scholarly journals Hepatic nNOS impaired hepatic insulin sensitivity through the activation of p38 MAPK

2021 ◽  
Author(s):  
Tianxue Zhao ◽  
Qian Li ◽  
Qianyun Mao ◽  
Kaida Mu ◽  
Chen Wang
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Hepg2 Cells ◽  
Mouse Liver ◽  
Active Form ◽  
Adaptor Protein ◽  
Glycogen Storage ◽  
Hepatic Insulin Resistance ◽  
Hepatic Insulin Sensitivity ◽  
Underlying Mechanisms

Neuronal nitric oxide synthase (nNOS) interacts with its adaptor protein NOS1AP through its PZD domain in the neurons. Previously, we had reported that NOS1AP enhanced hepatic insulin sensitivity through its PZD-binding domain, which suggested that nNOS might mediate the effect of NOS1AP. This study aimed to examine the role and underlying mechanisms of nNOS in regulating hepatic insulin sensitivity. nNOS co-localized with NOS1AP in mouse liver. The overexpression of NOS1AP in mouse liver decreased the level of phosphorylated nNOS (p-nNOS (Ser1417)), the active form of nNOS. Conversely, the liver-specific deletion of NOS1AP increased the level of p-nNOS (Ser1417). The overexpression of nNOS in the liver of high-fat diet-induced obese mice exacerbated glucose intolerance, enhanced intrahepatic lipid accumulation, decreased glycogen storage, and blunted insulin-induced phosphorylation of IRβ and Akt in the liver. Similarly, nNOS overexpression increased triglyceride production, decreased glucose utilization, and downregulated insulin-induced expression of p-IRβ, p-Akt, and p-GSK3β in the HepG2 cells. In contrast, treatment with Nω-propyl-L-arginine (L-NPA), a selective nNOS inhibitor, improved glucose tolerance and upregulated insulin-induced phosphorylation of IRβ and Akt in the liver of ob/ob mice. Furthermore, overexpression of nNOS increased p38MAPK phosphorylation in the HepG2 cells. In contrast, inhibition of p38MAPK with SB203580 significantly reversed the nNOS-induced inhibition of insulin signaling activity (all P < 0.05). This indicated that hepatic nNOS inhibited the insulin-signaling pathway through the activation of p38MAPK. These findings suggest that nNOS is involved in the development of hepatic insulin resistance and that nNOS might be a potential therapeutic target for diabetes.

scholarly journals Regulation of Mitochondria-Associated Membranes (MAMs) by NO/sGC/PKG Participates in the Control of Hepatic Insulin Response

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1319 ◽  
Author(s):  
Arthur Bassot ◽  
Marie-Agnès Chauvin ◽  
Nadia Bendridi ◽  
Jingwei Ji-Cao ◽  
Guillaume Vial ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Soluble Guanylate Cyclase ◽  
Insulin Response ◽  
Cyclophilin D ◽  
Hepatic Insulin Sensitivity ◽  
Physiological Conditions ◽  
Huh7 Cells ◽  
The Impact

Under physiological conditions, nitric oxide (NO) produced by the endothelial NO synthase (eNOS) upregulates hepatic insulin sensitivity. Recently, contact sites between the endoplasmic reticulum and mitochondria named mitochondria-associated membranes (MAMs) emerged as a crucial hub for insulin signaling in the liver. As mitochondria are targets of NO, we explored whether NO regulates hepatic insulin sensitivity by targeting MAMs. In Huh7 cells, primary rat hepatocytes and mouse livers, enhancing NO concentration increased MAMs, whereas inhibiting eNOS decreased them. In vitro, those effects were prevented by inhibiting protein kinase G (PKG) and mimicked by activating soluble guanylate cyclase (sGC) and PKG. In agreement with the regulation of MAMs, increasing NO concentration improved insulin signaling, both in vitro and in vivo, while eNOS inhibition disrupted this response. Finally, inhibition of insulin signaling by wortmannin did not affect the impact of NO on MAMs, while experimental MAM disruption, using either targeted silencing of cyclophilin D or the overexpression of the organelle spacer fetal and adult testis-expressed 1 (FATE-1), significantly blunted the effects of NO on both MAMs and insulin response. Therefore, under physiological conditions, NO participates to the regulation of MAM integrity through the sGC/PKG pathway and concomitantly improves hepatic insulin sensitivity. Altogether, our data suggest that the induction of MAMs participate in the impact of NO on hepatocyte insulin response.

scholarly journals EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance

2021 ◽  
Author(s):  
Kakali Ghoshal ◽  
Xiyue Li ◽  
Dungeng Peng ◽  
John R. Falck ◽  
Raghunath Reddy Anugu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Genetic Model ◽  
Water Soluble ◽  
Hepatic Insulin Resistance ◽  
Epoxyeicosatrienoic Acid ◽  
Genetic Mouse Model ◽  
Hepatic Insulin Signaling ◽  
Underlying Mechanisms

We previously showed that global deletion of the cytochrome P450 epoxygenase <i>Cyp2c44</i>, a major epoxyeicosatrienoic acid (EET) producing enzyme in mice, leads to impaired hepatic insulin signaling resulting in insulin resistance. This finding led us to investigate whether administration of a water soluble EET analog restores insulin signaling <i>in vivo</i> in <i>Cyp2c44(-/-)</i> mice and investigated the underlying mechanisms by which this effect is exerted. <i>Cyp2c44(-/-)</i> mice treated with the analog EET-A for 4 weeks improved fasting glucose and glucose tolerance compared to <i>Cyp2c44(-/-)</i> mice treated with vehicle alone. This beneficial effect was accompanied by enhanced hepatic insulin signaling, decreased expression of gluconeogenic genes and increased expression of glycogenic genes. Mechanistically, we show that insulin-stimulated phosphorylation of insulin receptor β (IRβ) is impaired in primary <i>Cyp2c44(-/-) </i>hepatocytes and this can be restored by cotreatment with EET-A and insulin. Plasma membrane fractionations of livers indicated that EET-A enhances the retention of IRβ in membrane rich fractions, thus potentiating its activation. Altogether, EET analogs ameliorate insulin signaling in a genetic model of hepatic insulin resistance by stabilizing membrane-associated IRβ and potentiating insulin signaling.

Effect of liver fat on insulin clearance

2007 ◽  
Vol 293 (6) ◽  
pp. E1709-E1715 ◽  
Author(s):  
Anna Kotronen ◽  
Satu Vehkavaara ◽  
Anneli Seppälä-Lindroos ◽  
Robert Bergholm ◽  
Hannele Yki-Järvinen
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Fat Content ◽  
Insulin Clearance ◽  
Liver Fat ◽  
Hepatic Insulin Resistance ◽  
Model Assessment ◽  
Liver Fat Content ◽  
Hepatic Insulin Sensitivity ◽  
Impaired Insulin

A fatty liver is associated with fasting hyperinsulinemia, which could reflect either impaired insulin clearance or hepatic insulin action. We determined the effect of liver fat on insulin clearance and hepatic insulin sensitivity in 80 nondiabetic subjects [age 43 ± 1 yr, body mass index (BMI) 26.3 ± 0.5 kg/m2]. Insulin clearance and hepatic insulin resistance were measured by the euglycemic hyperinsulinemic (insulin infusion rate 0.3 mU·kg−1·min−1for 240 min) clamp technique combined with the infusion of [3-3H]glucose and liver fat by proton magnetic resonance spectroscopy. During hyperinsulinemia, both serum insulin concentrations and increments above basal remained ∼40% higher ( P < 0.0001) in the high (15.0 ± 1.5%) compared with the low (1.8 ± 0.2%) liver fat group, independent of age, sex, and BMI. Insulin clearance (ml·kg fat free mass−1·min−1) was inversely related to liver fat content ( r = −0.52, P < 0.0001), independent of age, sex, and BMI ( r = −0.37, P = 0.001). The variation in insulin clearance due to that in liver fat (range 0–41%) explained on the average 27% of the variation in fasting serum (fS)-insulin concentrations. The contribution of impaired insulin clearance to fS-insulin concentrations increased as a function of liver fat. This implies that indirect indexes of insulin sensitivity, such as homeostatic model assessment, overestimate insulin resistance in subjects with high liver fat content. Liver fat content correlated significantly with fS-insulin concentrations adjusted for insulin clearance ( r = 0.43, P < 0.0001) and with directly measured hepatic insulin sensitivity ( r = −0.40, P = 0.0002). We conclude that increased liver fat is associated with both impaired insulin clearance and hepatic insulin resistance. Hepatic insulin sensitivity associates with liver fat content, independent of insulin clearance.

scholarly journals PGRN Induces Impaired Insulin Sensitivity and Defective Autophagy in Hepatic Insulin Resistance

2015 ◽  
Vol 29 (4) ◽  
pp. 528-541 ◽  
Author(s):  
Jiali Liu ◽  
Huixia Li ◽  
Bo Zhou ◽  
Lin Xu ◽  
Xiaomin Kang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Nuclear Factor Κb ◽  
Hepatic Insulin Resistance ◽  
Causative Role ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Impaired Insulin

Abstract Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the underlying mechanisms of PGRN in the regulation of insulin sensitivity and autophagy remain elusive. In this study, we aimed to address the direct effects of PGRN in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. We found that mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin tolerance and hepatic autophagy imbalance as well as defective insulin signaling. Furthermore, treatment of mice with TNF receptor (TNFR)-1 blocking peptide-Fc, a TNFR1 blocking peptide-Fc fusion protein to competitively block the interaction of PGRN and TNFR1, resulted in the restoration of systemic insulin sensitivity and the recovery of autophagy and insulin signaling in liver. Consistent with these findings in vivo, we also observed that PGRN treatment induced defective autophagy and impaired insulin signaling in hepatocytes, with such effects being drastically nullified by the addition of TNFR1 blocking peptide -Fc or TNFR1-small interference RNA via the TNFR1-nuclear factor-κB-dependent manner, indicating the causative role of PGRN in hepatic insulin resistance. In conclusion, our findings supported the notion that PGRN is a key regulator of hepatic insulin resistance and that PGRN may mediate its effects, at least in part, by inducing defective autophagy via TNFR1/nuclear factor-κB.

Endothelin antagonism improves hepatic insulin sensitivity associated with insulin signaling in Zucker fatty rats

Metabolism ◽  
2005 ◽  
Vol 54 (11) ◽  
pp. 1515-1523 ◽  
Author(s):  
Nathalie Berthiaume ◽  
Christian J. Carlson ◽  
Cristina M. Rondinone ◽  
Bradley A. Zinker
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Hepatic Insulin Sensitivity

scholarly journals A Single 60 mg Dose of Denosumab Might Improve Hepatic Insulin Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Elena Passeri ◽  
Stefano Benedini ◽  
Elena Costa ◽  
Sabrina Corbetta
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Serum Alkaline Phosphatase ◽  
Resistance Index ◽  
Tolerance Test ◽  
Hepatic Insulin Resistance ◽  
Oral Glucose ◽  
Insulinogenic Index ◽  
Glucose Response ◽  
Hepatic Insulin Sensitivity

Background. The RANKL/RANK/OPG signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis. The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation.Aim. To test whether systemic blockage of RANKL by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women.Study Design. This is a prospective study on the effect of a subcutaneously injected single 60 mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test.Results. A single 60 mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose, insulin, or HOMA-IR at both 4 and 12 weeks. No changes could be detected in glucose response to the glucose load, Matsuda Index, or insulinogenic index. Nonetheless, 60 mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks.Conclusions. A single 60 mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients.

PCBP2 regulates hepatic insulin sensitivity via HIF-1α and STAT3 pathway in HepG2 cells

2015 ◽  
Vol 463 (1-2) ◽  
pp. 116-122 ◽  
Author(s):  
Nana Xia ◽  
Zhuqi Tang ◽  
Cuifang Wang ◽  
Guangfei Xu ◽  
Xiaoke Nie ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Hepg2 Cells ◽  
Hepatic Insulin Sensitivity ◽  
Stat3 Pathway

scholarly journals Theaflavins Improve Insulin Sensitivity through Regulating Mitochondrial Biosynthesis in Palmitic Acid-Induced HepG2 Cells

2018 ◽  
Author(s):  
Tuantuan Tong ◽  
Ning Ren ◽  
Jiafan Wu ◽  
Na Guo ◽  
Xiaobo Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Palmitic Acid ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Mitochondrial Dna Copy Number ◽  
Increase Glucose Uptake

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improvement effects on insulin resistance-associated metabolic abnormalities including obesity and type 2 diebetes. However, the molecular mechanisms of theaflavins improving insulin sensitivity are still not clear. In this study, we investigated the protective effects and mechanisms of theaflavins on palmitic acid-induced insulin resistance in HepG2 cells. Theaflavins could significantly increase glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the glucose transporter 4 protein expression, increasing the phosphorylation of IRS-1 at Ser307, and reduced the phosphor-Akt (Ser473) level. Moreover, theaflavins were found to enhance mitochondrial DNA copy number through down-regulate the PGC-1&beta; mRNA level and up-regulate PRC mRNA expression in insulin-resistant HepG2 cells. These results indicated that theaflavins could improve free fatty acid-induced hepatic insulin resistance by promoting mitochondrial biogenesis, and were promising functional food and medicines for insulin resistance-related disorders.

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