scholarly journals Dipeptidyl Peptidase-4 Inhibition Ameliorates Western Diet–Induced Hepatic Steatosis and Insulin Resistance Through Hepatic Lipid Remodeling and Modulation of Hepatic Mitochondrial Function

Diabetes ◽  
2015 ◽  
Vol 64 (6) ◽  
pp. 1988-2001 ◽  
Author(s):  
Annayya R. Aroor ◽  
Javad Habibi ◽  
David A. Ford ◽  
Ravi Nistala ◽  
Guido Lastra ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Mitochondrial Function ◽  
Dipeptidyl Peptidase ◽  
Western Diet ◽  
Hepatic Lipid ◽  
Dipeptidyl Peptidase 4

scholarly journals Dipeptidyl-Peptidase 4 Inhibitor Sitagliptin Ameliorates Hepatic Insulin Resistance by Modulating Inflammation and Autophagy in ob/ob Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Wenbin Zheng ◽  
Jing Zhou ◽  
Shasha Song ◽  
Wen Kong ◽  
Wenfang Xia ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Inflammatory Responses ◽  
Body Weight Gain ◽  
Biological Activities ◽  
Dipeptidyl Peptidase ◽  
Hepatic Insulin Resistance ◽  
Dipeptidyl Peptidase 4 ◽  
Obesity And Diabetes ◽  
Dipeptidyl Peptidase 4 Inhibitor

Obesity and type 2 diabetes are the most common metabolic diseases globally. They are associated with inflammation, oxidative stress, autophagy, and insulin resistance. Sitagliptin, a dipeptidyl-peptidase 4 inhibitor, has been reported to show multiple biological activities beyond the antidiabetic property. This study was aimed at investigating the effect of sitagliptin on hepatic steatosis, insulin resistance, inflammation, and autophagy and exploring the underlying molecular mechanism. In the current study, ob/ob mice, a mouse model of genetic obesity and diabetes, were administered via gavage with sitagliptin 50 mg/kg daily for 4 weeks. Changes in glycolipid metabolism, inflammatory responses, and autophagy in the liver were evaluated. Body weight gain, lipid metabolic disorder, and hepatic steatosis as well as systemic and hepatic insulin sensitivity in ob/ob mice were significantly attenuated after sitagliptin treatment. Furthermore, sitagliptin decreased inflammatory responses by regulating macrophage M1/M2 polarization and inhibiting the activities of NF-κB and JNK. Moreover, sitagliptin increased the levels of phosphorylation of AMPK and decreased those of mTOR. This study indicates that sitagliptin significantly ameliorates the development of hepatic steatosis and insulin resistance in ob/ob mice by inhibiting inflammatory responses and activating autophagy via AMPK/mTOR signaling pathway.

Abstract 655: Dipeptidyl Peptidase-4 (dpp-4) Inhibition Decreases Cardiac And Vascular Stiffness And Improves Cardiac And Vascular Relaxation In Western Diet Fed Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Annayya R Aroor ◽  
Vincent G DeMarco ◽  
Guanghong Jia ◽  
Luis A Martinez-Lemus ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Endothelial Cell ◽  
Diastolic Dysfunction ◽  
Dipeptidyl Peptidase ◽  
Western Diet ◽  
Vascular Relaxation ◽  
S6 Kinase ◽  
Dipeptidyl Peptidase 4 ◽  
Endothelial Stiffness

A western diet (WD), high in sucrose and fat, is often accompanied by insulin resistance and cardiovascular disease characterized early by endothelial dysfunction and increased vascular and cardiac stiffness. Recently, Dipeptidyl peptidase-4 (DPP-4) inhibition has been shown to improve diastolic dysfunction in WD fed mice, but its effects on endothelial cell and cardiac stiffness have not been reported. We fed 4-week old C57BL/6 male mice with a WD with or without a DPP-4 inhibitor (MK0626) for 16 weeks and measured blood pressure by telemetry, insulin resistance via (HOMA), in vivo cardiac diastolic function (echocardiography), pulse wave velocity (PWV), and ex vivo aortic endothelial stiffness by atomic force microscopy. Systolic blood pressure and insulin resistance were increased by the WD. DPP-4 inhibition improved systemic insulin sensitivity and substantially reduced DPP-4 activity, but had no effect on 24-hour blood pressures. Heart weight was increased by WD in conjunction with S6 kinase translational signaling and DPP-4 inhibition reduced S6 kinase phosphorylation/activation in conjunction with a reduction in cardiac mass. Aortic stiffness, as assessed by PWV, was significantly increased in WD fed mice (16% increase) and was markedly decreased by DPP-4 inhibition. Endothelial cell stiffness was increased 5-fold in WD fed mice and DPP-4 inhibition significantly decreased endothelial stiffness (80% decrease). Acetylcholine but not sodium nitroprusside mediated vascular relaxation was impaired in WD fed mice and DPP-4 inhibition significantly improved this nitric oxide mediated relaxation. Increased vascular smooth muscle and endothelial stiffness was associated with impaired cardiac diastolic relaxation, which was also significantly improved by DPP-4 inhibition. Taken together, these results show that DPP-4 inhibition improves cardiac and vascular endothelial stiffness and cardiac diastolic dysfunction in a clinically translational mouse model (WD) of over nutrition and insulin resistance.

scholarly journals Treatment with Lobeglitazone Attenuates Hepatic Steatosis in Diet-Induced Obese Mice

PPAR Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Sorim Choung ◽  
Kyong Hye Joung ◽  
Bo Ram You ◽  
Sang Ki Park ◽  
Hyun Jin Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Plasma Cholesterol ◽  
Cholesterol Biosynthesis ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Expression ◽  
Expression Of Genes

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance. The peroxisome proliferator-activated receptor (PPAR) activators, thiazolidinediones, (TZDs), are insulin sensitizers used as a treatment for NAFLD. However, TZDs are a controversial treatment for NAFLD because of conflicting results regarding hepatic steatosis and fibrosis. To evaluate a possible effective drug for treatment of NAFLD, we investigated the effects of a newly developed TZD, lobeglitazone, with an emphasis on hepatic lipid metabolism. Lobeglitazone treatment for 4 weeks in high fat diet- (HFD-) induced obese mice (HL group) improved insulin resistance and glucose intolerance compared to HFD-induced obese mice (HU group). The gene levels related to hepatic gluconeogenesis also decreased after treatment by lobeglitazone. The livers of mice in the HL group showed histologically reduced lipid accumulation, with lowered total plasma cholesterol and triglyceride levels. In addition, the HL group significantly decreased the hepatic expression of genes associated with lipid synthesis, cholesterol biosynthesis, and lipid droplet development and increased the hepatic expression of genes associated with fatty acid β-oxidation, thus suggesting that lobeglitazone decreased hepatic steatosis and reversed hepatic lipid dysregulation. Livers with steatohepatitis contained increased levels of PPARγ and phosphorylated PPARγ at serine 273, leading to downregulation of expression of genes associated with insulin sensitivity. Notably, the treatment of lobeglitazone increased the protein levels of PPARα and diminished levels of PPARγ phosphorylated at serine 273, which were increased by a HFD, suggesting that induction of PPARα and posttranslational modification of PPARγ in livers by lobeglitazone might be an underlying mechanism of the improvement seen in NAFLD. Taken together, our data showed that lobeglitazone might be an effective treatment for NAFLD.

DPP-4 Inhibition with Anagliptin Reduces Lipotoxicity-Induced Insulin Resistance and Steatohepatitis in Male Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (10) ◽  
Author(s):  
Yuriko Sakai ◽  
Guanliang Chen ◽  
Yinhua Ni ◽  
Fen Zhuge ◽  
Liang Xu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Immune System ◽  
Cell Types ◽  
Hepatic Insulin Resistance ◽  
M2 Macrophage ◽  
High Fat ◽  
Hepatic Lipid ◽  
Dipeptidyl Peptidase 4 ◽  
M1 Macrophage ◽  
Macrophage Accumulation

Abstract Excessive hepatic lipid accumulation drives the innate immune system and aggravates insulin resistance, hepatic inflammation, and fibrogenesis, leading to nonalcoholic steatohepatitis (NASH). Dipeptidyl peptidase-4 (DPP-4) regulates glucose metabolism and is expressed in many different cell types, including the cells of the immune system. In addition, DPP-4 may be involved in macrophage-mediated inflammation and insulin resistance. This study investigated the effects of anagliptin (Ana), an inhibitor of DPP-4, on macrophage polarity and phenotype in the livers of mice with steatohepatitis. We investigated the effects of Ana on steatohepatitis induced via a high-cholesterol high-fat (CL) diet or a choline-deficient L-amino acid-defined, high-fat (CDAHF) diet. DPP-4 activity, liver histology, and insulin sensitivity were evaluated, and liver DPP-4+ macrophages were quantified using fluorescence-activated cell sorting (FACS). Liver and plasma DPP-4 activity increased significantly in mice on both diets. FACS revealed that, compared with chow-fed mice, the CL-fed mice exhibited a significant increase in the proportion of DPP-4+ liver macrophages, particularly the M1-type macrophages. Ana decreased hepatic lipid and M1 macrophage accumulation and stimulated M2 macrophage accumulation in the liver, thereby attenuating insulin resistance, steatohepatitis, and fibrosis. Importantly, Ana alleviated hepatic fibrosis and steatohepatitis in mice fed CL diet and CDAHF diet. Using Ana to inhibit DPP-4 reduced lipotoxicity-induced hepatic insulin resistance through regulating the M1/M2 macrophage status.

Biochanin A improves hepatic steatosis and insulin resistance by regulating the hepatic lipid and glucose metabolic pathways in diet-induced obese mice

2016 ◽  
Vol 60 (9) ◽  
pp. 1944-1955 ◽  
Author(s):  
Hee-Sook Park ◽  
Haeng Jeon Hur ◽  
Soon-Hee Kim ◽  
Su-Jin Park ◽  
Moon Ju Hong ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Metabolic Pathways ◽  
Biochanin A ◽  
Obese Mice ◽  
Hepatic Lipid

scholarly journals Adipose Dipeptidyl Peptidase-4 and Obesity: Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro

Diabetes Care ◽  
2013 ◽  
Vol 36 (12) ◽  
pp. 4083-4090 ◽  
Author(s):  
H. Sell ◽  
M. Bluher ◽  
N. Kloting ◽  
R. Schlich ◽  
M. Willems ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4

scholarly journals Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice

2016 ◽  
Vol 15 (1) ◽  
Author(s):  
Camila Manrique ◽  
Javad Habibi ◽  
Annayya R. Aroor ◽  
James R. Sowers ◽  
Guanghong Jia ◽  
...  
Keyword(s):  
Dipeptidyl Peptidase ◽  
Western Diet ◽  
Dipeptidyl Peptidase 4 ◽  
Vascular Abnormalities ◽  
Female Mice

Hibiscus sabdariffa polyphenols prevent palmitate-induced renal epithelial mesenchymal transition by alleviating dipeptidyl peptidase-4-mediated insulin resistance

2016 ◽  
Vol 7 (1) ◽  
pp. 475-482 ◽  
Author(s):  
Chien-Ning Huang ◽  
Chau-Jong Wang ◽  
Yi-Sun Yang ◽  
Chih-Li Lin ◽  
Chiung-Huei Peng
Keyword(s):  
Insulin Resistance ◽  
Diabetic Nephropathy ◽  
Epithelial Mesenchymal Transition ◽  
Dipeptidyl Peptidase ◽  
Socioeconomic Impact ◽  
Hibiscus Sabdariffa ◽  
Mesenchymal Transition ◽  
Dipeptidyl Peptidase 4

Diabetic nephropathy has a significant socioeconomic impact, but its mechanism is unclear and needs to be examined.

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