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.

scholarly journals Prevention and Reversal of Lipotoxicity-Induced Hepatic Insulin Resistance and Steatohepatitis in Mice by an Antioxidant Carotenoid, β-Cryptoxanthin

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 987-999 ◽  
Author(s):  
Yinhua Ni ◽  
Mayumi Nagashimada ◽  
Lili Zhan ◽  
Naoto Nagata ◽  
Masuko Kobori ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mrna Expression ◽  
Kupffer Cells ◽  
Lipid Accumulation ◽  
Hepatic Insulin Resistance ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
High Fat ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

Abstract Excessive hepatic lipid accumulation promotes macrophages/Kupffer cells activation, resulting in exacerbation of insulin resistance and progression of nonalcoholic steatohepatitis (NASH). However, few promising treatment modalities target lipotoxicity-mediated hepatic activation/polarization of macrophages for NASH. Recent epidemiological surveys showed that serum β-cryptoxanthin, an antioxidant carotenoid, was inversely associated with the risks of insulin resistance and liver dysfunction. In the present study, we first showed that β-cryptoxanthin administration ameliorated hepatic steatosis in high-fat diet-induced obese mice. Next, we investigated the preventative and therapeutic effects of β-cryptoxanthin using a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat (CL) diet. After 12 weeks of CL diet feeding, β-cryptoxanthin administration attenuated insulin resistance and excessive hepatic lipid accumulation and peroxidation, with increases in M1-type macrophages/Kupffer cells and activated stellate cells, and fibrosis in CL diet-induced NASH. Comprehensive gene expression analysis showed that β-cryptoxanthin down-regulated macrophage activation signal-related genes significantly without affecting most lipid metabolism-related genes in the liver. Importantly, flow cytometry analysis revealed that, on a CL diet, β-cryptoxanthin caused a predominance of M2 over M1 macrophage populations, in addition to reducing total hepatic macrophage and T-cell contents. In parallel, β-cryptoxanthin decreased lipopolysaccharide-induced M1 marker mRNA expression in peritoneal macrophages, whereas it augmented IL-4-induced M2 marker mRNA expression, in a dose-dependent manner. Moreover, β-cryptoxanthin reversed steatosis, inflammation, and fibrosis progression in preexisting NASH in mice. In conclusion, β-cryptoxanthin prevents and reverses insulin resistance and steatohepatitis, at least in part, through an M2-dominant shift in macrophages/Kupffer cells in a lipotoxic model of NASH.

scholarly journals Eplerenone prevented obesity-induced inflammasome activation and glucose intolerance

2017 ◽  
Vol 235 (3) ◽  
pp. 179-191 ◽  
Author(s):  
Tsutomu Wada ◽  
Akari Ishikawa ◽  
Eri Watanabe ◽  
Yuto Nakamura ◽  
Yusuke Aruga ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Intolerance ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
M2 Macrophage ◽  
Expression Levels ◽  
Nlrp3 Inflammasome Activation ◽  
M1 Macrophage ◽  
Anti Inflammatory

Obesity-associated activation of the renin-angiotensin-aldosterone system is implicated in the pathogenesis of insulin resistance; however, influences of mineralocorticoid receptor (MR) inhibition remain unclear. Therefore, we aimed to clarify the anti-inflammatory mechanisms of MR inhibition using eplerenone, a selective MR antagonist, in C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks. Eplerenone prevented excessive body weight gain and fat accumulation, ameliorated glucose intolerance and insulin resistance and enhanced energy metabolism. In the epididymal white adipose tissue (eWAT), eplerenone prevented obesity-induced accumulation of F4/80+CD11c+CD206−-M1-adipose tissue macrophage (ATM) and reduction of F4/80+CD11c−CD206+-M2-ATM. Interestingly, M1-macrophage exhibited lower expression levels of MR, compared with M2-macrophage, in the ATM of eWAT and in vitro-polarized bone marrow-derived macrophages (BMDM). Importantly, eplerenone and MR knockdown attenuated the increase in the expression levels of proIl1b, Il6 and Tnfa, in the eWAT and liver of HFD-fed mice and LPS-stimulated BMDM. Moreover, eplerenone suppressed IL1b secretion from eWAT of HFD-fed mice. To reveal the anti-inflammatory mechanism, we investigated the involvement of NLRP3-inflammasome activation, a key process of IL1b overproduction. Eplerenone suppressed the expression of the inflammasome components, Nlrp3 and Caspase1, in the eWAT and liver. Concerning the second triggering factors, ROS production and ATP- and nigericin-induced IL1b secretion were suppressed by eplerenone in the LPS-primed BMDM. These results indicate that eplerenone inhibited both the priming and triggering signals that promote NLRP3-inflammasome activation. Therefore, we consider MR to be a crucial target to prevent metabolic disorders by suppressing inflammasome-mediated chronic inflammation in the adipose tissue and liver under obese conditions.

scholarly journals Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

2014 ◽  
Vol 35 (1) ◽  
pp. 26-40 ◽  
Author(s):  
Ahmed Lawan ◽  
Lei Zhang ◽  
Florian Gatzke ◽  
Kisuk Min ◽  
Michael J. Jurczak ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Energy Homeostasis ◽  
Mitogen Activated Protein Kinase ◽  
Hepatic Insulin Resistance ◽  
Fibroblast Growth Factor 21 ◽  
High Fat ◽  
Mitogen Activated Protein ◽  
Fat Feeding

The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.

scholarly journals CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice

2020 ◽  
Vol 244 (2) ◽  
pp. 353-367 ◽  
Author(s):  
Jiali Liu ◽  
Yue Li ◽  
Xiaoyan Zhou ◽  
Xi Zhang ◽  
Hao Meng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Inflammatory Response ◽  
Mitochondrial Dysfunction ◽  
High Fat Diet ◽  
Insulin Action ◽  
Hepatic Insulin Resistance ◽  
Obese Mice ◽  
High Fat ◽  
Impaired Insulin

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

Ethno-pharmacological insulin signaling induction of aqueous extract of Syzygium paniculatum fruits in a high-fat diet induced hepatic insulin resistance

2020 ◽  
pp. 113576
Author(s):  
Prabhakar Yellanur Konda ◽  
Vidyasagar Chennupati ◽  
Sreenivasulu Dasari ◽  
Nishesh Sharma ◽  
Muthukumaran Muthulingam ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Aqueous Extract ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Hepatic Insulin Resistance ◽  
High Fat

scholarly journals Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

2016 ◽  
Vol 291 (33) ◽  
pp. 17066-17076 ◽  
Author(s):  
Carrie M. Elks ◽  
Peng Zhao ◽  
Ryan W. Grant ◽  
Hardy Hang ◽  
Jennifer L. Bailey ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Cell Types ◽  
Oncostatin M ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation ◽  
Fat Feeding

Oncostatin M (OSM) is a multifunctional gp130 cytokine. Although OSM is produced in adipose tissue, it is not produced by adipocytes. OSM expression is significantly induced in adipose tissue from obese mice and humans. The OSM-specific receptor, OSM receptor β (OSMR), is expressed in adipocytes, but its function remains largely unknown. To better understand the effects of OSM in adipose tissue, we knocked down Osmr expression in adipocytes in vitro using siRNA. In vivo, we generated a mouse line lacking Osmr in adiponectin-expressing cells (OSMRFKO mice). The effects of OSM on gene expression were also assessed in vitro and in vivo. OSM exerts proinflammatory effects on cultured adipocytes that are partially rescued by Osmr knockdown. Osm expression is significantly increased in adipose tissue T cells of high fat-fed mice. In addition, adipocyte Osmr expression is increased following high fat feeding. OSMRFKO mice exhibit increased insulin resistance and adipose tissue inflammation and have increased lean mass, femoral length, and bone volume. Also, OSMRFKO mice exhibit increased expression of Osm, the T cell markers Cd4 and Cd8, and the macrophage markers F4/80 and Cd11c. Interestingly, the same proinflammatory genes induced by OSM in adipocytes are induced in the adipose tissue of the OSMRFKO mouse, suggesting that increased expression of proinflammatory genes in adipose tissue arises both from adipocytes and other cell types. These findings suggest that adipocyte OSMR signaling is involved in the regulation of adipose tissue homeostasis and that, in obesity, OSMR ablation may exacerbate insulin resistance by promoting adipose tissue inflammation.

scholarly journals PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling

2018 ◽  
Vol 115 (38) ◽  
pp. E8996-E9005 ◽  
Author(s):  
Brandon M. Gassaway ◽  
Max C. Petersen ◽  
Yulia V. Surovtseva ◽  
Karl W. Barber ◽  
Joshua B. Sheetz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Phosphorylation ◽  
Cross Talk ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Large Scale ◽  
Kinase Assay ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
The Impact

Insulin resistance drives the development of type 2 diabetes (T2D). In liver, diacylglycerol (DAG) is a key mediator of lipid-induced insulin resistance. DAG activates protein kinase C ε (PKCε), which phosphorylates and inhibits the insulin receptor. In rats, a 3-day high-fat diet produces hepatic insulin resistance through this mechanism, and knockdown of hepatic PKCε protects against high-fat diet-induced hepatic insulin resistance. Here, we employed a systems-level approach to uncover additional signaling pathways involved in high-fat diet-induced hepatic insulin resistance. We used quantitative phosphoproteomics to map global in vivo changes in hepatic protein phosphorylation in chow-fed, high-fat–fed, and high-fat–fed with PKCε knockdown rats to distinguish the impact of lipid- and PKCε-induced protein phosphorylation. This was followed by a functional siRNA-based screen to determine which dynamically regulated phosphoproteins may be involved in canonical insulin signaling. Direct PKCε substrates were identified by motif analysis of phosphoproteomics data and validated using a large-scale in vitro kinase assay. These substrates included the p70S6K substrates RPS6 and IRS1, which suggested cross talk between PKCε and p70S6K in high-fat diet-induced hepatic insulin resistance. These results identify an expanded set of proteins through which PKCε may drive high-fat diet-induced hepatic insulin resistance that may direct new therapeutic approaches for T2D.

scholarly journals GRP94 regulates M1 macrophage polarization and insulin resistance

2020 ◽  
Vol 318 (6) ◽  
pp. E1004-E1013 ◽  
Author(s):  
Lili Song ◽  
Do-sung Kim ◽  
Wenyu Gou ◽  
Jingjing Wang ◽  
Ping Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Macrophage Polarization ◽  
Conditional Knockout ◽  
Marker Genes ◽  
M2 Macrophage ◽  
Macrophage Marker ◽  
M1 Macrophage ◽  
Lower Expression

Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation.

715 EXOGENOUS STEATOSIS AND HEPATIC INSULIN RESISTANCE ARE EARLY CONSEQUENCES OF HIGH FAT FEEDING

2009 ◽  
Vol 50 ◽  
pp. S262 ◽  
Author(s):  
N. Lanthier ◽  
M. Petit ◽  
V. Lebrun ◽  
O. Molendi ◽  
P.D. Cani ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Fat Feeding
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