Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction

doi:10.1016/j.bcp.2014.10.008

Biochemical Pharmacology

Volume 92, Issue 4, 15 December 2014, Pages 607-617

https://doi.org/10.1016/j.bcp.2014.10.008 Get rights and content

Abstract

Growing evidence suggests that hepatic-insulin resistance is sufficient to promote progression to cardiovascular disease. We have shown previously that liver-specific protein-tyrosine-phosphatase 1B (PTP1B) deficiency improves hepatic-insulin sensitivity and whole-body glucose homeostasis. The aim of this study was to investigate the impact of liver-specific PTP1B-deficiency (L-PTP1B^−/−) on cardiac and peripheral vascular function, with special emphasis on endothelial function in the context of high-fat diet (HFD)-induced obesity.

L-PTP1B^−/− mice exhibited an improved glucose and lipid homeostasis and increased insulin sensitivity, without changes in body weight. HFD-feeding increased systolic blood pressure (BP) in both L-PTP1B^−/− and control littermates; however, this was significantly lower in L-PTP1B^−/− mice. HFD-feeding increased diastolic BP in control mice only, whilst the L-PTP1B^−/− mice were completely protected. The analysis of the function of the left ventricle (LV) revealed that HFD-feeding decreased LV fractional shortening in control animals, which was not observed in L-PTP1B^−/− mice. Importantly, HFD feeding significantly impaired endothelium-dependent vasorelaxation in response to acetylcholine in aortas from control mice, whilst L-PTP1B^−/− mice were fully protected. This was associated with alterations in eNOS phosphorylation. Selective inhibition of COX-2, using NS-398, decreased the contractile response in response to serotonin (5-HT) only in vessels from control mice. HFD-fed control mice released enhanced levels of prostaglandin E, a vasoconstrictor metabolite; whilst both chow- and HFD-fed L-PTP1B^−/− mice released higher levels of prostacylin, a vasorelaxant metabolite.

Our data indicate that hepatic-PTP1B inhibition protects against HFD-induced endothelial dysfunction, underscoring the potential of peripheral PTP1B inhibitors in reduction of obesity-associated cardiovascular risk in addition to its anti-diabetic effects.

Graphical abstract

Introduction

Obesity incidence is reaching epidemic proportions worldwide, and is associated with an increased risk of premature death [1], [2]. As a consequence, the incidence of obesity-related disorders, such as metabolic syndrome, diabetes and cardiovascular disease, is rising at an alarming rate. A common feature of these disorders is the development of insulin resistance, resulting in decreased insulin-stimulated glucose uptake, failure to suppress hepatic glucose production, and accumulation of hepatic lipids. Obesity, in particular abdominal obesity, was pointed out as a primary contributor to acquired insulin resistance, as increasing adiposity is correlated with impaired insulin action [1], [3].

Growing evidence suggests that hepatic insulin resistance is sufficient to induce several components of the metabolic syndrome and promote progression to cardiovascular disease [1]. Vascular dysfunction related to obesity, in particular endothelial dysfunction in various vascular beds and in response to different vasodilator stimuli, might affect both peripheral vascular resistance and the delivery of substrates to metabolically active tissues, thereby contributing to both hypertension and metabolic abnormalities. Endothelial dysfunction is characterized by defects in the normal vasodilator response to mediators such as acetylcholine or to shear stress. It is considered as an independent predictor of cardiovascular events that has been consistently associated with obesity and the metabolic syndrome in a complex interplay with insulin resistance and inflammation. Deficiency of endothelial nitric oxide (NO) is believed to be the primary defect that links insulin resistance and endothelial dysfunction.

The mechanisms linking insulin resistance to endothelial dysfunction remain not well understood. There is evidence to suggest that the direct effects of insulin on the endothelium or disrupted endothelial insulin signalling may disturb endothelial function. Insulin stimulates endothelial cell production of NO [4], and, therefore, insulin resistance at the level of the endothelium might be expected to be associated with decreased insulin-stimulated NO. Duncan et al. [5] demonstrated that transgenic mice with endothelium-targeted over-expression of a dominant-negative mutant of human insulin receptor had a significant endothelial dysfunction, as evidenced by blunted aortic vasodilation in response to acetylcholine. The insulin receptor is a classic receptor tyrosine kinase and, as such, is inactivated by protein tyrosine phosphatases, notably the protein tyrosine phosphatase (PTP)1B [6]. PTP1B is also a negative regulator of leptin receptor signalling [7]. Whole-body PTP1B knockout studies in mice established PTP1B as a key negative regulator of body mass and insulin sensitivity. PTP1B^−/− mice are lean, insulin sensitive, and have enhanced muscle and liver insulin receptor phosphorylation [8], [9]. Mice with brain-specific PTP1B^−/− deficiency exhibit a similar phenotype to the global knockouts in terms of resistance to diet-induced obesity and enhanced insulin sensitivity, mostly due to central effect on leptin signalling [10]. Muscle-specific PTP1B deficient mice exhibit marked improvement in whole-body glucose homeostasis, without changes in body mass or adiposity as well as myeloid-cell specific knockouts [11]; whilst adipocyte-PTP1B deficient mice exhibit mild glucose intolerance and increased adipocyte cell size [12], [13].

Liver-specific PTP1B deletion (L-PTP1B^−/−) improves whole-body glucose and lipid homeostasis, independently of changes in body mass/adiposity [14], [15]. Liver-specific PTP1B^−/− mice exhibit increased hepatic insulin signalling, enhanced insulin-induced suppression of hepatic glucose production in clamp studies and decreased expression of gluconeogenic genes. L-PTP1B^−/− mice are also protected against HFD-induced increase in serum and liver triglyceride and cholesterol levels, associated with decreased expression of lipogenic genes [14], [15]. Hepatic PTP1B may affect lipid metabolism via a pathway distinct from the insulin signalling where its location within the endoplasmic reticulum (ER) membrane appears critical. This was mainly attributable to L-PTP1B^−/− mice being protected against obesity-induced ER stress in the liver [14], [15]. ER stress has been reported to play a crucial role in insulin resistance and lipid accumulation [16].

Considering that in vivo liver-PTP1B deficiency improves hepatic insulin sensitivity and both global glucose homeostasis and lipid metabolism independently of changes in adiposity and body mass, we hypothesized that liver-specific PTP1B deficiency would also lead to protection against obesity-induced endothelial dysfunction and reduction of cardiovascular risk.

Section snippets

Animal studies

All animal studies were performed under a project licence approved by the Home Office under the Animals (Scientific Procedures) Act 1986. Mice were maintained on a 12-h light/dark cycle in a temperature-controlled barrier facility, with free access to water and food. L-PTP1B^−/− mice were described previously and were achieved using an Albumin-Cre promoter [14], [15]. All mice studied were age-matched littermate males on the mixed 129Sv/C57Bl6 background. Genotyping for the PTP1B floxed allele

In vivo liver-PTP1B deficiency improves glucose and lipid homeostasis

As expected from our previous findings, this cohort of L-PTP1B^−/− mice exhibited ∼80% decrease in PTP1B protein in whole liver lysates compared to control littermates (Fig. 1A). However, aortas from L-PTP1B^−/− and control (fl/fl) mice expressed PTP1B to the same level (Fig. 1A).

L-PTP1B^−/− and control mice were weaned either onto normal chow diet (4.5% fat) or HFD (55% kcal from fat). There were no differences in body weight between the control and L-PTP1B^−/− mice on either diet (Fig. 1B) and as

Discussion

We have previously shown that selectively deleting PTP1B in mouse liver results in improved glucose homeostasis and decreased levels of triglycerides and cholesterol, independently of changes in body weight or adiposity [14], [24]. More recently, we also demonstrated that inflammatory ER-stress response and hepatic PTP1B expression are interlinked and that directly down-regulating PTP1B expression in liver can relieve over-activation of the ER-stress response associated with HFD-feeding,

Conflict of interest

None to declare.

Acknowledgments

This work was supported by a Diabetes UK project grant to Dr M. Delibegović (BDARD08/0003597), Tenovus Scotland grant to Dr. M. Delibegovic and Dr. A. Agouni and travel grants from the Physiological Society and Company of Biologists to Dr. A. Agouni. Dr Delibegovic is also funded by an RCUK Fellowship, British Heart Foundation, EFSD/Lilly diabetes programme grant and the Royal Society. Dr Agouni is funded by the Royal Society and the Physiological Society. This work is supported by the INSERM

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Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction

Abstract

Graphical abstract

Introduction

Section snippets

Animal studies

In vivo liver-PTP1B deficiency improves glucose and lipid homeostasis

Discussion

Conflict of interest

Acknowledgments

Best Pract Res Clin Endocrinol Metab

Am J Pathol

Med Clin North Am

Am J Cardiol

Lancet

J Mol Cell Cardiol

Metabolism

Prostaglandins Leukot Essent Fatty Acids

Is insulin resistance: the link between TG-rich lipoproteins and excess death?

J Intern Med

type 2 diabetes, essential hypertension, and cardiovascular disease: similarities and differences

J Clin Hypertens (Greenwich)

Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells

Circulation

Effect of endothelium-specific insulin resistance on endothelial function in vivo

Diabetes

Obesity as a medical problem

Nature

The Genetics of PTPN1 and obesity: insights from mouse models of tissue-specific PTP1B deficiency

J Obes

Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene

Science

Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice

Mol Cell Biol

Neuronal PTP1B regulates body weight, adiposity and leptin action

Nat Med

Myeloid-cell protein tyrosine phosphatase-1B deficiency in mice protects against high-fat diet and lipopolysaccharide-induced inflammation, hyperinsulinemia, and endotoxemia through an IL-10 STAT3-dependent mechanism

Diabetes

Improved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1B

Mol Cell Biol

Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis

PLoS One

Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress

Diabetes

Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically-induced endoplasmic reticulum stress

Biochem J