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Several proteins of the Renin Angiotensin system have been demonstrated to be present in the adipose tissue. These include Renin, Angiotensinogen, Angiotensin I, Angiotensin II, Angiotensin type I (AT1) and type 2 (AT2) receptors, Angiotensin Converting Enzyme (ACE), as well as other proteases capable of producing Angiotensin II namely chymase, Hypertension. 1998 Sep;32(3):387-92   cathepsin D and G, and tonin. Int J Biochem Cell Biol. 2003 Jun;35(6):807-25   Angiotensin II is involved in vasoconstriction as well as aldosterone secretion from the adrenals resulting in increased sodium retention, both of which facilitate hypertension development. The presence of an active RAA system in the adipose tissue could be the potential link between obesity and  the hypertension with which it is closely associated. 

Angiotensin II Actions

 Angiotensin II is an octapeptide hormone produced by ACE (a dipeptidyl carboxypeptidase) from Angiotensin I which is an inactive decapeptide. Angiotensin II is in turn degraded to Angiotensin III and Angiotensin IV which are also active. Trends Pharmacol Sci. 2002 Apr;23(4):177-83.  Angiotensin II is a potent vasoconstrictor and its presence and activity in the adipose tissue could potentially link obesity and its accompanying hypertension. In keeping with this hypothesis, visceral adipose tissue which is thought to be the dangerous and undesirably located fat mass, produces more of ACE, Angiotensinogen and AT1 receptor. In man, plasma levels of Angiotensinogen, Renin and plasma ACE positively correlate with adiposity,  Obes Rev. 2003 Feb;4(1):43-55  


Angiotensin II produced locally in the adipose tissue may exert autocrine effects to regulate adipose tissue growth. Angiotensin II promotes adipocyte growth and differentiation, directly through lipogenesis stimulation and indirectly through prostaglandin (PGI2) synthesis stimulation. Int J Obes Relat Metab Disord. 1994 Dec;18(12):783-8.   At the same time secretion of Angiotensin II from mature adipocytes may exert a negative feed back to inhibit further recruitment of pre adipocytes.  Angiotensin II can alter the blood flow to the adipose tissue through its action on sympathetic nervous system and by direct effects on the stromal vascular cells in the adipose tissue, thus regulating adipose tissue function to a degree.  The Angiotensin II induced vasoconstriction and concomitant reduction in adipose tissue blood flow Obes Res. 2001 Aug;9(8):486-91 could result in accumulation of free fatty acids, resulting in inhibition of further lipolysis and instead increased fatty acid re-esterification.  Stimulation of the alpha 2 adrenergic system by Angiotensin II may contribute to it's anti-lipolytic action. J Neural Transm. 1999;106(7-8):631-44.    Angiotensin thus inhibits lipolysis while increasing lipogenesis. Int J Biochem Cell Biol. 2003 Jun;35(6):807-25 .


While a favourable effect of Angiotensin II on adipocyte  differentiation has been demonstrated, issues have been confused by contrary findings which seem to suggest that Angiotensin II might in fact inhibit adipose tissue differentiation in cultured human pre adipocytes. Diabetes. 2002 Jun;51(6):1699-707.  On a similar note, Angiotensin II has also been shown to reduce insulin-induced adipocyte differentiation. Horm Metab Res. 2001 Apr;33(4):189-95.  Also, blockade of the RAS with ACE Inhibition did not produce significant whole-body lipolysis. Metabolism. 2001 Apr;50(4):468-72.

Mice over-expressing Angiotensinogen in adipose tissue had increased circulating Angiotensinogen as well and were hypertensive. Angiotensinogen deficient mice have decreased blood pressure and adipose tissue mass,  Endocrinology. 2001 Dec;142(12):5220-5.  while mice with over expression of Angiotensinogen in adipose tissue have increased blood pressure and adipose tissue with weight gain. FASEB J. 2001 Dec;15(14):2727-9  But chronic Angiotensin II infusion into rats produced weight loss with reduction in adipose tissue, an effect attributed to sympathetic system activation with reduced food intake and changing plasma leptin concentrations. Am J Physiol. 1998 May;274(5 Pt 1):E867-76. 
Angiotensin II and insulin resistance

Angiotensin II inhibits insulin-dependent activation of P13 kinase thus impairing insulin signal transduction and decreasing glucose uptake into cells.  J Clin Invest. 1997 Nov 1;100(9):2158-69.   These actions facilitate insulin resistance, an effect that has been shown to be reduced by acute and chronic AT1 antagonism. Hypertension. 2001 Oct;38(4):884-90.   In fact, Angiotensin II receptor blockade in skeletal muscle improves insulin action Metabolism. 1995 Feb;44(2):267-72.   through increased GLUT4 expression. Hypertension. 2001 Oct;38(4):884-90.   Angiotensin II increases hepatic gluconeogenesis and glycogenolysis.  Clinical studies with ACE inhibition  N Engl J Med. 2000 Jan 20;342(3):145-53,    Lancet. 1999 Feb 20;353(9153):611-6. (HOPE, CAPP, PROGRESS, SOLVD)  and Angiotensin II receptor blockers  Drugs.2004;64(22):2537-65.    Lancet. 2003 Sep 6;362(9386):777-81, (CHARM, SCOPE, LIFE, VALUE) have shown prevention of development of new onset diabetes in the study populations, which could be explained by these mechanisms. Bradykinin has been shown to induce GLUT4 translocation with increased basal and insulin-stimulated glucose uptake in skeletal muscles of insulin-resistant obese Zucker rats.  Am J Physiol. 1999 Jul;277(1 Pt 2):R332-6.  This might be an added advantage that ACEI have over Angiotensin II receptor blockers. Blockade of Angiotensin II causes decreased adipocyte maturation which results in larger adipocytes which may act as a sump for fat accumulation preventing fat deposition in liver and skeletal muscle, thus decreasing development of insulin resistance.
Angiotensin II receptors

Angiotensin II acts through two separate receptors namely AT1 and AT2. Two AT1 receptor subtypes (AT1A and AT1B) have been described. FEBS Lett. 1992 Feb 24;298(2-3):257-60.   AT1 receptors are distributed widely in tissues including the adipose tissue as well as vasculature, heart, kidney, brain, liver, adrenal gland and lung. Am J Hypertens. 2000 Jan;13(1 Pt 2):31S-38S.  The classic effects of Angiotensin II namely vasoconstriction, as well as aldosterone stimulation from the adrenal gland with sodium and water reabsorption in the kidneys are mediated through the AT1 receptors. Pharmacol Rev. 1993 Jun;45(2):205-51.  AT2 receptor expression which is initially widespread in the foetus, decreases post-natally and remains expressed in the adipose tissue as well as the vasculature, heart, adrenal gland, pancreas and female reproductive organs. Am J Hypertens. 2000 Jan;13(1 Pt 2):31S-38S.  Angiotensin seems to act on AT2 receptors to produce effects totally opposed to those mediated by the AT1 receptor resulting in vasodilatation, apoptosis and inhibition of cell growth and proliferation. Circ Res. 1998 Dec 14-28;83(12):1182-91  although further clarification of actions  mediated by the AT2 receptor in physiological and pathological states is awaited. Activation of AT2 receptor has been shown to have beneficial cardiovascular effects in pathological states.Hypertension. 1999 Nov;34(5):1112-6.   Chronic AT1 receptor blockade results in compensatory increase in Angiotensin II production which then probably acts preferentially on  AT2 receptors to produce vasodilation and other beneficial effects seen with AT1 receptor blockade. LDL can up-regulate the AT1 receptor thus increasing the response of vascular tissue to Angiotensin II. Circulation. 1997 Jan 21;95(2):473-8.
Angiotensin II regulation in adipose tissue

Fasting decreases Angiotensinogen expression in the adipose tissue,  with increase on feeding; changes that are paralleled by blood pressure changes. Hypertension. 1992 Apr;19(4):339-44. Insulin Am J Physiol. 1997 Jul;273(1 Pt 2):R236-42  .and fatty acids Biochem J. 1997 Feb 15;322 ( Pt 1):235-9   have also been shown to regulate Angiotensinogen expression in adipose tissue. Glucocorticoids increase Angiotensinogen expression in adipose tissue. In keeping with this, mice over expressing 11 beta hydroxysteroid dehydrogenase type 1 (11βHSD1)  develop hypertension associated with an activation of the Renin Angiotensin system with increased plasma Angiotensinogen and Angiotensin II. J Clin Invest. 2003 Jul;112(1):83-90.



Angiotensin II Antagonism

ACE inhibition or AT1 receptor blockade  in rodents decreases weight and improves insulin sensitivity. Similar beneficial effects have been demonstrated in large clinical trials in humans with a reduced incidence of new onset diabetes in patients treated with ACEI or AT2 receptor blockers. Combining the bradykinin-potentiating effects of ACE inhibition with the pro-cardiovascular effects of preferential AT2 receptor actions induced by ARB (Angiotensin receptor blockers) offer a lucrative therapy to combat not only hypertension but the insulin resistance state as a whole.

It is important to be aware that while the presence of the different  peptides of the RAA system has been demonstrated in adipose tissue, there has still been no definite demonstration of Angiotensin II production in vivo in the adipose tissue.