Single nucleotide polymorphisms of protein tyrosine phosphatase 1B gene are associated with obesity in morbidly obese French subjects

Kipfer-Coudreau, S.; Eberlé, Delphine; Sahbatou, Mourad; Bonhomme, Alice; Guy‐Grand, Bernard; Froguel, Philippe; Galán, Pilar; Basdevant, Arnaud; Clément, Karine

doi:10.1007/s00125-004-1432-5

Cited by 34 publications

(32 citation statements)

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“…Similarly, PTP1B re-expression in liver of PTP1B-deficient mice leads to a marked attenuation of their enhanced insulin sensitivity (14). In humans, PTP1B polymorphisms are associated with insulin resistance, obesity, or other characteristics of the metabolic syndrome in some populations (3,(15)(16)(17).Reports of PTP1B overexpression in tissues of insulin-resistant, obese, and/or diabetic animals and humans are somewhat inconsistent. Several studies have reported that PTP1B levels and activity are increased in muscle and adipose tissue of obese, insulin-resistant, and/or diabetic rodents (18 -22) and humans (23)(24)(25)(26).…”

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Protein-tyrosine Phosphatase 1B Expression Is Induced by Inflammation in Vivo

Zabolotny

Kim

Welsh

et al. 2008

Journal of Biological Chemistry

363

295

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Protein-tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin and leptin sensitivity. PTP1B overexpression in adipose tissue and skeletal muscle of humans and rodents may contribute to insulin resistance and obesity. The mechanisms mediating PTP1B overexpression in obese and diabetic states have been unclear. We find that adipose tissue inflammation and the pro-inflammatory cytokine tumor necrosis factor ␣ (TNF␣) regulate PTP1B expression in vivo. High fat feeding of mice increased PTP1B expression 1.5-to 7-fold in adipose tissue, liver, skeletal muscle, and arcuate nucleus of hypothalamus. PTP1B overexpression in high fat-fed mice coincided with increased adipose tissue expression of the macrophage marker CD68 and TNF␣, which is implicated in causing obesity-induced insulin resistance. TNF␣ increased PTP1B mRNA and protein levels by 2-to 5-fold in a dose-and time-dependent manner in adipocyte and hepatocyte cell lines. TNF␣ administration in mice increased PTP1B mRNA 1.4-to 4-fold in adipose tissue, liver, skeletal muscle, and hypothalamic arcuate nucleus and PTP1B protein 2-fold in liver. Actinomycin D treatment blocked, and high dose salicylate treatment inhibited by 80%, TNF␣-induced PTP1B expression in adipocyte cell lines, suggesting TNF␣ may induce PTP1B transcription via nuclear factor B (NFB) activation. Chromatin immunoprecipitation from adipocyte cell lines and liver of mice demonstrated TNF␣-induced recruitment of NFB subunit p65 to the PTP1B promoter in vitro and in vivo. In mice with diet-induced obesity, TNF␣ deficiency also partly blocked PTP1B overexpression in adipose tissue. Our data suggest that PTP1B overexpression in multiple tissues in obesity is regulated by inflammation and that PTP1B may be a target of anti-inflammatory therapies.According to current World Health Organization estimates, twice as many people worldwide suffer ill health effects from the accumulation of excess adipose mass (1.6 billion) than from malnutrition (800 million). Obesity contributes to the pathogenesis of many important human diseases, including type 2 diabetes and cancer (1). Obesity is accompanied by resistance to insulin and leptin, key hormones regulating glucose homeostasis and body weight (2). The molecular mechanisms underlying leptin and insulin resistance in obesity are not completely understood. PTP1B 2 is a major negative regulator of insulin and leptin sensitivity, acting to dephosphorylate the insulin receptor and the leptin receptor-associated Janus kinase 2 (3, 4). PTP1B may also dephosphorylate more distal components of these signaling pathways, such as insulin receptor substrate 1 (5, 6). In vivo, PTP1B is widely expressed in multiple cell types and tissues, including skeletal muscle, liver, adipose tissue, and brain (3, 4). PTP1B deficiency enhances insulin signaling and sensitivity in skeletal muscle and liver (7-10). PTP1B Ϫ/Ϫ mice also have reduced adiposity and are protected from diet-induced obesity (7, 8) due to enhanced leptin action (11, 12) in neurons (9). Conversely...

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confidence: 99%

Protein-tyrosine Phosphatase 1B Expression Is Induced by Inflammation in Vivo

Zabolotny

Kim

Welsh

et al. 2008

Journal of Biological Chemistry

363

295

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“…PTP1B, which is widely expressed and localizes predominantly to the endoplasmic reticulum (5, 6), is a major IR phosphatase (7, 8), dephosphorylates IR preferentially at the tandem Tyr 1162 and Tyr 1163 residues in vitro (9) and in cultured cells (10), and may also dephosphorylate IRS-1 (11, 12). Its expression and activity are increased in obese and insulin-resistant human subjects as well as in some obese rodent models (13-16), and some studies suggest that PTP1B polymorphisms may be associated with obesity and insulin resistance in humans (17)(18)(19). The overexpression of PTP1B in muscle results in insulin resistance (20).…”

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Protein-tyrosine Phosphatase 1B Deficiency Reduces Insulin Resistance and the Diabetic Phenotype in Mice with Polygenic Insulin Resistance

Xue¹,

Kim²,

Lee³

et al. 2007

Journal of Biological Chemistry

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Mice heterozygous for insulin receptor (IR) and IR substrate (IRS)-1 deficiency provide a model of polygenic type 2 diabetes in which early-onset, genetically programmed insulin resistance leads to diabetes. Protein-tyrosine phosphatase 1B (PTP1B) dephosphorylates tyrosine residues in IR and possibly IRS proteins, thereby inhibiting insulin signaling. Mice lacking PTP1B are lean and have increased insulin sensitivity. To determine whether PTP1B can modify polygenic insulin resistance, we crossed PTP1B ؊/؊ mice with mice with a double heterozygous deficiency of IR and IRS-1 alleles (DHet). DHet mice weighed slightly less than wild-type mice and exhibited severe insulin resistance and hyperglycemia, with ϳ35% of DHet males developing diabetes by 9 -10 weeks of age. Body weight in DHet mice with PTP1B deficiency was similar to that in DHet mice. However, absence of PTP1B in DHet mice markedly improved glucose tolerance and insulin sensitivity at 10 -11 weeks of age and reduced the incidence of diabetes and hyperplastic pancreatic islets at 6 months of age. Insulin-stimulated phosphorylation of IR, IRS proteins, Akt/protein kinase B, glycogen synthase kinase 3␤, and p70 S6K was impaired in DHet mouse muscle and liver and was differentially improved by PTP1B deficiency. In addition, increased phosphoenolpyruvate carboxykinase expression in DHet mouse liver was reversed by PTP1B deficiency. In summary, PTP1B deficiency reduces insulin resistance and hyperglycemia without altering body weight in a model of polygenic type 2 diabetes. Thus, even in the setting of high genetic risk for diabetes, reducing PTP1B is partially protective, further demonstrating its attractiveness as a target for prevention and treatment of type 2 diabetes.Insulin plays a dominant role in regulating glucose homeostasis through a highly orchestrated constellation of effects, which include promoting glucose uptake in peripheral tissues such as muscle and fat, suppressing hepatic glucose output, and regulating lipid metabolism. Failure of peripheral tissues to respond to insulin (i.e. insulin resistance) can initially be overcome by a compensatory increase in insulin secretion from pancreatic ␤-cells. When this mechanism fails to compensate sufficiently, frank diabetes and its attendant complications ensue (1-4).Insulin action is mediated through a complex network of signaling events, which are initiated by the binding of insulin to its cell-surface receptor, the insulin receptor (IR).3 This triggers the intrinsic protein-tyrosine kinase activity of IR, resulting in autophosphorylation of several IR tyrosyl residues and the recruitment and tyrosyl phosphorylation of IR substrate (IRS) proteins. Subsequently, molecules such as the growth factor receptor-binding protein Grb-2, the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), and the SH2 domaincontaining protein-tyrosine phosphatase Shp2 bind to IRS proteins, leading to the metabolic and growth-promoting effects of insulin (2, 3).The insulin signaling cascade is negatively regulate...

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“…In humans, PTPN1, the gene coding for PTP-1B, maps to a region in which a major human quantitative trait locus for obesity and type 2 diabetes has been reported (8 -10). Several rare PTPN1 single nucleotide polymorphisms (SNPs) have been shown to be associated with insulin resistance and diabetes in different populations (11)(12)(13)(14). Recently, Palmer et al (15) mounted an extensive study of 35 SNPs spanning a 161-kb region including the PTPN1 gene in Ͼ800 Hispanic Americans.…”

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Protein Tyrosine Phosphatase-1B Gene PTPN1

et al. 2005

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Protein tyrosine phosphatase-1B negatively regulates leptin and insulin signaling, potentially contributing to hormonal resistance. We selected six tagging single nucleotide polymorphisms (SNPs) representing 18 common variants in the protein tyrosine phosphatase-1B gene (PTPN1) and tested their effect on serum leptin, body fat, and measures of insulin sensitivity and the metabolic syndrome in a large sample of normal female Caucasian twins (n ‫؍‬ 2,777; mean age, 47.4 ؎ 12.5 years) from the St. Thomas' U.K. Adult Twin Registry. SNP rs718049 was significantly associated with waist circumference (P ‫؍‬ 0.008) and central fat (P ‫؍‬ 0.035) and also with Avignon's insulin sensitivity index (SiM) (P ‫؍‬ 0.007), fasting insulin (P ‫؍‬ 0.004), fasting glucose (P ‫؍‬ 0.022), triglyceride (P ‫؍‬ 0.023), and systolic blood pressure (P ‫؍‬ 0.046). SNPs rs2282146 and rs1885177 were associated with SiM (P ‫؍‬ 0.049 and P ‫؍‬ 0.013, respectively), and 1484insG was associated with triglyceride (P ‫؍‬ 0.029). A risk haplotype (7.3%) was associated with lower SiM (P ‫؍‬ 0.036) and a protective haplotype (5.2%) with higher SiM (P ‫؍‬ 0.057), with mean values in homozygotes differing by >1 SD (P ‫؍‬ 0.003). The protective haplotype also showed lower triglyceride (P ‫؍‬ 0.045) and lower systolic blood pressure (P ‫؍‬ 0.006). Fine mapping analyses predicted significant associations with SiM and fasting insulin for several ungenotyped SNPs. PTPN1 variants appear to contribute to central fat and metabolic syndrome traits, secondary to their effect on insulin sensitivity. Diabetes 54:3296 -3304, 2005 O besity poses one of the most pressing current public health problems and is a major risk factor for type 2 diabetes. Protein tyrosine phosphatase-1B (PTP-1B) negatively regulates the signaling pathways of insulin and leptin, two hormones involved in the central regulation of energy balance (1). Activated insulin receptor and receptor substrate-1 are dephosphorylated by PTP-1B (2), and phosphorylated JAK2 and STAT3 have been identified as its targets in the leptin pathway (3,4). PTP-1B-deficient mice are hypersensitive to insulin (5) and leptin (4,6) and are protected from diet-induced obesity (4 -6). Hence, increased activity of PTP-1B potentially contributes to leptin resistance associated with overweight (7) and resistance to insulin, which predisposes to type 2 diabetes. In humans, PTPN1, the gene coding for PTP-1B, maps to a region in which a major human quantitative trait locus for obesity and type 2 diabetes has been reported (8 -10). Several rare PTPN1 single nucleotide polymorphisms (SNPs) have been shown to be associated with insulin resistance and diabetes in different populations (11)(12)(13)(14). Recently, Palmer et al. (15) mounted an extensive study of 35 SNPs spanning a 161-kb region including the PTPN1 gene in Ͼ800 Hispanic Americans. Twenty SNPs showed significant association with fasting glucose and the insulin sensitivity index S i . Through its effect on insulin sensitivity, changes in PTP-1B activity may also be refl...

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Single nucleotide polymorphisms of protein tyrosine phosphatase 1B gene are associated with obesity in morbidly obese French subjects

Cited by 34 publications

References 38 publications

Protein-tyrosine Phosphatase 1B Expression Is Induced by Inflammation in Vivo

Protein-tyrosine Phosphatase 1B Expression Is Induced by Inflammation in Vivo

Protein-tyrosine Phosphatase 1B Deficiency Reduces Insulin Resistance and the Diabetic Phenotype in Mice with Polygenic Insulin Resistance

Protein Tyrosine Phosphatase-1B Gene PTPN1

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