP-4 inhibitors and their mechanism of action and, principally, the potential impact of DPP-4 inhibition on the cardiovascular system. Some pre-clinical data, small mechanistic stud ies and post-hoc analyses of randomized clinical trials sug gest a possible beneficial effect on cardiovascular risk. However, the relationship between DPP-4 inhibition and actual cardiovascular outcomes remains unknown. We therefore also review ongoing large, randomized clinical trials examining this very question.

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“…To measure adipocyte area (46), formalin-fixed, paraffin-embedded adipose tissue sections were stained with H & E, and stained images of 100 adipocytes in the adipose tissue of each mouse were used for quantitative evaluation by microscopy. Immunostaining of F4/80, a marker of tissue macrophages, was carried out for adipose tissue (45). Briefly, after endogenous peroxidase activity was blocked, deparaffinized adipose sections were incubated with the primary antibody rat monoclonal anti-mouse F4/80 antibody (4.0 g/ml) A: experimental protocol.…”

Section: Histological Analysis Of Liver and White Adipose Tissuementioning

confidence: 99%

Maternal high-fat diet induces insulin resistance and deterioration of pancreatic β-cell function in adult offspring with sex differences in mice

Yokomizo

Inoguchi

Sonoda

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

107

120

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Intrauterine environment may influence the health of postnatal offspring. There have been many studies on the effects of maternal high-fat diet (HFD) on diabetes and glucose metabolism in offspring. Here, we investigated the effects in male and female offspring. C57/BL6J mice were bred and fed either control diet (CD) or HFD from conception to weaning, and offspring were fed CD or HFD from 6 to 20 wk. At 20 wk, maternal HFD induced glucose intolerance and insulin resistance in offspring. Additionally, liver triacylglycerol content, adipose tissue mass, and inflammation increased in maternal HFD. In contrast, extending previous observations, insulin secretion at glucose tolerance test, islet area, insulin content, and PDX-1 mRNA levels in isolated islets were lower in maternal HFD in males, whereas they were higher in females. Oxidative stress in islets increased in maternal HFD in males, whereas there were no differences in females. Plasma estradiol levels were lower in males than in females and decreased in offspring fed HFD and also decreased by maternal HFD, suggesting that females may be protected from insulin deficiency by inhibiting oxidative stress. In conclusion, maternal HFD induced insulin resistance and deterioration of pancreatic ␤-cell function, with marked sex differences in adult offspring accompanied by adipose tissue inflammation and liver steatosis. Additionally, our results demonstrate that potential mechanisms underlying sex differences in pancreatic ␤-cell function may be related partially to increases in oxidative stress in male islets and decreased plasma estradiol levels in males.

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Diet-Induced Adipose Tissue Inflammation and Liver Steatosis Are Prevented by DPP-4 Inhibition in Diabetic Mice

Cited by 239 publications

References 49 publications

Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob/ob male mice

Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob/ob male mice

Cardiovascular effects of the DPP-4 inhibitors

Maternal high-fat diet induces insulin resistance and deterioration of pancreatic β-cell function in adult offspring with sex differences in mice

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