Liver-Specific Deletion of Protein-Tyrosine Phosphatase 1B (PTP1B) Improves Metabolic Syndrome and Attenuates Diet-Induced Endoplasmic Reticulum Stress

Delibegović, Mirela; Zimmer, Derek J.; Kauffman, Caitlin; Rak, Kimberly; Hong, Eun‐Gyoung; Cho, You-Ree; Kim, Jason K.; Kahn, Barbara B.; Neel, Benjamin G.; Bence, Kendra K.

doi:10.2337/db08-0913

Cited by 249 publications

(300 citation statements)

References 55 publications

Supporting

Mentioning

257

Contrasting

Order By: Relevance

“…Body weight was comparable between HFD-fed alb-crePtp1b -/-and HFD-fed Ptp1b fl/fl control female mice throughout the study ( Figure 1A), as previously reported in male mice [7] . There was ~50%…”

Section: Resultssupporting

confidence: 87%

“…As with other mouse models of PTP1B-specific deletion [7,10,11] body weight, body fat and bone mineral density of the female liver-specific PTP1B knockout mice did not differ from control mice. This is the first examination of the body weight phenotype in liver-specific PTP1B knockout animals in females and reveals that there is no sexual dimorphism in body weight regulation in these animals.…”

Section: Discussionsupporting

confidence: 65%

“…Animal studies. Female Ptp1b fl/fl mice and alb-crePtp1b -/-mice expressing Cre recombinase under the control of the serum albumin promoter were described previously [7] .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of growth hormone induced JAK2 and mTOR signalling by hepatic protein tyrosine phosphatase 1B

Owen

Lees

Mody

et al. 2015

Diabetes & Metabolism

View full text Add to dashboard Cite

Protein tyrosine phosphatase 1B (PTP1B) regulates various signalling pathways including insulin, leptin, IGF-1 and growth hormone (GH) signalling. Transmission of the GH signal depends on JAK2, which is how PTP1B is thought to modulate GH signalling in the liver, based on studies utilising global PTP1B knockout mice (Ptp1b -/-). Here, we investigated the liver-specific role of PTP1B in GH signalling, using liver-specific Ptp1b -/-mice (alb-crePtp1b -/-), under physiological (chow) or insulin resistant (high-fat diet (HFD)) feeding conditions.Body weight and adiposity were comparable between female alb-crePtp1b -/-and Ptp1b fl/fl control mice. On chow diet, under 48-hour fasting GH-resistant conditions, GH stimulation in vivo led to a robust stimulation of the JAK-STAT signalling pathway. Alb-crePtp1b -/-mice exhibited significantly higher GH-induced JAK2 phosphorylation and SOCS3 gene expression post-GH stimulation. However, STAT3, STAT5 and ERK1/2 phosphorylation and SOCS2 gene expression were similar between groups. Interestingly, GH-induced mTOR phosphorylation was significantly higher in alb-crePtp1b -/-mice 5-min post-GH stimulation compared to controls, revealing this part of the pathway under direct control of PTP1B. Under ad lib HFD-fed conditions, GH-induced STAT5 phosphorylation significantly increased in albcrePtp1b -/-mice only, with no alterations in the controls. Overall, our data demonstrate that liver-specific PTP1B deletion leads to significant alterations in GH signalling with increased phosphorylation of JAK2, STAT5 and mTOR phosphorylation and SOCS3 gene expression.

show abstract

Section: Resultssupporting

confidence: 87%

Section: Discussionsupporting

confidence: 65%

See 1 more Smart Citation

Regulation of growth hormone induced JAK2 and mTOR signalling by hepatic protein tyrosine phosphatase 1B

Owen

Lees

Mody

et al. 2015

Diabetes & Metabolism

View full text Add to dashboard Cite

show abstract

“…Glucose tolerance tests (GTT) were performed as described previously [18][19][20][21]. Briefly, mice were fasted overnight (16 h) and experiments started at 09:00 hours the following day.…”

Section: Methodsmentioning

confidence: 99%

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

et al. 2011

View full text Add to dashboard Cite

Aims/hypothesis Obesity is a major risk factor for development of insulin resistance, a proximal cause of type 2 diabetes and is also associated with an increased relative risk of Alzheimer's disease. We therefore investigated the susceptibility of transgenic mice carrying human mutated transgenes for amyloid precursor protein (APP SWE ) and presenilin 1 (PSEN1 A246E ) (APP/PSEN1), or PSEN1 A246E alone, which are well-characterised animal models of Alzheimer's disease, to develop obesity, glucose intolerance and insulin resistance, and whether this was age-and/or diet-dependent. Methods We analysed the effects of age and/or diet on body weight of wild-type, PSEN1 and APP/PSEN1 mice. We also analysed the effects of diet on glucose homeostasis and insulin signalling in these mice. Results While there were no body weight differences between 16-17-and 20-21-month-old PSEN1 mice, APP/PSEN1 mice and their wild-type controls on standard, low-fat, chow diet, the APP/PSEN1 mice still exhibited impaired glucose homeostasis, as investigated by glucose tolerance tests. This was associated with increased brain protein tyrosine phosphatase 1B protein levels in APP/PSEN1 mice. Interestingly, short-term high-fat diet (HFD) feeding of wild-type, PSEN1and APP/PSEN1 mice for a period of 8 weeks led to higher body weight gain in APP/PSEN1 than in PSEN1 mice and wild-type controls. In addition, HFD-feeding caused fasting hyperglycaemia and worsening of glucose maintenance in PSEN1 mice, the former being further exacerbated in APP/ PSEN1 mice. The mechanism(s) behind this glucose intolerance in PSEN1 and APP/PSEN1 mice appeared to involve increased levels of brain retinol-binding protein 4 and basal phosphorylation of S6 ribosomal protein, and decreased insulin-stimulated phosphorylation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 in the brain. Conclusions/interpretation Our results indicate that Alzheimer's disease increases susceptibility to body weight gain induced by HFD, and to the associated glucose intolerance and insulin resistance.

show abstract

“…Whole-body PTP1B knockout (KO) mice exhibit improved systemic insulin sensitivity, enhanced glucose tolerance, and resistance to high-fat dieteinduced obesity. 24,25 Tissue-specific PTP1B deletion helped define the functions of this phosphatase in many tissues, including muscle, 26 liver, 27 and brain. 28,29 In addition, several studies implicate PTP1B in pancreas function.…”

mentioning

confidence: 99%

Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice

Bettaieb

Koike

Chahed

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

Acute pancreatitis (AP) is a common and devastating gastrointestinal disorder that causes significant morbidity. The disease starts as local inflammation in the pancreas that may progress to systemic inflammation and complications. Protein tyrosine phosphatase 1B (PTP1B) is implicated in inflammatory signaling, but its significance in AP remains unclear. To investigate whether PTP1B may have a role in AP, we used pancreas PTP1B knockout (panc-PTP1B KO) mice and determined the effects of pancreatic PTP1B deficiency on cerulein-and arginine-induced acute pancreatitis. We report that PTP1B protein expression was increased in the early phase of AP in mice and rats. In addition, histological analyses of pancreas samples revealed enhanced features of AP in cerulein-treated panc-PTP1B KO mice compared with controls. Moreover, cerulein-and arginine-induced serum amylase and lipase were significantly higher in panc-PTP1B KO mice compared with controls. Similarly, pancreatic mRNA and serum concentrations of the inflammatory cytokines IL-1B, IL-6, and tumor necrosis factor-a were increased in panc-PTP1B KO mice compared with controls. Furthermore, panc-PTP1B KO mice exhibited enhanced cerulein-and arginine-induced NF-kB inflammatory response accompanied with increased mitogen-activated protein kinases activation and elevated endoplasmic reticulum stress. Notably, these effects were recapitulated in acinar cells treated with a pharmacological inhibitor of PTP1B. These findings reveal a novel role for pancreatic PTP1B in cerulein-and arginine-induced acute pancreatitis. (Am J Pathol 2016 http://dx

show abstract

Liver-Specific Deletion of Protein-Tyrosine Phosphatase 1B (PTP1B) Improves Metabolic Syndrome and Attenuates Diet-Induced Endoplasmic Reticulum Stress

Cited by 249 publications

References 55 publications

Regulation of growth hormone induced JAK2 and mTOR signalling by hepatic protein tyrosine phosphatase 1B

Regulation of growth hormone induced JAK2 and mTOR signalling by hepatic protein tyrosine phosphatase 1B

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice

Contact Info

Product

Resources

About