Restoring Perivascular Adipose Tissue Function in Obesity Using Exercise

Sophie N Saxton,Anthony M Heagerty,Sarah B Withers,Robert G Aldous,Lauren K Toms,Jacqueline Ohanian

doi:10.1007/s10557-020-07136-0

Abstract

PurposePerivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and β3-adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function.MethodsVascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of β3-adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT.ResultsHigh fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via β3-adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing β3-adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored.ConclusionLoss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity.

Highlights

Perivascular adipose tissue (PVAT) is a highly metabolically active tissue which surrounds the majority of blood vessels and contributes to the modulation of vascular tone [1,2,3]
We have indicated that PVAT function is mediated in part by β3-adrenoceptors [37]; in an attempt to rescue PVAT dysfunction in obesity, the effects of the β3-adrenoceptor agonist were tested
We have previously demonstrated that the PVAT anti-contractile effect in health is mediated by a combination of β3-adrenoceptormediated anti-contractile factor release, and NA uptake into adipocytes by organic cation transporter 3 (OCT3) [37]

Summary

Introduction

Perivascular adipose tissue (PVAT) is a highly metabolically active tissue which surrounds the majority of blood vessels and contributes to the modulation of vascular tone [1,2,3]. We have presented evidence that the mechanisms of this effect are mediated via the sympathetic nervous system and are two-fold [4]; first, sympathetic nerve-derived noradrenaline (NA) activates adipocyte β3-adrenoceptors, which. PVAT function is lost, which may contribute to development of metabolic syndrome [5,6,7]. It is well known that in obesity, pathological over-activity of the sympathetic nervous system occurs [8, 9]. Cardiac βadrenoceptors become desensitised in heart failure, as a result of sympathetic nerve over-activity [10]. It is possible that in PVAT, increased sympathetic activity could result in a desensitisation of β3-adrenoceptors, leading to reduced adiponectin release. Bioavailability of adiponectin has already been demonstrated to be reduced in human obesity [11], hypertension [12], and type II diabetes [13]

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