PMID- 15837949
OWN - NLM
STAT- MEDLINE
DCOM- 20051115
LR  - 20181201
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 111
IP  - 15
DP  - 2005 Apr 19
TI  - Insulin-mediated upregulation of the renin angiotensin system in human 
      subcutaneous adipocytes is reduced by rosiglitazone.
PG  - 1954-61
AB  - 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. 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 (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.
FAU - Harte, Alison
AU  - Harte A
AD  - Unit for Diabetes and Metabolism, Warwick Medical School, University of Warwick, 
      Coventry, CV4 7AL, United Kingdom.
FAU - McTernan, Philip
AU  - McTernan P
FAU - Chetty, Rajkumar
AU  - Chetty R
FAU - Coppack, Simon
AU  - Coppack S
FAU - Katz, Jonathan
AU  - Katz J
FAU - Smith, Stephen
AU  - Smith S
FAU - Kumar, Sudhesh
AU  - Kumar S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Antihypertensive Agents)
RN  - 0 (Insulin)
RN  - 0 (Thiazolidinediones)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 05V02F2KDG (Rosiglitazone)
RN  - 11128-99-7 (Angiotensin II)
SB  - IM
MH  - Adipocytes/*metabolism
MH  - Angiotensin II/metabolism
MH  - Antihypertensive Agents/pharmacology
MH  - Cells, Cultured
MH  - Drug Antagonism
MH  - Humans
MH  - Insulin/*pharmacology
MH  - Obesity/complications
MH  - Renin-Angiotensin System/*drug effects
MH  - Rosiglitazone
MH  - Thiazolidinediones/*pharmacology
MH  - Tumor Necrosis Factor-alpha/metabolism/pharmacology
MH  - Up-Regulation/*drug effects/physiology
EDAT- 2005/04/20 09:00
MHDA- 2005/11/16 09:00
CRDT- 2005/04/20 09:00
PHST- 2005/04/20 09:00 [pubmed]
PHST- 2005/11/16 09:00 [medline]
PHST- 2005/04/20 09:00 [entrez]
AID - 111/15/1954 [pii]
AID - 10.1161/01.CIR.0000161954.17870.5D [doi]
PST - ppublish
SO  - Circulation. 2005 Apr 19;111(15):1954-61. doi: 
      10.1161/01.CIR.0000161954.17870.5D.