Reduction of Hypothalamic Protein Tyrosine Phosphatase Improves Insulin and Leptin Resistance in Diet-Induced Obese Rats

Picardi, Paty Karoll; Calegari, Vivian C.; Prada, Patrícia O.; Moraes, João Carlos Silos; Araújo, Eliana P.; Marcondes, Maria Cristina Cintra Gomes; Ueno, Mirian; Carvalheira, José Barreto Campello; Velloso, Lı́cio A.; Saad, Mário José Abdalla

doi:10.1210/en.2007-1506

Cited by 108 publications

(114 citation statements)

References 40 publications

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“…PTP1B is known as a nonreceptor type tyrosine phosphatase and negatively regulates insu lin and leptin signaling (11,12). The genetic deletion or pharmacological intervention of PTP1B is known to have antidiabetic and antiobesity effects by amplifying insulin and leptin signaling, respectively (13,14). KY 201 was previously reported to reduce plasma glucose and triglyceride (TG) levels more effectively than rosi glitazone in KKA y mice, even though both compounds have similar human PPARg agonistic activities in COS1 cells (10), which suggests the involvement of PTP1B inhibition in its insulinsensitizing effects.…”

Section: Introductionmentioning

confidence: 99%

Insulin Sensitization by a Novel Partial Peroxisome Proliferator-Activated Receptor γ Agonist With Protein Tyrosine Phosphatase 1B Inhibitory Activity in Experimental Osteoporotic Rats

et al. 2014

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Abstract. The pharmacological profile of (S)7(2{2[(E)2cyclopentylvinyl]5methyloxazol 4yl}ethoxy)2[(2E,4E)hexadienoyl]1,2,3,4tetrahydroisoquinoline3carboxylic acid (KY201), a peroxisome proliferatoractivated receptor (PPAR) g agonist, was compared with that of rosiglitazone in ovariectomized rats. The serum triglyceride and nonesterified fatty acid reducing effects of KY201 at 3 and 10 mg/kg per day for 6 weeks were similar to those of rosiglitazone despite its weaker PPARg agonistic activity. KY201 had no effects on body weight gain, blood volume, or heart and adipose weights, while rosiglitazone at 10 mg/kg per day increased them. KY201 had few effects on bone mineral density (BMD) or fat in marrow (FM), whereas rosiglitazone strongly decreased BMD and increased FM. The PPARγ agonistic activity of KY201 was weaker than that of rosiglitazone in ST2 cells, and KY201 reduced osteoblast differentiation and increased adipocyte differentiation less potently than rosiglitazone in rat bone marrowderived mesenchymal stem cells. KY201, but not rosiglitazone inhibited protein tyrosine phosphatase 1B (PTP1B) and increased phosphorylation of the insulin receptor in HepG2 cells. These results suggest that the hypolipidemic effects of KY201 are similar to those of rosiglitazone, but with less adverse effects, due to the combination of PPARg partial activation and PTP1B inhibition. KY201 would be useful for treatments of diabetic patients at high risk of osteoporosis, cardiovascular disease, and/or obesity.

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Section: Introductionmentioning

confidence: 99%

Insulin Sensitization by a Novel Partial Peroxisome Proliferator-Activated Receptor γ Agonist With Protein Tyrosine Phosphatase 1B Inhibitory Activity in Experimental Osteoporotic Rats

et al. 2014

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“…Positive energy balance and obesity pathogenesis are thought to result from defects in inhibitory feedback signaling to the CNS (including neuronal insulin and leptin resistance and impaired nutrient sensing) (44,45). We hypothesized that increases in NPY tone within these neural circuits may contribute to dyslipidemia in addition to obesity.…”

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confidence: 99%

Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats

Rojas

Stafford

Saadat

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Rojas JM, Stafford JM, Saadat S, Printz RL, Beck-Sickinger AG, Niswender KD. Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats. Am J Physiol Endocrinol Metab 303: E1479 -E1488, 2012. First published October 16, 2012; doi:10.1152/ajpendo.00351.2012.-Elevated plasma triglyceride (TG) levels contribute to an atherogenic dyslipidemia that is associated with obesity, diabetes, and metabolic syndrome. Numerous models of obesity are characterized by increased central nervous system (CNS) neuropeptide Y (NPY) tone that contributes to excess food intake and obesity. Previously, we demonstrated that intracerebroventricular (icv) administration of NPY in lean fasted rats also elevates hepatic production of very low-density lipoprotein (VLDL)-TG. Thus, we hypothesize that elevated CNS NPY action contributes to not only the pathogenesis of obesity but also dyslipidemia. Here, we sought to determine whether the effects of NPY on feeding and/or obesity are dissociable from effects on hepatic VLDL-TG secretion. Pair-fed, icv NPY-treated, chow-fed LongEvans rats develop hypertriglyceridemia in the absence of increased food intake and body fat accumulation compared with vehicle-treated controls. We then modulated CNS NPY signaling by icv injection of selective NPY receptor agonists and found that Y1, Y2, Y4, and Y5 receptor agonists all induced hyperphagia in lean, ad libitum chow-fed LongEvans rats, with the Y2 receptor agonist having the most pronounced effect. Next, we found that at equipotent doses for food intake NPY Y1 receptor agonist had the most robust effect on VLDL-TG secretion, a Y2 receptor agonist had a modest effect, and no effect was observed for Y4 and Y5 receptor agonists. These findings, using selective agonists, suggest the possibility that the effect of CNS NPY signaling on hepatic VLDL-TG secretion may be relatively dissociable from effects on feeding behavior via the Y1 receptor.brain; obesity dyslipidemia; hepatic lipid metabolism DESPITE THE FACT THAT CLINICIANS have become increasingly adept at treating classical cardiovascular risk factors (i.e., hypertension, smoking, and cholesterol) (24), cardiovascular disease remains one of the leading causes of deaths worldwide (20), potentially due to the parallel diabetes and obesity epidemics (39). The dyslipidemia associated with diabetes and obesity consists of elevated very low-density lipoprotein (VLDL)-triglyceride (TG) together with small, dense, lowdensity lipoprotein cholesterol (LDL-C) and reduced highdensity lipoprotein cholesterol (HDL-C) levels (22,23,26) and is an increasingly recognized component of cardiovascular risk, morbidity, and mortality (26).Models of obesity/diabetes dyslipidemia suggest that increased visceral fat mass and insulin resistance lead to elevated adipocyte lipolysis, which increases free fatty acid (FFA) delivery to liver, where it is efficiently cleared, reesterified to TG, and loaded onto a nascent apolipoprotein B (apoB) part...

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“…In all three models, the expression of 72k-5ptase was significantly increased in both skeletal muscle and white adipose tissue. Interestingly, a number of studies have shown that PTP1B, a tyrosine phosphatase known to exert an important regulatory role in insulin and leptin signaling, is increased in obesity, and this increased expression is thought to be one of the main mechanisms connecting increased adiposity to insulin and leptin resistance (Bence et al 2006, Picardi et al 2008. Thus, we suspect that the increased expression of 72k-5ptase in obesity is yet another mechanism promoting resistance to insulin and leptin.…”

Section: Discussionmentioning

confidence: 92%

Inhibition of 72 kDa inositol polyphosphate 5-phosphatase E improves insulin signal transduction in diet-induced obesity

Bertelli

Coope

Caricilli

et al. 2013

Journal of Endocrinology

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The 72 kDa inositol polyphosphate 5-phosphatase E (72k-5ptase) controls signal transduction through the catalytic dephosphorylation of the 5-position of membrane-bound phosphoinositides. The reduction of 72k-5ptase expression in the hypothalamus results in improved hypothalamic insulin signal transduction and reduction of food intake and body mass. Here, we evaluated the tissue distribution and the impact of obesity on the expression of 72k-5ptase in peripheral tissues of experimental animals. In addition, insulin signal transduction and action were determined in an animal model of obesity and insulin resistance treated with an antisense (AS) oligonucleotide that reduces 72k-5ptase expression. In lean Wistar rats, 72k-5ptase mRNA and protein are found in highest levels in heart, skeletal muscle, and white adipose tissue. In three distinct models of obesity, Wistar rats, Swiss mice fed on high-fat diet, and leptin-deficient ob/ob mice, the expression of 72k-5ptase is increased in skeletal muscle and adipose tissue. The treatment of obese Wistar rats with an anti-72k-5ptase AS oligonucleotide results in significant reduction of 72k-5ptase catalytic activity, which is accompanied by reduced food intake and body mass and improved insulin signal transduction and action as determined by immunoblotting and clamp studies respectively. 72k-5ptase expression is increased in obesity and its AS inhibition resulted in a significant improvement in insulin signal transduction and restoration of glucose homeostasis.

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Reduction of Hypothalamic Protein Tyrosine Phosphatase Improves Insulin and Leptin Resistance in Diet-Induced Obese Rats

Cited by 108 publications

References 40 publications

Insulin Sensitization by a Novel Partial Peroxisome Proliferator-Activated Receptor γ Agonist With Protein Tyrosine Phosphatase 1B Inhibitory Activity in Experimental Osteoporotic Rats

Insulin Sensitization by a Novel Partial Peroxisome Proliferator-Activated Receptor γ Agonist With Protein Tyrosine Phosphatase 1B Inhibitory Activity in Experimental Osteoporotic Rats

Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats

Inhibition of 72 kDa inositol polyphosphate 5-phosphatase E improves insulin signal transduction in diet-induced obesity

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