Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.656488
Title: The role of the NOS-ADMA-DDAH1 pathway in adipocytes and obesity
Author: Dowsett, Laura Bethany
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Abstract:
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) which is metabolised by two isoforms of the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Inhibition of DDAH has been shown to increase ADMA concentrations both in vitro and in vivo. Clinically, high concentrations of ADMA have been associated with a range of diseases, particularly cardiovascular disease and more recently obesity. The role of the NO-ADMA-DDAH pathway has not yet been studied in adipose tissue. This thesis sets out to investigate the effects of pathological ADMA exposure firstly on adipocytes in vitro and secondly, on whole adipose physiology in vivo. In vitro the existence of the NO-ADMA-DDAH pathway was established in the 3T3-L1 cell line before investigating the effect of chronic ADMA exposure of their biology. ADMA was found to cause adipocyte hypertrophy through mTOR signalling in an NO independent manner. The effect of elevated ADMA on adipocytes in vivo was investigated through an adipocyte specific DDAH1 knockout. These mice developed visceral obesity with adipocyte hypertrophy with an increase in mTOR signalling. On a high fat diet there is a large increase in intracellular adipocyte ADMA in both knockout and control mice. Adipose vasculature is an important regulator of adipose expansion; to investigate the role of ADMA in this process an endothelial specific DDAH1 knockout mouse was developed. Angiogenesis in these mice is reduced restricting adipose growth in obesity. This thesis establishes that the NO-ADMA-DDAH1 pathway to be important in adipose physiology. Elevated ADMA in adipocytes and endothelial cells is detrimental to their function and increases various factors associated with the metabolic syndrome.
Supervisor: Leiper, James Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.656488  DOI: Not available
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