title: 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-alpha (TNF-alpha), 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.
  
  
  RESULTS
  Sera were obtained from the arterial circulation and from venous blood by draining subcutaneous abdominal adipose tissue. Isolated human abdominal subcutaneous adipocytes (n=12) 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-alpha secretion. Subcutaneous adipocytes were also treated with TNF-alpha (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 (>23%; P<0.001). Insulin increased TNF-alpha secretion in a concentration-dependent manner (P<0.01), whereas RSG (10 nmol/L) significantly reduced the insulin-mediated rise in TNF-alpha (P<0.001), as well as angiotensin and angiotensin II. TNF-alpha 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-alpha-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.
authors.affiliation: Unit for Diabetes and Metabolism, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Harte
authors.forename: Philip
authors.initials: P
authors.lastname: McTernan
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Chetty
authors.forename: Simon
authors.initials: S
authors.lastname: Coppack
authors.forename: Jonathan
authors.initials: J
authors.lastname: Katz
authors.forename: Stephen
authors.initials: S
authors.lastname: Smith
authors.forename: Sudhesh
authors.initials: S
authors.lastname: Kumar
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000959:Antihypertensive Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004336:Drug Antagonism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D009765:Obesity / Q000150:complications; D012084:Renin-Angiotensin System / Q000187:drug effects*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D000959:Antihypertensive Agents; D007328:Insulin; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D000804:Angiotensin II