Regulation of the renin-angiotensin-aldosterone system in adipose tissue by AMP-activated protein kinase

White, Anna Dorothy (2018) Regulation of the renin-angiotensin-aldosterone system in adipose tissue by AMP-activated protein kinase. PhD thesis, University of Glasgow.

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Obesity and type 2 diabetes are a growing concern worldwide and changes within adipose tissue are implicated in their development. Adipocytes contain a complete renin angiotensin aldosterone system (RAAS) implicated in obesity-related complications. The energy regulating kinase AMP-activated protein kinase (AMPK) has anti-inflammatory properties in adipose tissue and systemic insulin sensitising effects.
Initial studies compared the human adipocyte model SW872 with the well-described murine 3T3-L1 adipocyte model. AMPK signalling in SW872 adipocytes was evident with similar responses to two structurally-unrelated AMPK activators, AICAR and A769662 compared with 3T3-L1 adipocytes. Key components of the RAAS were present in SW872 adipocytes and induced upon adipocyte differentiation. AICAR and A769662 were found to negatively regulate classical RAAS components including the mineralocorticoid receptor and angiotensinogen whilst upregulating the ratio of expression of angiotensin converting enzyme-2 to angiotensin converting enzyme-1. However, AMPK activation increased aldosterone secretion and the downstream target SGK1. Interestingly, angiotensin II, likely via the type 2 angiotensin II receptor, and angiotensin 1-7, likely via the Mas receptor, both increased AMPK activity. Despite this AMPK activation there was no effect of angiotensin 1-7 seen on inflammatory processes or insulin signalling in adipocytes so the functional effects of this AMPK activation remain unknown. Wild type and AMPKα1-/- mice were subjected to 12 weeks of high fat diet (HFD) with no significant metabolic differences. Interestingly, the adipose tissue from AMPKα1-/- mice fed chow diet showed increased basal inflammatory signalling which decreased following HFD suggesting a possible pro-inflammatory effect of AMPK upon HFD exposure. However, the systemic RAAS appeared to be upregulated in the AMPKα1-/- HFD group.
The cross-talk between AMPK and RAAS in adipose tissue likely has an important part to play in the development of obesity-related disorders and this work identifies several potential therapeutic avenues.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Adipose tissue, RAAS, AMPK, angiotensin, aldosterone, inflammation, insulin signalling, diabetes.
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Funder's Name: Diabetes UK (DIABETUK)
Supervisor's Name: Salt, Dr. Ian
Date of Award: 2018
Depositing User: Dr Anna White
Unique ID: glathesis:2018-30816
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Sep 2018 06:56
Last Modified: 20 Nov 2018 11:45
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