Bakhamis, AAA; (2015) Investigation of effect of hyperinsulinaemia on adipose tissue microvasculature. Doctoral thesis , UCL (University College London).

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Abstract

Background: Obesity in Qatar is amongst the highest globally and constitutes a serious health risk. Obese individuals are at greater risk of vascular disease compared to the lean, especially in the insulin resistant state. The impact of obesity on endothelial vasomotor function is also adipose tissue depot-dependent, with the visceral environment being more pathogenic. It is, however, unclear how severe the impact of vascular dysfunction is in a relatively young and obese population. Further, it is becoming apparent that obesity-associated vascular dysfunction is heterogeneous. Recent research has focussed on different groups of obese subjects in order to elucidate the mediators of the differential cardiometabolic risk. In pathological obese (PO) subjects, sub-cutaneous adipocyte dysfunction and inflammation have been reported along with adipocyte hypertrophy. This led to the following hypotheses: 1. The enlarged adipocytes are more susceptible to hypoxia due to decreased capillary density of the depot and changes in vascular tone. Hypoxia leads to cell necrosis and the formation of immunological foci. 2. The more hypoxic and inflamed fat depot secretes less adiponectin, which then may determine the increased systemic insulin resistance and dyslipidaemia seen in the PO. Specifically differences between metabolically healthy but obese (MHO) and pathologically obese (PO) in relation to capillary density and vascular function was determined. To facilitate the overall objectives, in this study: 1. A cohort of MHO and PO subjects were identified. 2. Vascular differences in the adipose tissue of PO versus MHO by functional studies (myography) and histological assessment of vascular density were carried out, and, 3. Mechanisms that underlie these differences were investigated. Methods: Patients were recruited from the local hospital and blood and adipose tissue (Omental, OM; Subcutaneous, SC) samples collected. Fasting plasma glucose and insulin were assayed to determine insulin resistance status. Vascular function was assessed by wire myography. Cumulative concentration-response curves were generated for various vasoconstrictors (e.g. noradrenaline, potassium chloride), and vasodilators (e.g. acetylcholine, Sodium nitroprusside (SNP), and prostaglandin E2). Relaxation to acetylcholine was recorded in the absence or presence of Nω-Nitro-L¬arginine methyl ester (L-NAME), indomethacin, diclofenac, BaCl2, apamin+charybdotoxin, and arginine. mRNA expression of hypertension associated genes in stromal vascular fractions (SVFs) of both depots was assessed by real time RT-PCR. Paraffin-embedded tissues were used for histological studies. Results: OM arterioles were less sensitive to noradrenaline-mediated vasoconstriction compared with SC (log EC50 -5.9±0.2 vs. -6.5±0.1, p<0.05). Vasorelaxation to acetylcholine was attenuated in OM vessels compared with SC vessels (p<0.01). In contrast, relaxation to SNP was greater in OM compared with SC vessels (p<0.01). Acetylcholine curves for insulin-sensitive patients were less attenuated compared with insulin-resistant patients. L-NAME, apamin, charybdotoxin, and BaCl2 caused right-ward shifts of the acetylcholine curves, while indomethacin, diclofenac and arginine produced the reverse. In the whole group, COX2 mRNA, but not eNOS and COX1, were up regulated in OM compared with SC SVFs. However, when analyzed separately, in the OM compared to SC SVFs, of the MHO several genes were unregulated (AGT, ARG2, CLIC5, EPHX2, ITPR1 and PRKG1), while in the PO only two were significantly different between the depots (CLIC5 and PDE3B). Conclusions: Hyperinsulinaemia in adipose tissue microvessels was associated with і) vasocontractile insensitivity to noradrenaline and іі) to changes in NO-mediated vasodilation, at least partially mediated through components of the COX2 pathway.

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