AMPK as a therapeutic target for metabolic disorders: interactions with the renin-angiotensin-aldosterone system in adipocytes

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• 作者：Dr Anna White ; MBChB^a ; ^{anna.white@glasgow.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Aurelie Nguyen Dinh Cat ; PhD^a ; Augusto Montezano ; PhD^a ; Ian Salt ; PhD^a ; Prof Rhian Touyz ; MBBCh^a
• 刊名：The Lancet
• 出版年：2016
• 出版时间：25 February 2016
• 年：2016
• 卷：387
• 期：supp_S1
• 页码：S105
• 全文大小：59 K

文摘

Upregulation of the renin-angiotensin-aldosterone system (RAAS) in adipocytes has been implicated in low-grade adipose inflammation, obesity, the metabolic syndrome, and insulin resistance. These adverse effects can be counter-regulated by AMP-activated protein kinase (AMPK), which has anti-inflammatory actions. We investigated the association between AMPK and the RAAS in human adipocytes to determine whether AMPK activation ameliorates injurious effects of angiotensin II and aldosterone.

Methods

Human liposarcoma-derived SW872 cells were differentiated into adipocytes and then stimulated in the presence or absence of the AMPK activators AICAR (1 mM, 8–24 h) or A769662 (100–300 μM, 8–24 h), angiotensin II (100 nM, 5 min), angiotensin II type 2 receptor inhibitor PD123319, aldosterone (1 μM, 6h), and the proinflammatory cytokines tumour necrosis factor (TNF) α and interleukin (IL) 1β (10 ng/mL, 6 h). RT-PCR, immunoblotting, and ELISA were performed to evaluate expression and activation of the RAAS and proinflammatory signalling pathways.

Findings

Angiotensinogen (m>AGTm>), angiotensin II type 2 receptor (m>AGTR2m>), and mineralocorticoid receptor (m>MRm>) expression increased during adipocyte differentiation; angiotensin II type 1 receptor (m>AGTR1m>) was undetectable. AICAR decreased m>AGTm>, angiotensin I converting enzyme (m>ACEm>), and m>MRm> gene expression, and chemokines m>MCP-1, CXCL-1m>, and m>CXCL-10m>. A769662 also decreased MR expression yet increased aldosterone secretion and levels of downstream MR target serum and glucocorticoid regulated kinase (SGK-1). Conversely, aldosterone stimulation decreased m>SGK1m> gene expression and attenuated proinflammatory effects of TNFα and IL1β on m>IL6m> gene expression. Angiotensin II stimulated AMPK, effects that were blocked by PD123319.

Interpretation

Our findings suggest an interaction between AMPK and the RAAS in adipocytes, where AMPK downregulates the local RAAS and attenuates inflammatory responses. These processes are associated with activation of the angiotensin II type 2 receptor, which is the protective axis of angiotensin II signalling. AMPK might be an important modulator of RAAS signalling in adipocytes and could be an attractive target to ameliorate adipose inflammation in conditions associated with upregulation of the RAAS.

Funding

Diabetes UK, Sir George Alberti Research Training Fellowship.