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1.  Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance 
Diabetes  2012;61(8):1949-1958.
The protein-tyrosine phosphatase Shp1 negatively regulates insulin action on glucose homeostasis in liver and muscle, but its potential role in obesity-linked insulin resistance has not been examined. To investigate the role of Shp1 in hepatic insulin resistance, we generated hepatocyte-specific Shp1 knockout mice (Ptpn6H-KO), which were subjected to extensive metabolic monitoring throughout an 8-week standard chow diet (SD) or high-fat diet (HFD) feeding. We report for the first time that Shp1 expression is upregulated in metabolic tissues of HFD-fed obese mice. When compared with their Shp1-expressing Ptpn6f/f littermates, Ptpn6H-KO mice exhibited significantly lowered fasting glycemia and heightened hepatic insulin sensitivity. After HFD feeding, Ptpn6H-KO mice developed comparable levels of obesity as Ptpn6f/f mice, but they were remarkably protected from liver insulin resistance, as revealed by euglycemic clamps and hepatic insulin signaling determinations. Although Ptpn6H-KO mice still acquired diet-induced peripheral insulin resistance, they were less hyperinsulinemic during a glucose tolerance test because of reduced insulin secretion. Ptpn6H-KO mice also exhibited increased insulin clearance in line with enhanced CC1 tyrosine phosphorylation in liver. These results show that hepatocyte Shp1 plays a critical role in the development of hepatic insulin resistance and represents a novel therapeutic target for obesity-linked diabetes.
PMCID: PMC3402325  PMID: 22698917
2.  Nobiletin Attenuates VLDL Overproduction, Dyslipidemia, and Atherosclerosis in Mice With Diet-Induced Insulin Resistance 
Diabetes  2011;60(5):1446-1457.
Increased plasma concentrations of apolipoprotein B100 often present in patients with insulin resistance and confer increased risk for the development of atherosclerosis. Naturally occurring polyphenolic compounds including flavonoids have antiatherogenic properties. The aim of the current study was to evaluate the effect of the polymethoxylated flavonoid nobiletin on lipoprotein secretion in cultured human hepatoma cells (HepG2) and in a mouse model of insulin resistance and atherosclerosis.
Lipoprotein secretion was determined in HepG2 cells incubated with nobiletin or insulin. mRNA abundance was evaluated by quantitative real-time PCR, and Western blotting was used to demonstrate activation of cell signaling pathways. In LDL receptor–deficient mice (Ldlr−/−) fed a Western diet supplemented with nobiletin, metabolic parameters, gene expression, fatty acid oxidation, glucose homeostasis, and energy expenditure were documented. Atherosclerosis was quantitated by histological analysis.
In HepG2 cells, activation of mitogen-activated protein kinase-extracellular signal–related kinase signaling by nobiletin or insulin increased LDLR and decreased MTP and DGAT1/2 mRNA, resulting in marked inhibition of apoB100 secretion. Nobiletin, unlike insulin, did not induce phosphorylation of the insulin receptor or insulin receptor substrate-1 and did not stimulate lipogenesis. In fat-fed Ldlr−/− mice, nobiletin attenuated dyslipidemia through a reduction in VLDL-triglyceride (TG) secretion. Nobiletin prevented hepatic TG accumulation, increased expression of Pgc1α and Cpt1α, and enhanced fatty acid β-oxidation. Nobiletin did not activate any peroxisome proliferator–activated receptor (PPAR), indicating that the metabolic effects were PPAR independent. Nobiletin increased hepatic and peripheral insulin sensitivity and glucose tolerance and dramatically attenuated atherosclerosis in the aortic sinus.
Nobiletin provides insight into treatments for dyslipidemia and atherosclerosis associated with insulin-resistant states.
PMCID: PMC3292317  PMID: 21471511
3.  Inducible Nitric Oxide Synthase Induction Underlies Lipid-Induced Hepatic Insulin Resistance in Mice 
Diabetes  2010;59(4):861-871.
The present study was undertaken to assess the contribution of inducible nitric oxide (NO) synthase (iNOS) to lipid-induced insulin resistance in vivo.
Wild-type and iNOS−/− mice were infused for 6 h with a 20% intralipid emulsion, during which a hyperinsulinemic-euglycemic clamp was performed.
In wild-type mice, lipid infusion led to elevated basal hepatic glucose production and marked insulin resistance as revealed by impaired suppression of liver glucose production and reduced peripheral glucose disposal (Rd) during insulin infusion. Liver insulin resistance was associated with a robust induction of hepatic iNOS, reduced tyrosine phosphorylation of insulin receptor (IR) β, insulin receptor substrate (IRS)-1, and IRS-2 but elevated serine phosphorylation of IRS proteins as well as decreased Akt activation. The expression of gluconeogenic enzymes Pepck and G6Pc was also increased in the liver of wild-type mice. In contrast to their wild-type counterparts, iNOS−/− mice were protected from lipid-induced hepatic and peripheral insulin resistance. Moreover, neither the phosphorylation of insulin signaling intermediates nor expression of gluconeogenic enzymes were altered in the lipid-infused iNOS−/− mice compared with their saline-infused controls. Importantly, lipid infusion induced tyrosine nitration of IRβ, IRS-1, IRS-2, and Akt in wild-type mice but not in iNOS−/− animals. Furthermore, tyrosine nitration of hepatic Akt by the NO derivative peroxynitrite blunted insulin-induced Akt tyrosine phosphorylation and kinase activity.
These findings demonstrate that iNOS induction is a novel mechanism by which circulating lipids inhibit hepatic insulin action. Our results further suggest that iNOS may cause hepatic insulin resistance through tyrosine nitration of key insulin signaling proteins.
PMCID: PMC2844834  PMID: 20103705
4.  Endotoxin Mediated-iNOS Induction Causes Insulin Resistance via ONOO− Induced Tyrosine Nitration of IRS-1 in Skeletal Muscle 
PLoS ONE  2010;5(12):e15912.
It is believed that the endotoxin lipopolysaccharide (LPS) is implicated in the metabolic perturbations associated with both sepsis and obesity (metabolic endotoxemia). Here we examined the role of inducible nitric oxide synthase (iNOS) in skeletal muscle insulin resistance using LPS challenge in rats and mice as in vivo models of endotoxemia.
Methodology/Principal Findings
Pharmacological (aminoguanidine) and genetic strategies (iNOS−/− mice) were used to counter iNOS induction in vivo. In vitro studies using peroxynitrite (ONOO−) or inhibitors of the iNOS pathway, 1400 W and EGCG were conducted in L6 myocytes to determine the mechanism by which iNOS mediates LPS-dependent insulin resistance. In vivo, both pharmacological and genetic invalidation of iNOS prevented LPS-induced muscle insulin resistance. Inhibition of iNOS also prevented insulin resistance in myocytes exposed to cytokine/LPS while exposure of myocytes to ONOO− fully reproduced the inhibitory effect of cytokine/LPS on both insulin-stimulated glucose uptake and PI3K activity. Importantly, LPS treatment in vivo and iNOS induction and ONOO− treatment in vitro promoted tyrosine nitration of IRS-1 and reduced insulin-dependent tyrosine phosphorylation.
Our work demonstrates that iNOS-mediated tyrosine nitration of IRS-1 is a key mechanism of skeletal muscle insulin resistance in endotoxemia, and presents nitrosative modification of insulin signaling proteins as a novel therapeutic target for combating muscle insulin resistance in inflammatory settings.
PMCID: PMC3011021  PMID: 21206533

Results 1-4 (4)