Insulin-Mediated Upregulation of the Renin Angiotensin System in Human Subcutaneous Adipocytes Is Reduced by Rosiglitazone

Abstract

Background-Obesity-associated hypertension is likely to be due to multiple mechanisms. Identification of the renin-angiotensin system (RAS) within adipose tissue does, however, suggest a potential causal role for it in obesity-associated hypertension. Obese patients are often hyperinsulinemic, but mechanisms underlying insulin upregulation of the RAS in adipose tissue are unclear. Tumor necrosis factor-␣ (TNF-␣), an inducer of angiotensinogen in hepatocytes, is elevated in hyperinsulinemic, obese individuals and may provide a link in mediating insulin upregulation of the RAS in adipose tissue. Furthermore, thiazolidinediones lower blood pressure in vivo, and downregulation of the RAS in adipose tissue may contribute to this effect. We therefore examined the effect of rosiglitazone (RSG) on the insulin-mediated upregulation of the RAS. Methods and Results-Sera were obtained from the arterial circulation and from venous blood by draining subcutaneous abdominal adipose tissue. Isolated human abdominal subcutaneous adipocytes (nϭ12) were treated with insulin (1 to 1000 nmol/L), insulin in combination with RSG (10 nmol/L), and RSG (10 nmol/L) alone to determine angiotensinogen expression and angiotensin II, bradykinin, and TNF-␣ secretion. Subcutaneous adipocytes were also treated with TNF-␣ (10 to 100 ng/mL) to examine the direct effect on angiotensinogen expression and angiotensin II secretion. The findings showed that the arteriovenous difference in angiotensin II levels was significant (Ͼ23%; PϽ0.001). Insulin increased TNF-␣ secretion in a concentration-dependent manner (PϽ0.01), whereas RSG (10 nmol/L) significantly reduced the insulin-mediated rise in TNF-␣ (PϽ0.001), as well as angiotensin and angiotensin II. TNF-␣ also increased angiotensinogen and angiotensin II in isolated adipocytes. Conclusions-The present in vivo data suggest that human subcutaneous adipose tissue is a significant source of angiotensin II. This study also demonstrates a potential TNF-␣-mediated mechanism through which insulin may stimulate the RAS and may contribute to explain obesity-associated hypertension. RSG downregulates the RAS in subcutaneous adipose tissue, and this effect may contribute to the long-term effect of RSG on blood pressure.

Analysis of White Adipose Tissue Gene Expression Reveals CREB1 Pathway Altered in Huntington’s Disease

“…Adipose tissue exerts the largest source of extra hepatic circulating angiotensin, and adipose tissue-derived angiotensin has been suggested to be a factor contributing to the association between obesity and hypertension [24], with plasma levels of both angiotensinogen and angiotensin II showing positive correlations with BMI [42]. In our study, however, plasma angiotensin II levels are not altered with disease state.…”

Pioglitazone Decreases Plasma Angiotensin II Concentration inType 2 Diabetes

“…In this study, pioglitazone treatment decreased plasma A markedly by 20%. This is the first report of the effect of thiazolidinediones on circulating RAS components in a clinical study, although an in vitro study has shown that rosiglitazone downregulates RAS expression and production in human adipocytes 19) . Some studies have reported the relationship between PPAR-gamma and RAS in adipocytes 23) ; however, the mechanism by which pioglitazone downregulates RAS in adipocytes is still unknown.…”

“…Our in vitro study has shown that A inhibits adipogenic differentiation of 3T3-L1 cells, and the inhibitory effect is reversed by pioglitazone 18) . Furthermore, other investigators have reported that the thiazolidinedione agent rosiglitazone decreases both angiotensinogen protein expression in isolated human subcutaneous adipocytes and A release from the cells 19) . These findings suggest that the beneficial effects of pioglitazone on glucose and lipid metabolism as well as insulin sensitivity may be due to the reduced production of adipocyte RAS components; however, the effect of pioglitazone on circulating RAS components has not been investigated in clinical study.…”

The role of leptin/adiponectin ratio in metabolic syndrome and diabetes

“…However, in these patients, plasma levels of other inflammatory markers evaluated, such as C-reactive protein (CRP), IL-6, and TNF-α, did not differ according to the presence or absence of AO [24]. Ang II is produced in adipocytes [25], and plasma levels of angiotensinogen and Ang II are positively associated with BMI [26]. Several studies in obese, insulin-resistant, or hypertensive animals and humans show that treatment with Ang II AT1 receptor antagonists reduces IR [27,28].…”