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1.  Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice 
Metabolic syndrome describes a set of obesity-related disorders that increase diabetes, cardiovascular, and mortality risk. Studies of liver-specific protein-tyrosine phosphatase 1b (PTP1b) deletion mice (L-PTP1b−/−) suggest that hepatic PTP1b inhibition would mitigate metabolic-syndrome through amelioration of hepatic insulin resistance, endoplasmic-reticulum stress, and whole-body lipid metabolism. However, the altered molecular-network states underlying these phenotypes are poorly understood. We used mass spectrometry to quantitfy protein-phosphotyrosine network changes in L-PTP1b−/− mouse livers relative to control mice on normal and high-fat diets. We applied a phosphosite-set-enrichment analysis to identify known and novel pathways exhibiting PTP1b- and diet-dependent phosphotyrosine regulation. Detection of a PTP1b-dependent, but functionally uncharacterized, set of phosphosites on lipid-metabolic proteins motivated global lipidomic analyses that revealed altered polyunsaturated-fatty-acid (PUFA) and triglyceride metabolism in L-PTP1b−/− mice. To connect phosphosites and lipid measurements in a unified model, we developed a multivariate-regression framework, which accounts for measurement noise and systematically missing proteomics data. This analysis resulted in quantitative models that predict roles for phosphoproteins involved in oxidation-reduction in altered PUFA and triglyceride metabolism.
PMCID: PMC3759823  PMID: 23685806
PTP1b; Phosphoproteomics; Lipidomics; Liver; Computational Modeling
2.  BAF60c drives glycolytic muscle formation and improves glucose homeostasis through Deptor-mediated AKT activation 
Nature medicine  2013;19(5):640-645.
A shift from oxidative to glycolytic metabolism has been associated with skeletal muscle insulin resistance in type 2 diabetes1–5. However, whether this metabolic switch is deleterious or adaptive remains controversial6–8, in part due to limited understanding of the regulatory network that directs the metabolic and contractile specification of fast-twitch glycolytic muscle. Here we show that BAF60c, a transcriptional cofactor enriched in fast-twitch muscle, promotes a switch from oxidative to glycolytic myofiber type through Deptor-mediated AKT activation. Muscle-specific transgenic expression of BAF60c activates a program of molecular, metabolic, and contractile changes characteristic of glycolytic muscle. In addition, BAF60c is required for maintaining glycolytic capacity in adult skeletal muscle in vivo. BAF60c expression is significantly decreased in skeletal muscle from obese mice. Unexpectedly, transgenic activation of the glycolytic muscle program by BAF60c protects mice from diet-induced insulin resistance and glucose intolerance. Further mechanistic studies revealed that Deptor is induced by the BAF60c/Six4 transcriptional complex and mediates activation of AKT and glycolytic metabolism by BAF60c in a cell-autonomous manner. This work defines a fundamental mechanism underlying the specification of fast glycolytic muscle and illustrates that the oxidative to glycolytic metabolic shift in skeletal muscle is potentially adaptive and beneficial in the diabetic state.
PMCID: PMC3650110  PMID: 23563706
Aging Cell  2012;11(2):284-296.
Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes (T2DM). In this study, we have evaluated the role of PTP1B in the development of aging-associated obesity, inflammation and peripheral insulin resistance by assessing metabolic parameters at 3 and 16 months in PTP1B−/− mice maintained on mixed genetic background (C57Bl/6J x 129Sv/J). Whereas fat mass and adipocyte size were increased in wild-type control mice at 16 months, these parameters did not change with aging in PTP1B−/− mice. Increased levels of pro-inflammatory cytokines, crown-like structures and hypoxia-inducible factor (HIF)-1α were observed only in adipose tissue from 16-month old wild-type mice. Similarly, islet hyperplasia and hyperinsulinemia were observed in wild-type mice with aging-associated obesity, but not in PTP1B−/− animals. Leanness in 16-month old PTP-1B−/− mice was associated with increased energy expenditure. Whole body insulin sensitivity decreased in 16-month old control mice; however studies with the hyperinsulinemic-euglycemic clamp revealed that PTP1B-deficiency prevented this obesity-related decreased peripheral insulin sensitivity. At a molecular level, PTP1B expression and enzymatic activity were up-regulated in liver and muscle of 16-month old wild-type mice as were the activation of stress kinases and the expression of p53. Conversely, insulin receptor-mediated Akt/Foxo1 signaling was attenuated in these aged control mice. Collectively, these data implicate PTP1B in the development of inflammation and insulin resistance associated with obesity during aging and suggest that inhibition of this phosphatase by therapeutic strategies might protect against age-dependent T2DM.
PMCID: PMC3306541  PMID: 22221695
insulin resistance; type 2 diabetes; obesity; inflammation; PTP1B
4.  Cytoplasmic Polyadenylation Element Binding Protein Deficiency Stimulates PTEN and Stat3 mRNA Translation and Induces Hepatic Insulin Resistance 
PLoS Genetics  2012;8(1):e1002457.
The cytoplasmic polyadenylation element binding protein CPEB1 (CPEB) regulates germ cell development, synaptic plasticity, and cellular senescence. A microarray analysis of mRNAs regulated by CPEB unexpectedly showed that several encoded proteins are involved in insulin signaling. An investigation of Cpeb1 knockout mice revealed that the expression of two particular negative regulators of insulin action, PTEN and Stat3, were aberrantly increased. Insulin signaling to Akt was attenuated in livers of CPEB–deficient mice, suggesting that they might be defective in regulating glucose homeostasis. Indeed, when the Cpeb1 knockout mice were fed a high-fat diet, their livers became insulin-resistant. Analysis of HepG2 cells, a human liver cell line, depleted of CPEB demonstrated that this protein directly regulates the translation of PTEN and Stat3 mRNAs. Our results show that CPEB regulated translation is a key process involved in insulin signaling.
Author Summary
One major hallmark of diabetes is insulin resistance in peripheral tissues that is controlled at the posttranslational level. For example, insulin activates a kinase cascade that leads to the phosphorylation of Akt, a centrally important molecule that regulates glucose metabolism. In this study, we define a translational regulatory pathway that mediates insulin action in the liver. The Cytoplasmic Polyadenylation Binding Protein (CPEB) interacts with mRNA to control translation; knockout mice that lack CPEB exhibit high-fat-diet-induced liver insulin resistance and do so by having aberrant expression of major insulin signaling molecules, in particular PTEN 3 and Stat3. Our data further suggest that CPEB modulates, in a manner similar to a rheostat, functionally related mRNAs that encode proteins involved in insulin signaling.
PMCID: PMC3257279  PMID: 22253608
5.  PKCζ-regulated inflammation in the non-hematopoietic compartment is critical for obesity-induced glucose intolerance 
Cell metabolism  2010;12(1):65-77.
Obesity-induced inflammation is critical for the development of insulin resistance. Here we show, that genetic inactivation of PKCζ in vivo leads to a hyperinflammatory state in obese mice that correlates with a higher glucose intolerance and insulin resistance. Previous studies implicated PKCζ in the regulation of type 2 inflammatory responses in T cells. By using ex vivo and in vivo experiments, here we demonstrate that although PKCζ is involved in the alternative (M2) activation of macrophages, surprisingly, PKCζ ablation in the non-hematopoietic compartment but not in the hematopoietic system is sufficient to drive inflammation and IL-6 synthesis in the adipose tissue, as well as insulin resistance. Experiments using PKCζ/IL-6 double-knockout mice demonstrated that IL-6 production accounts for obesity-associated glucose intolerance induced by PKCζ deficiency. These results establish PKCζ as a critical negative regulator of IL-6 in the control of obesity-induced inflammation in adipocytes.
PMCID: PMC2907185  PMID: 20620996
6.  Fat Cell–Specific Ablation of Rictor in Mice Impairs Insulin-Regulated Fat Cell and Whole-Body Glucose and Lipid Metabolism 
Diabetes  2010;59(6):1397-1406.
Rictor is an essential component of mammalian target of rapamycin (mTOR) complex (mTORC) 2, a kinase that phosphorylates and activates Akt, an insulin signaling intermediary that regulates glucose and lipid metabolism in adipose tissue, skeletal muscle, and liver. To determine the physiological role of rictor/mTORC2 in insulin signaling and action in fat cells, we developed fat cell–specific rictor knockout (FRic−/−) mice.
Insulin signaling and glucose and lipid metabolism were studied in FRic−/− fat cells. In vivo glucose metabolism was evaluated by hyperinsulinemic-euglycemic clamp.
Loss of rictor in fat cells prevents insulin-stimulated phosphorylation of Akt at S473, which, in turn, impairs the phosphorylation of downstream targets such as FoxO3a at T32 and AS160 at T642. However, glycogen synthase kinase-3β phosphorylation at S9 is not affected. The signaling defects in FRic−/− fat cells lead to impaired insulin-stimulated GLUT4 translocation to the plasma membrane and decreased glucose transport. Furthermore, rictor-null fat cells are unable to suppress lipolysis in response to insulin, leading to elevated circulating free fatty acids and glycerol. These metabolic perturbations are likely to account for defects observed at the whole-body level of FRic−/− mice, including glucose intolerance, marked hyperinsulinemia, insulin resistance in skeletal muscle and liver, and hepatic steatosis.
Rictor/mTORC2 in fat cells plays an important role in whole-body energy homeostasis by mediating signaling necessary for the regulation of glucose and lipid metabolism in fat cells.
PMCID: PMC2874700  PMID: 20332342
7.  Requirement of the ATM/p53 Tumor Suppressor Pathway for Glucose Homeostasis▿  
Molecular and Cellular Biology  2010;30(24):5787-5794.
Ataxia telangiectasia (A-T) patients can develop multiple clinical pathologies, including neuronal degeneration, an elevated risk of cancer, telangiectasias, and growth retardation. Patients with A-T can also exhibit an increased risk of insulin resistance and type 2 diabetes. The ATM protein kinase, the product of the gene mutated in A-T patients (Atm), has been implicated in metabolic disease, which is characterized by insulin resistance and increased cholesterol and lipid levels, blood pressure, and atherosclerosis. ATM phosphorylates the p53 tumor suppressor on a site (Ser15) that regulates transcription activity. To test whether the ATM pathway that regulates insulin resistance is mediated by p53 phosphorylation, we examined insulin sensitivity in mice with a germ line mutation that replaces the p53 phosphorylation site with alanine. The loss of p53 Ser18 (murine Ser15) led to increased metabolic stress, including severe defects in glucose homeostasis. The mice developed glucose intolerance and insulin resistance. The insulin resistance correlated with the loss of antioxidant gene expression and decreased insulin signaling. N-Acetyl cysteine (NAC) treatment restored insulin signaling in late-passage primary fibroblasts. The addition of an antioxidant in the diet rendered the p53 Ser18-deficient mice glucose tolerant. This analysis demonstrates that p53 phosphorylation on an ATM site is an important mechanism in the physiological regulation of glucose homeostasis.
PMCID: PMC3004274  PMID: 20956556
8.  Grp78 Heterozygosity Promotes Adaptive Unfolded Protein Response and Attenuates Diet-Induced Obesity and Insulin Resistance 
Diabetes  2009;59(1):6-16.
To investigate the role of the endoplasmic reticulum (ER) chaperone glucose-regulated protein (GRP) 78/BiP in the pathogenesis of obesity, insulin resistance, and type 2 diabetes.
Male Grp78+/− mice and their wild-type littermates were subjected to a high-fat diet (HFD) regimen. Pathogenesis of obesity and type 2 diabetes was examined by multiple approaches of metabolic phenotyping. Tissue-specific insulin sensitivity was analyzed by hyperinsulinemic-euglycemic clamps. Molecular mechanism was explored via immunoblotting and tissue culture manipulation.
Grp78 heterozygosity increases energy expenditure and attenuates HFD-induced obesity. Grp78+/− mice are resistant to diet-induced hyperinsulinemia, liver steatosis, white adipose tissue (WAT) inflammation, and hyperglycemia. Hyperinsulinemic-euglycemic clamp studies revealed that Grp78 heterozygosity improves glucose metabolism independent of adiposity and following an HFD increases insulin sensitivity predominantly in WAT. As mechanistic explanations, Grp78 heterozygosity in WAT under HFD stress promotes adaptive unfolded protein response (UPR), attenuates translational block, and upregulates ER degradation-enhancing α-mannosidase–like protein (EDEM) and ER chaperones, thus improving ER quality control and folding capacity. Further, overexpression of the active form of ATF6 induces protective UPR and improves insulin signaling upon ER stress.
HFD-induced obesity and type 2 diabetes are improved in Grp78+/− mice. Adaptive UPR in WAT could contribute to this improvement, linking ER homeostasis to energy balance and glucose metabolism.
PMCID: PMC2797945  PMID: 19808896
9.  Interleukin-10 Prevents Diet-Induced Insulin Resistance by Attenuating Macrophage and Cytokine Response in Skeletal Muscle 
Diabetes  2009;58(11):2525-2535.
Insulin resistance is a major characteristic of type 2 diabetes and is causally associated with obesity. Inflammation plays an important role in obesity-associated insulin resistance, but the underlying mechanism remains unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine with lower circulating levels in obese subjects, and acute treatment with IL-10 prevents lipid-induced insulin resistance. We examined the role of IL-10 in glucose homeostasis using transgenic mice with muscle-specific overexpression of IL-10 (MCK-IL10).
MCK-IL10 and wild-type mice were fed a high-fat diet (HFD) for 3 weeks, and insulin sensitivity was determined using hyperinsulinemic-euglycemic clamps in conscious mice. Biochemical and molecular analyses were performed in muscle to assess glucose metabolism, insulin signaling, and inflammatory responses.
MCK-IL10 mice developed with no obvious anomaly and showed increased whole-body insulin sensitivity. After 3 weeks of HFD, MCK-IL10 mice developed comparable obesity to wild-type littermates but remained insulin sensitive in skeletal muscle. This was mostly due to significant increases in glucose metabolism, insulin receptor substrate-1, and Akt activity in muscle. HFD increased macrophage-specific CD68 and F4/80 levels in wild-type muscle that was associated with marked increases in tumor necrosis factor-α, IL-6, and C-C motif chemokine receptor-2 levels. In contrast, MCK-IL10 mice were protected from diet-induced inflammatory response in muscle.
These results demonstrate that IL-10 increases insulin sensitivity and protects skeletal muscle from obesity-associated macrophage infiltration, increases in inflammatory cytokines, and their deleterious effects on insulin signaling and glucose metabolism. Our findings provide novel insights into the role of anti-inflammatory cytokine in the treatment of type 2 diabetes.
PMCID: PMC2768157  PMID: 19690064
10.  Nutrient Stress Activates Inflammation and Reduces Glucose Metabolism by Suppressing AMP-Activated Protein Kinase in the Heart 
Diabetes  2009;58(11):2536-2546.
Heart failure is a major cause of mortality in diabetes and may be causally associated with altered metabolism. Recent reports indicate a role of inflammation in peripheral insulin resistance, but the impact of inflammation on cardiac metabolism is unknown. We investigated the effects of diet-induced obesity on cardiac inflammation and glucose metabolism in mice.
Male C57BL/6 mice were fed a high-fat diet (HFD) for 6 weeks, and heart samples were taken to measure insulin sensitivity, glucose metabolism, and inflammation. Heart samples were also examined following acute interleukin (IL)-6 or lipid infusion in C57BL/6 mice and in IL-6 knockout mice following an HFD.
Diet-induced obesity reduced cardiac glucose metabolism, GLUT, and AMP-activated protein kinase (AMPK) levels, and this was associated with increased levels of macrophages, toll-like receptor 4, suppressor of cytokine signaling 3 (SOCS3), and cytokines in heart. Acute physiological elevation of IL-6 suppressed glucose metabolism and caused insulin resistance by increasing SOCS3 and via SOCS3-mediated inhibition of insulin receptor substrate (IRS)-1 and possibly AMPK in heart. Diet-induced inflammation and defects in glucose metabolism were attenuated in IL-6 knockout mice, implicating the role of IL-6 in obesity-associated cardiac inflammation. Acute lipid infusion caused inflammation and raised local levels of macrophages, C-C motif chemokine receptor 2, SOCS3, and cytokines in heart. Lipid-induced cardiac inflammation suppressed AMPK, suggesting the role of lipid as a nutrient stress triggering inflammation.
Our findings that nutrient stress activates cardiac inflammation and that IL-6 suppresses myocardial glucose metabolism via inhibition of AMPK and IRS-1 underscore the important role of inflammation in the pathogenesis of diabetic heart.
PMCID: PMC2768176  PMID: 19690060
11.  KSR2 Is An Essential Regulator of AMP Kinase, Energy Expenditure, and Insulin Sensitivity 
Cell metabolism  2009;10(5):366-378.
Kinase Suppressors of Ras 1 and 2 (KSR1 and KSR2) function as molecular scaffolds to potently regulate the MAP kinases ERK1/2 and affect multiple cell fates. Here we show that KSR2 interacts with and modulates the activity of AMPK. KSR2 regulates AMPK-dependent glucose uptake and fatty acid oxidation in mouse embryo fibroblasts and glycolysis in a neuronal cell line. Disruption of KSR2 in vivo impairs AMPK-regulated processes affecting fatty acid oxidation and thermogenesis to cause obesity. Despite their increased adiposity, ksr2-/- mice are hypophagic and hyperactive, but expend less energy than wild type mice. In addition, hyperinsulinemic-euglycemic clamp studies reveal that ksr2-/- mice are profoundly insulin resistant. The expression of genes mediating oxidative phosphorylation is also down regulated in the adipose tissue of ksr2-/- mice. These data demonstrate that ksr2-/- mice are highly efficient in conserving energy, revealing a novel role for KSR2 in AMPK-mediated regulation of energy metabolism.
PMCID: PMC2773684  PMID: 19883615
12.  Role of Muscle c-Jun NH2-Terminal Kinase 1 in Obesity-Induced Insulin Resistance▿  
Molecular and Cellular Biology  2009;30(1):106-115.
Obesity caused by feeding of a high-fat diet (HFD) is associated with an increased activation of c-Jun NH2-terminal kinase 1 (JNK1). Activated JNK1 is implicated in the mechanism of obesity-induced insulin resistance and the development of metabolic syndrome and type 2 diabetes. Significantly, Jnk1−/− mice are protected against HFD-induced obesity and insulin resistance. Here we show that an ablation of the Jnk1 gene in skeletal muscle does not influence HFD-induced obesity. However, muscle-specific JNK1-deficient (MKO) mice exhibit improved insulin sensitivity compared with control wild-type (MWT) mice. Thus, insulin-stimulated AKT activation is suppressed in muscle, liver, and adipose tissue of HFD-fed MWT mice but is suppressed only in the liver and adipose tissue of MKO mice. These data demonstrate that JNK1 in muscle contributes to peripheral insulin resistance in response to diet-induced obesity.
PMCID: PMC2798290  PMID: 19841069
13.  Prevention of Steatosis by Hepatic JNK1 
Cell metabolism  2009;10(6):491-498.
Non-alcoholic steatosis (fatty liver) is a major cause of liver dysfunction that is associated with insulin resistance and metabolic syndrome. The cJun NH2-terminal kinase 1 (JNK1) signaling pathway is implicated in the pathogenesis of hepatic steatosis and drugs that target JNK1 may be useful for treatment of this disease. Indeed, mice with defects in JNK1 expression in adipose tissue are protected against hepatic steatosis. Here we report that mice with specific ablation of Jnk1 in hepatocytes exhibit glucose intolerance, insulin resistance, and hepatic steatosis. JNK1 therefore serves opposing actions in liver and adipose tissue to both promote and prevent hepatic steatosis. This finding has profound implications for the design of JNK1-selective drugs for the treatment of metabolic syndrome.
PMCID: PMC2804105  PMID: 19945406
14.  Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice 
Diabetes  2009;58(1):250-259.
OBJECTIVE—Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet–induced obesity (DIO) model.
RESEARCH DESIGN AND METHODS—DIO or normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques.
RESULTS—FGF21 dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity.
CONCLUSIONS—FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes.
PMCID: PMC2606881  PMID: 18840786
15.  Skeletal Muscle–Specific Deletion of Lipoprotein Lipase Enhances Insulin Signaling in Skeletal Muscle but Causes Insulin Resistance in Liver and Other Tissues 
Diabetes  2009;58(1):116-124.
OBJECTIVE—Skeletal muscle–specific LPL knockout mouse (SMLPL−/−) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight, and composition.
RESEARCH DESIGN AND METHODS—Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulin-signaling molecules were compared in skeletal muscle and liver of SMLPL−/− and control mice.
RESULTS—Nine-week-old SMLPL−/− mice showed no differences in body weight, fat mass, or whole-body insulin sensitivity, but older SMLPL−/− mice had greater weight gain and whole-body insulin resistance. High-fat diet feeding accelerated the development of obesity. In young SMLPL−/− mice, insulin-stimulated glucose uptake was increased 58% in the skeletal muscle, but was reduced in white adipose tissue (WAT) and heart. Insulin action was also diminished in liver: 40% suppression of hepatic glucose production in SMLPL−/− vs. 90% in control mice. Skeletal muscle triglyceride was 38% lower, and insulin-stimulated phosphorylated Akt (Ser473) was twofold greater in SMLPL−/− mice without changes in IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase activity. Hepatic triglyceride and liver X receptor, carbohydrate response element–binding protein, and PEPCK mRNAs were unaffected in SMLPL−/− mice, but peroxisome proliferator–activated receptor (PPAR)-γ coactivator-1α and interleukin-1β mRNAs were higher, and stearoyl–coenzyme A desaturase-1 and PPARγ mRNAs were reduced.
CONCLUSIONS—LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition. Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance.
PMCID: PMC2606858  PMID: 18952837
16.  A Stress Signaling Pathway in Adipose Tissue Regulates Hepatic Insulin Resistance 
Science (New York, N.Y.)  2008;322(5907):1539-1543.
A high-fat diet causes activation of the regulatory protein cJun NH2-terminal kinase 1 (JNK1) and triggers the development of insulin resistance. JNK1 is therefore a potential target for therapeutic treatment of metabolic syndrome. We explored the mechanism of JNK1 signaling by engineering mice in which the Jnk1 gene was ablated selectively in adipose tissue. JNK1-deficiency in adipose tissue suppressed high fat diet-induced insulin resistance in the liver. JNK1-dependent secretion of the inflammatory cytokine IL6 by adipose tissue caused increased expression of liver SOCS3, a protein that induces hepatic insulin resistance. Thus, JNK1 activation in adipose tissue can cause insulin resistance in the liver.
PMCID: PMC2643026  PMID: 19056984
17.  Improved Glucose Homeostasis in Mice with Muscle-Specific Deletion of Protein-Tyrosine Phosphatase 1B▿  
Molecular and Cellular Biology  2007;27(21):7727-7734.
Obesity and type 2 diabetes are characterized by insulin resistance. Mice lacking the protein-tyrosine phosphatase PTP1B in all tissues are hypersensitive to insulin but also have diminished fat stores. Because adiposity affects insulin sensitivity, the extent to which PTP1B directly regulates glucose homeostasis has been unclear. We report that mice lacking PTP1B only in muscle have body weight and adiposity comparable to those of controls on either chow or a high-fat diet (HFD). Muscle triglycerides and serum adipokines are also affected similarly by HFD in both groups. Nevertheless, muscle-specific PTP1B−/− mice exhibit increased muscle glucose uptake, improved systemic insulin sensitivity, and enhanced glucose tolerance. These findings correlate with and are most likely caused by increased phosphorylation of the insulin receptor and its downstream signaling components. Thus, muscle PTP1B plays a major role in regulating insulin action and glucose homeostasis, independent of adiposity. In addition, rosiglitazone treatment of HFD-fed control and muscle-specific PTP1B−/− mice revealed that rosiglitazone acts additively with PTP1B deletion. Therefore, combining PTP1B inhibition with thiazolidinediones should be more effective than either alone for treating insulin-resistant states.
PMCID: PMC2169063  PMID: 17724080

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