Endocrine Abstracts

The increasing global prevalence of obesity requires urgent intervention to limit the anticipated surge of associated cardiometabolic morbidity and mortality. The energy sensor AMP-activated protein kinase (AMPK) is one proposed target for treating metabolic disorders and is downregulated in adipose tissue of obese insulin resistant individuals. Given the strong relationship between metabolic syndrome and overactivity of the renin-angiotensin-aldosterone system (RAAS) we investigated the role of AMPK in regulating adipocyte RAAS and mineralocorticoid receptor (MR) signalling. In vitro studies were carried out using differentiated 3T3-L1 (mouse) and SW872 (human) adipocytes. AMPK activators AICAR (1 mM) and A769662 (300 μM) were applied for 8 or 24 h. RT-PCR, immunoblotting and ELISA were used to assess effects on components of the renin-angiotensin-aldosterone system. Angiotensinogen, angiotensin II type 2 receptor and mineralocorticoid receptor mRNA levels were upregulated in differentiated adipocytes compared to undifferentiated fibroblasts. Aldosterone secretion by 3T3-L1 adipocytes and SW872 adipocytes was increased by 8 h of incubation with AICAR or A769662 respectively. Expression of Steroidogenic Acute Regulatory (StAR) mRNA was upregulated in accordance with aldosterone secretion along with associated down-regulation of MR mRNA and protein. Furthermore, we examined downstream MR targets serum and glucocorticoid-regulated kinase 1 (SGK1) and Lipocalin 2 which were both upregulated despite decreased MR. Interestingly, cells which produced aldosterone in response to AMPK activators exhibited a severe down-regulation of AMPK protein levels by 24 h. These data suggest that AMPK acts to control RAAS activity in adipocytes. We hypothesise that prolonged AMPK hyperactivation in vitro results in AMPK depletion allowing aldosterone secretion with subsequent increase in MR signalling. The upregulation of RAAS previously reported in obesity may be partially explained by the downregulation of AMPK related to excess nutrition.

Disclosure: This work was supported by Diabetes UK.