Review
Adipose tissue renin–angiotensin–aldosterone system (RAAS) and
progression of insulin resistance
Yonit Marcus a,1
, Gabi Shefer a,b,1
, Naftali Stern a,c,⇑
a
Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel
b
Department of Biological Structure, University of Washington School of Medicine, Seattle, Washington, USA
c
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
a r t i c l e i n f o
Article history:
Available online 29 June 2012
Keywords:
Visceral fat
Hypertension
Adipocytes
Inflammation
Obesity
Type 2 diabetes
a b s t r a c t
This review focuses on the expression of the key components of the renin–angiotensin–aldosterone axis
in fat tissue. At the center of this report is the role of RAAS in normal and excessive fat mass enlargement,
the leading etiology of insulin resistance. Understanding the expression and regulation of RAAS components
in various fat depots allows insight not only into the processes by which these complex patterns are
modified by the enlargement of adipose tissue, but also into their impact on local and systemic response
to insulin.
Ó 2012 Elsevier Ireland Ltd. All rights reserved.
Contents
1. Introduction: Basic components of the renin–angiotensin–aldosterone system (RAAS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. RAAS components are locally expressed in white adipose tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1. Angiotensinogen, renin, Ang II forming enzymes, Ang II and Ang II receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.2. ACE2, Ang 1–7/MAS and adipose tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.3. Aldosterone interactions with adipose tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.4. The effects of RAAS on the different body fat depots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3. Regulation of fat RAAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.1. Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.2. Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.3. Ang II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.4. Cyclic adenosine monophosphate (cAMP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.5. Glucocorticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.6. TNF-a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.7. Androgens and estrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.8. Free Fatty Acids (FFAs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.9. Fat RAAS in aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4. Effect of fat tissue RAAS on systemic/circulating RAAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.1. Fat AGT contributes to circulating and non-fat tissue AGT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.2. Fat-tissue derived Ang II may be released to the circulation under increased sympathetic drive. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5. RAAS, Ang II and fat tissue metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5.1. Rate of TG storage and blood flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5.2. Lipolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
6. Adipose RAAS, Ang II and preadipocyte differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
7. RAAS, Ang II and adipocyte volume and hypertrophy: Ang II and fat mass. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
0303-7207/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.mce.2012.06.021
⇑ Corresponding author. Address: Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel.
Tel./fax: +972 36974578.
E-mail address: stern@tasmc.health.gov.il (N. Stern).
1
First two authors contributed equally to this manuscript.
Molecular and Cellular Endocrinology 378 (2013) 1–14
Contents lists available at SciVerse ScienceDirect
Molecular and Cellular Endocrinology
journal homepage: www.elsevier.com/locate/mce
8. Central involvement of RAAS in adipose tissue homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
9. Adipocyte dysfunction and systemic RAAS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
10. Ang II and adipose tissue inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
11. Fat RAAS, fibrosis and hypoxia/hyperoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
11.1. Fibrosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
11.2. Hypoxia and fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
12. Disruption of RAAS protects from obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
13. Fat RAAS and insulin resistance: an integrated overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1. Introduction: Basic components of the renin–angiotensin–
aldosterone system (RAAS)
The classical systemic RAAS generates hormones that are key
regulators of blood pressure, fluid and electrolyte balance and play
a role in the pathogenesis of cardiovascular diseases. Renin is a proteolyitic
enzyme that is produced in the juxtaglomerular (JG) apparatus
in the kidney and its secretion is stimulated mainly by (a)
reduced renal perfusion pressure, hypotension, that translate into
(b) low NaCl levels in the distal tubules of the kidney; and (c) increased
sympathetic activity (sensed by b1-adrenoceptors located
on the JG). There is evidence that prostaglandins (PGE2 and PGI2)
stimulate renin release in response to reduced NaCl levels in the
kidney. When renin is released to the circulation it metabolizes its
only substrate, angiotensinogen (AGT), which is primarily synthesized
in and released from the liver to the blood stream. The action
of renin on AGT results in the production of a decapeptide, angiotensin
I (Ang I). Mostly in pulmonary circulation, Ang I is converted
into the octapeptide Ang II by the angiotensin converting enzyme
type 1 (ACE1 or ACE) which is nearly ubiquitously bound to vascular
endothelial cells. ACE also inactivates the potent vasodilators bradykinin
and kallidin (Carey and Siragy 2003). Taken together, the
succession of enzymatic actions of renin and ACE result in increased
vasoconstriction and decreased vasodilation. The most important
and well studied effects of Ang II are mediated by two distinct
G-protein-coupled receptors, AT1 and AT2. Ang II elicits an increase
in blood pressure and blood volume by: (a) stimulating vasoconstriction
through interaction with AT1 receptors (AT1R) located in
vascular smooth muscle cells of the arterial wall; (b) sodium retention,
both directly by increasing sodium (Na) reabsorbtion in the renal
proximal tubules via AT1R and indirectly, via activation of AT1R
in the adrenal zona glomerulosa (Aguilar et al., 2004). AT1R activation
in the adrenal glands induces the synthesis and secretion of
aldosterone that enhances sodium and water retention, increases
potassium (K) excretion and increases blood pressure. Ang II itself
via the interaction with AT2R mediates some ‘‘counter effects’’,
including subtle vasodilator and anti-proliferative effects.
In addition to this dominant effector arm of RAAS, comprised
mainly of ACE, Ang II, and AT1R as the mediator for the biological
actions of Ang II, a functionally opposing arm has been more recently
appreciated. In this branch, angiotensin–converting enzyme
2 (ACE2) is a key enzyme which generates Ang 1–7 by hydrolysis of
Ang II. The Mas receptor then mediates ‘‘counter effects’’ of Ang
1–7 such as vasodilatation, inhibition of proliferation and
anti-fibrosis (Santos et al., 2003).
2. RAAS components are locally expressed in white adipose
tissue
2.1. Angiotensinogen, renin, Ang II forming enzymes, Ang II and Ang II
receptors
There is evidence for mRNA expression of all, and protein
expression of some, of the components essential for a complete
local RAAS in adipocytes of the white adipose tissue (WAT). Specifically,
the gene that encodes renin was found to be expressed in
adipose tissue, which also expresses Cathepsin D and G, enzymes
that can produce Ang I and Ang II, respectively, through RAAS alternative
routes (Karlsson et al., 1998). There is evidence that cell
membrane associated renin- receptors are present in human adipose
tissue, predominantly in the stromal vascular fraction. Further,
renin receptor expression was higher in visceral than in
subcutaneous adipose tissue of both lean and obese human subjects
(Achard et al., 2007). Post-natal high-fat diet in rats resulted
in an increased fraction of pro-renin receptor expressing cells in
adipose tissue. Moreover, a positive relationship was seen between
plasma renin activity and the density of pro-renin receptor
expressing cells (Achard et al., 2011). Renin and pro-renin binding
to renin-receptors evokes enhanced renin enzymatic activity that
results in increased Ang II formation and also independently activates
intracellular signaling which mediates the expression of fibrotic
proteins (Nguyen 2011). Thus, food-induced increased
expression of the renin-receptor in fat could lead to increased local
RAAS activity, overproduction of Ang II that may leak out of WAT to
the circulation and increase systemic levels of Ang II. Elevated levels
of Ang II exert unwanted effects on blood pressure.
Rodent and human adipose tissues express the AGT gene and
protein (Cassis et al., 1988; Jones et al., 1997; Karlsson et al.,
1998). There is a strong association between the expression of adipose
AGT gene and blood pressure. Targeted expression of AGT in
adipocytes of wild type and AGT-knockout mice resulted in elevated
blood pressure. In the same vein, mice that do not express
AGT exclusively in their WAT have reduced plasma AGT levels
and lower systolic blood pressures compared with controls
(Massiera, et al. 2001a). These data attest for the contribution of
adipocyte-derived AGT to the systemic RAAS and the control of
blood pressure (Yiannikouris et al., 2012). Additionally, adipocyte
specific targeted overexpression of an enzyme that generates active
cortisol (11b-hydroxysteroid dehydrogenase-1) induced elevated
blood pressure in association with high plasma AGT and
adipose tissue AGT gene expression in mice (Masuzaki et al.,
2003). This could have resulted, at least in part, from cortisoldependent
induction of adipose-AGT expression. Other components
of the RAAS system such as the ACE and ACE2 genes, and
Ang II receptors (predominantly AT1R), at the protein level, were
also detected in adipose tissue (Gupte et al., 2008; Jonsson et al.,
1994; Crandall et al., 1994). AT1R is nearly ubiquitously expressed,
and AT2R expression is generally low and restricted to just a handful
of tissues in adults. AT2R expression levels were reported to
increase during adipocyte differentiation (Mallow et al., 2000). In
fact, both adipocytes and preadipocytes express not only AT1R
and AT2R, but also the less well recognized receptors for Ang IV
and Ang 1–7 (MasR; (Weiland and Verspohl 2008).
An interesting question is whether the local adipose tissue RAAS
is totally or partially independent of systemic RAAS, as reflected in
its circulating effector hormones. A study in rats showed that WAT
renin was independent of plasma renin levels, exclusive of extremely
high levels. This is unlike the heart, where the expression
2 Y. Marcus et al. / Molecular and Cellular Endocrinology 378 (2013) 1–14
of cardiac tissue and plasma renin were positively correlated.
Moreover, in rodents, adipocyte-derived AGT comprised about
30% of the circulating AGT levels (Cassis et al., 2008; Faloia et al.,
2002; Massiera et al., 2001a). The local adipose RAAS appears,
therefore, to function independently of plasma RAAS via independent
control of renin levels but influences circulatory RAAS (Fowler
et al., 2009b). This complex relationship is especially intriguing
considering that excess body fat, particularly in the visceral depot,
is closely related to hypertension and the dysmetabolic state. Likewise,
the ability of adipose cells to produce and secrete Ang II may
explain, at least partially, the deterioration of typically non-fatty
organs which become the target of ectopic fat deposition once fat
storage capacity in adipose tissue is exceeded. The best known
examples for such ectopic fat infiltration are visceral organs such
as the liver, pancreas and kidneys, as well as myocardial, perivascular
and skeletal muscle fat deposition. Fat accumulates in these
tissues either as an adipose tissue capsule or as a fibrous cover containing
adipocytes.
2.2. ACE2, Ang 1–7/MAS and adipose tissue
ACE2 (mRNA and protein) is expressed in adipose tissue
(Gembardt et al., 2005), but its physiological role is not as well
understood. Several mechanisms for ACE2 actions were suggested,
including differential glycosylation, shedding from the cell membrane
and tissue-specific regulation through inhibition of Ang II
synthesis or activity (Ferrario et al., 2005; Lambert et al., 2005). Recent
studies demonstrate that ADAM17, the metallopeptidase that
cleaves TNF-a from cell membranes, can also mediate the shedding
of ACE2 (Lambert et al. 2005). Increased ADAM17-dependent shedding
of TNF-a has been implicated as a link between obesity and
T2D, albeit the role of ADAM17-mediated ACE2 shedding in diseases
that are associated with activated RAAS has not been established.
Recently, Gupte et al. (2008) reported that short-term high
fat diet increased ACE2 expression in adipose tissue whereas
chronic fat rich diet continued to promote ACE2 mRNA expression
but did not increase ACE2 protein or enzymatic activity. The shedding
of ACE2 from adipocyte cell membranes may down regulate
local Ang II concentrations and thus affect adipose tissue remodeling.
ACE2 shedding from adipocytes may also explain discrepancies
between ACE2 mRNA expression and protein abundance/
activity as reflected by the finding that despite an increase in
ACE2 mRNA upon high fat diet, systemic RAAS was actually activated.
Not only can adipose ACE2 reduce local Ang II concentration,
but in primary cultured mouse epididymal adipocytes, Ang 1–7
(the product of ACE2) was shown to reduce ROS formation and
NADPH oxidase mRNA levels and increase basal and insulin-stimulated
glucose uptake, possibly through induction of adiponectin
expression (Liu, et al., 2011).
Downstream to ACE2, interference with the Mas receptor integrity
resulted in disruption of normal adipose tissue function: Masknockout
(Mas-KO) mice developed $50% increase in abdominal
fat mass associated with reduced insulin sensitivity hyperinsulinemia,
hyperleptinemisa, hypercholesterolemia and hypertriglyceridemia.
Decreased GLUT4 in adipose tissue along with increased
expression of TGFb and AGT genes was also seen in Mas-KO
animals (Santos et al., 2008).
2.3. Aldosterone interactions with adipose tissue
Human adipocytes produce an as yet uncharacterized mineralocorticoid-releasing
factor which stimulates adrenal aldosterone
production (Lamounier-Zepter and Ehrhart-Bornstein, 2006). One
candidate compound which could link obesity to increased circulating
aldosterone is an epoxy-keto derivative of linoleic acid. This
substance is a potent stimulator of aldosterone production and is
present in obese persons with increased levels of free fatty acids
(FFAs). Increased oxidative stress could drive the production of this
aldosterone-stimulating FFA oxidation product (Goodfriend et al.,
2004). Consistent with this is the finding that the aldosterone
secretagogue activity of adipocyte–conditioned medium from obese
spontaneously hypertensive rats (SHR) was significantly
zgreater than that from nonobese SHRs (Nagase et al., 2006). Very
low-density lipoproteins (VLDL) comprises another potential link
between dysmetabolic obesity and increased aldosterone levels
as VLDL was shown to directly enhance aldosterone synthesis inand
secretion from-human and bovine adrenal cells and in the
adrenocortical cell line H295R, largely via induction of the protein
expression of steroidogenic acute regulatory (StAR) and aldosterone
synthase (CYP11B2) (Xing et al., 2012). Additionally, weight
reduction (that results in reduced VLDL levels) decreases plasma
aldosterone levels and improves insulin sensitivity in both normotensive
and hypertensive patients (Dall’Asta et al., 2009; Tuck et al.,
1981).
In rodent adipose tissue, aldosterone and mineralocorticoid
receptor activation increase proinflammatory adipokine expression,
that in turn results in reduced insulin receptor expression
and impaired insulin-induced glucose uptake (Ehrhart-Bornstein
et al., 2004; Rondinone et al., 1993). Indeed, adipocytes from the
subcutaneous adipose tissue of a patient with primary aldosteronism
(PA) had lower mRNA and protein expression of insulin receptors
(IR) (Carranza et al., 1991). Interference of aldosterone with
insulin’s action may underlie the increased rate of the metabolic
syndrome and aberrant glucose metabolism in PA reported in
some, but not all, studies (Fallo et al., 2006; Giacchetti et al.,
2007; Matrozova et al., 2009). Increased levels of circulating resistin,
another adipose tissue derived inducer of insulin resistance,
were also reported in subjects with PA (Iacobellis et al., 2010).
Caprio et al. showed that aldosterone, acting via mineralocorticoid
receptors (MR), accelerated adipose conversion of 3T3-L1 cells and
differentiation of 3T3-F442A cells in a time- and dose-dependent
manner. MR, but not glucocorticoid receptor knockdown inhibited
glucocorticoid-stimulated adipose conversion of 3T3-L1 cells
(Caprio et al., 2007; Guo et al., 2008). Finally, studies in obese diabetic
mice have demonstrated that MR blockade reduced adipocyte
size and lowered the expression of proinflammatory and prothrombotic
factors in adipose tissue, along with increased expression
of adiponectin, thus potentially reversing fat-tissue excess
induced adipocye dysfunction (Guo et al., 2008).
MR activation apparently plays a complex role also in brown
adipocyte differentiation and function. In a cell line of rodent
brown preadipocytes (T37i) aldosterone accelerated triglyceride
accumulation, along with increased expression of adipogenic genes
such as lipoprotein lipase (LPL), peroxisome proliferator- activated
receptor c (PPARc) and adipocyte-specific fatty acid binding protein
(aP2) but prevented the expression and function of brownfat
specific uncoupling protein–1 (UCP–1). These results indicate
that MR activation may not only promote brown adipocyte differentiation
but also block thermogenesis (reviewed in (Marzolla
et al., 2012). MR activation may be critical also for white adipose
cell differentiation (Caprio et al., 2011), however this effect is probably
exerted in vivo by cortisol rather than aldosterone, considering
the large excess of cortisol over aldosterone in WAT, along with the
lack of the cortisol-neutralizing enzyme 11b hydroxysteroid dehydrogenase
type 2 in white adipocytes.
2.4. The effects of RAAS on the different body fat depots
The health risk of overweight depends, to a large extent, on the
particular distribution pattern of excessive adipose tissue. In the
late 50s, the terms ‘‘android’’ and ‘‘gynoid’’ obesity were used to
describe upper-body and lower-body adiposity, respectively
Y. Marcus et al. / Molecular and Cellular Endocrinology 378 (2013) 1–14 3
(Vague, 1956). More accurately defined, body fat may be stored in
the following compartments:
 Subcutaneous adipose tissue – beneath the surface of the skin
 Visceral/central adipose tissue – inside the peritoneal cavity, on
the visceral tree and between the internal organs and torso
 Lower body/gluteo-femoral region adipose tissue – hips, posterior
pelvic region and thighs
 Ectopic/Non-adipose intra-abdominal solid organs – liver, pancreas,
kidney, skeletal muscle, the heart and the perivascular
space.
Subcutaneous fat is the largest adipose depot in humans, yet
visceral fat, which makes up only about 20% of total fat, exerts a
more potent metabolic effect and is strongly associated with
obesity-related complications such as type 2 diabetes (T2D) and
coronary artery disease (Hamdy et al., 2006). Three likely explanations
underlie this increased negative influence of visceral fat,
which far exceeds its relative actual size: (1) its intra-abdominal
location, allowing direct drainage of its products to the portal circulation,
leading to disproportionately increased effects on the liver
and its metabolic machinery; (2) enhanced lipolytic activity
of intra-abdominal adipocytes, allowing access to the liver of high
concentrations of released FFAs (Bays et al., 2007; Bergman and
Mittelman, 1998); (3) increased output of proinflammatory cytokines
like tumor necrosis factor-alpha (TNF-a) and interleukin-6
(IL-6) and decreased adiponectin production in visceral adipose tissue
in association with an apparently more abundant and inflammation-prone
population of resident macrophages (Yokota et al.,
2000).
In this unique environment, visceral adipose tissue also exhibits
significantly elevated AGT mRNA compared with subcutaneous
adipose tissue (Giacchetti et al., 2002). In patients with the metabolic
syndrome, blockade of the AT1 receptor by telmisartan decreased
visceral and not subcutaneous fat area after 24 weeks of
treatment (Shimabukuro et al., 2007), thus suggesting that local
Ang II production by visceral adipocytes may act in a paracrine
manner to further facilitate adipose growth and proliferation.
Unlike other fat depots, the gluteofemoral fat apparently possesses
protective properties in subjects with a wide range of age,
BMI and co-morbidities. Specifically, gluteofemoral fat is associated
with lower total cholesterol, low-density lipoprotein (LDL)
cholesterol, VLDL and higher high-density lipoprotein-cholesterol
(HDL) levels (Ozbey et al., 2002; Seidell et al., 2001; Williams
et al., 1997; Yim et al., 2008). The mechanisms underlying these
striking features of gluteofemoral adipose tissue remain obscure,
but could be related to differential regulation of upper- and lower-body
fat in terms of lipolysis, fatty acid uptake and inflammation.
Bluntly phrased, upper/visceral fat may be more easily
evoked by excess fat storage to put out a large flow of metabolic
disruptors such as fatty acids per se, inflammatory cytokines, chemoattractants,
eicosanoids and fat-derived hormones, whereas the
lower body fat may act as a ‘‘fat cushion’’, absorbing fat and fatderived
disruptors with only a limited negative metabolic
response. Poorer RAAS expression in the gluteofemoral could be
one component of such more metabolically quiescent fat, although
this remains entirely conjectural at the present time.
Studies suggest that ectopic fat is metabolically active and
exerts both positive and negative effects on intimately neighboring
organ (Cassis et al., 2008; Szasz and Webb 2012). For example, periaortic
adipose tissue was shown to increase vascular smooth muscle
contractile responses to some perturbations, such as electrical
stimulation (Lu et al., 2010; Soltis and Cassis 1991). Conversely,
in transgenic mice that lacked periaortic adipose tissue, blood
pressure was elevated (Lee et al., 2009; Takemori et al., 2007).
Accumulation of lipids occurs also in the skeletal muscle tissue
and interferes with insulin action and results in insulin resistance
(Pan et al., 1997). The contribution of RAAS to this process was
exemplified in experiments demonstrating that intramuscular lipid
content in fructose fed rats was reduced by RAAS blockade with
either AT1R blocker or ACE inhibitor (Furuhashi et al., 2004).
3. Regulation of fat RAAS
Nutrition and aging are key factors that regulate adipose local
RAAS. Human and animal models demonstrated that systemic
RAAS activity positively correlated with body weight and more
specifically with body fat, and that weight loss associated with
decreased RAAS activity both systemically and locally in WAT
(Boustany et al., 2004; Engeli et al., 2005; Rahmouni et al.,
2004; Tuck et al., 1981). ACE2 is also nutritionally regulated.
For example it was shown that high-fat diet induced increased
ACE2 expression and activity (Gupte et al., 2008). Signaling molecules
implicated in the regulation of AGT expression in the liver
and other tissues have been assessed for their potential role in
adipocytes include glucocorticoids, androgens, cAMP, Ang II and
insulin (Aubert et al., 1997, 1998; McGehee et al., 1993; Serazin-Leroy
et al., 2000).
3.1. Nutrition
Overnutrition regulates the development of abdominal adipose
tissue and RAAS components, regardless of the phase in life in
which excessive feeding occurs. Specifically, the in vivo expression
of AGT in adipose tissue was reduced by fasting and markedly increased
by re-feeding (Frederich et al., 1992; Yasue et al., 2010).
Feeding-related changes in the adipocyte expression of AGT were
shown to be accompanied by parallel changes in blood pressure
(Boustany et al., 2004; Frederich et al., 1992) and were most notably
independent of plasma and hepatic AGT levels, which did not
change (Frederich et al., 1992). Increased local formation of Ang
II in adipose tissue has been originally observed in genetically or
diet-induced obese rodents and in obese humans (Frederich
et al., 1992; Hainault et al., 2002; van Harmelen et al., 2000).
Post-natal overnutrition plays a role the development of visceral
adipose tissue and apparently in the subsequent evolution of metabolic
dysregulation in adulthood. In rats, both post-natal overfeeding
and high-fat diet were shown to induce increased immunoreactivity
for (pro)renin receptor in fat tissue stromal cells
(Achard et al., 2011).
In adults, biopsies taken from healthy men at the beginning and
after 2 weeks and 2 months of over-feeding showed that the early
adaptive response to weight gain associated with enhanced
expression of a number of RAAS components, including proteases
that specifically produce angiotensin-related peptides, such as
ACE, membrane metallo-endopeptidase (MME), mast cell protease
(CMA1), cathepsin G (CTSG) and glutamyl aminopeptidase (ENPEP).
This coordinated regulation strongly suggests an increase of
angiotensin activity in human adipose tissue during weight gain
(Alligier et al., 2012). In contrast, weight loss or fasting leads to a
decrease in fat and plasma AGT (de Kloet et al., 2010; Yasue
et al., 2010).
Not only the amount but also the type of nutrition (e.g., high fat,
carbohydrates or high salt) affects RAAS. Activation of RAAS occurred
in response to 10–11 weeks of high-fat diet in rodents, with
a marked increase in plasma concentration of Ang II (Benson et al.,
2004; Boustany et al., 2004). Decreased ability to accumulate body
fat was seen in RAAS deficient animals such as the AGT-deficient
(AgtÀ/À
) mice (Massiera et al., 2001a), renin Ren2c (À/À
) mice
(Takahashi et al., 2007), AT1R- and AT2R-deficient mice (Kouyama
et al., 2005; Yvan-Charvet et al., 2005) or in animals receiving AT1R
4 Y. Marcus et al. / Molecular and Cellular Endocrinology 378 (2013) 1–14
blockers (Araki et al., 2006). The ACE inhibitor captopril reduced
the synthesis of adipose Ang II and also decreased leptin synthesis
and release (Cassis et al., 2004). In the same vein, the renin inhibitor
aliskiren reduced adipose levels of Ang I and Ang II, mainly in
lumbar adipose tissue, and limited the gain in fat mass in young
mice. Interestingly, the effects of aliskiren were independent of
the type of nutrition (regular or high fat) suggesting that aliskiren
might also induce changes in adipose tissue of lean subjects
(Stucchi et al., 2009). Finally, in view of the role of RAAS in electrolyte
and volume homeostasis, the effects of high salt diet on this
system were studied in tissue interstitial fluid and biopsies from
subcutaneous abdominal adipose tissue from young men (Engeli
et al., 2006). The results clearly showed that adipose-tissue RAAS
is not part of a feedback mechanism regulating sodium homeostasis
and blood pressure (Engeli et al., 2006).
3.2. Insulin
Insulin is an important, well established stimulator of liver AGT,
but conflicting reports have been published regarding its effect on
fat AGT. Although streptozotocin-induced insulin deficiency in rats
was linked to a fall of adipose tissue AGT expression, which was restored
by insulin treatment, these effects were difficult to discern
from the general impact of experimental diabetes (Cassis 1992).
Insulin supplementation was reported not to affect the secretion
of AGT from primary adipocytes extracted from Obese Zucker rats
(Turban et al., 2001) but increased AGT expression in human
abdominal subcutaneous adipocytes at the protein and mRNA levels
(Harte et al., 2003; Jones et al., 1997). Still in other reports, actual
insulin-dependent suppression of mRNA expression and the
secretion of AGT from Ob1771 and 3T3-F442A adipose cell lines
was seen (Aubert et al., 1998). It should be noted that the latter
study was done with cell-lines and may not be necessarily extrapolated
to the in vivo setting.
3.3. Ang II
Ang II is one of a series of known activators of hepatic AGT (e.g.,
estrogens, triiodothyronine, and glucose) which failed to affect fat
cell AGT (Aubert et al., 1997; Jones et al., 1997). It is noteworthy
however that the lack of Ang II effect could have been fortuitous
due to opposing concomitant effects on AT1R and AT2R. Indeed,
in mice with AT2 receptor deficiency, adipose AGT expression
clearly increased, and this effect was blocked by an AT1R antagonist
(Thatcher et al., 2009). Chronic infusion of Ang II robustly stimulated
AGT and AT1aR mRNA in adipose tissue (Lu et al., 2007), but
not in the liver. In Ang II-infused mice, plasma AGT concentrations
paralleled adipose AGT mRNA expression. These results are consistent
with a positive-feedback loop where Ang II regulates adipose
AGT via activation of the AT1aR.
3.4. Cyclic adenosine monophosphate (cAMP)
The role of cAMP in regulating ATG expression and secretion
is of interest since (1) levels of this molecule are increased in
adipocytes upon b–adrenergic stimulation; (2) cAMP is a positive
regulator of adipogenesis; and (3) there is a clear link between
fat body mass and elevated sympathetic stimulation. A study
with cultured primary rat differentiated preadipocytes showed
that agents known to increase intracellular cAMP (FSK, IBMX)
and the membrane-permeable cAMP analog 8–BrcAMP induce
an increase in the ATG mRNA level in differentiated rat preadipocytes
via the protein kinase A–dependent pathway. In rat adipose
tissue fragments, the same positive effect was observed not only
on ATG mRNA but also on ATG protein secretion (Serazin et al.,
2004).
3.5. Glucocorticosteroids
Based on experiments with dexamethasone–treated 3T3-L1
cells, it was suggested that glucocorticoids play an important role
in the expression of fat cell AGT gene (Saye et al., 1989). Further
experiments with rodent cell lines Ob1771 and 3T3-F442A as well
as explants of rat periepididymal adipose tissue showed that glucocorticoids
regulate AGT gene transcription in late differentiated
adipocytes, interacting with the glucocorticoid receptor (GR)
(Aubert et al., 1997). Mice that were genetically modified to overexpress
adipose tissue 11b hydroxysteroid dehydrogenase type
1(11b HSD-1), the enzyme which converts inactive cortisone to active
cortisol, developed abdominal obesity and had about threefold
increased expression of AGT gene in their adipose cells. The increase
in adipose levels of cortisol did not correlate with its plasma
levels which remained unchanged (Masuzaki et al., 2001). These
features of the transgenic mice are similar to those observed in humans
with metabolic syndrome (Rask et al., 2002). Based on these
results it has been suggested that increased fat tissue cortisol content
leads to excessive GR activation with the ensuing stimulation
of GR inducible genes, including AGT (Jain et al., 2005).
3.6. TNF-a
In cultured cryo-preserved human subcutaneous preadipocytes,
derived from human adipose tissue of female subjects, treatment
with human recombinant TNF-a (5 or 100 ng/ml) resulted in a significant
reduction in AGT mRNA levels (Wang et al., 2005). However
TNF-a increased renin protein secretion in cultured 3T3
cells (Fowler et al., 2009a).
3.7. Androgens and estrogens
Both adipocyte metabolism and blood pressure development
are, to some extent, gender-related and potential sex-dependent
differential activation of Ang II is therefore of much interest (Chen
et al., 1992). That adipocyte AGT expression and secretion driven
by androgens is suggested by the finding that ATG expression decreased
after castration but was fully restored in response to testosterone
treatment. Moreover, an androgen receptor antagonist
prevented the positive in vitro influence of androgens on ATG
mRNA expression in adipocytes (Serazin-Leroy et al., 2000). In contrast,
estradiol had no effect on AGT mRNA in the preadipocyte
clonal cell line Ob1771 (Aubert et al., 1997).
3.8. Free Fatty Acids (FFAs)
Elevated FFA were shown to enhance Ang II production in
mononuclear and polymorphonuclear cells and to cause Ang IIdependent
leukocyte activation, a process that results in endothelial
dysfunction partially via oxidative stress (Azekoshi et al., 2010).
Interference of the FFA-rich environment in fat tissue with local
vasodilator mechanisms could augment the vasconstrictor response
to Ang II, thus reducing blood supply to fat cells. There is
also evidence that in committed preadipocytes the AGT gene can
be upregulated by long chain fatty acids and downregulated in response
to fatty acid removal (Safonova et al., 1997), this provides a
potential link between the fatty acid rich milieu in adipose tissue
and the ability of adipocytes to produce AGT. In contrast, fatty
acids were not found to affect renin gene expression or protein
secretion in 3T3-L1 adipocytes (Fowler et al., 2009a).
3.9. Fat RAAS in aging
RAAS is regarded a positive regulator of hypertrophic enlargement
of adipose tissue, in good accordance with the fact that and
Y. Marcus et al. / Molecular and Cellular Endocrinology 378 (2013) 1–14 5
body fat increases with age. However, in a presumable contraintuitive
manner plasma levels of systemic RAAS components seem to
decrease with age (Abadir 2011). In one study with rats, by the age
of 24 weeks, AGT expression became significantly greater in epididymal
(a rodent equivalent of visceral) fat than in subcutaneous
adipose tissue (Adams et al., 2002). In a study that compared 9–
26 week-old rats in terms of AGT, ACE and AT1R mRNA expression
in epididymal adipose tissue, AGT and ACE expression decreased
with increased age and adiposity (Krskova et al., 2011). These RAAS
parameters correlated with the expression of the adiposity-dependent
proteins leptin, adiponectin, the insulin-dependent glucose
transporter (GLUT4) and PPARc. AT1R mRNA and protein expression,
however, was significantly elevated in 26-week-old rats but
this was not reflected in changes in Ang II binding. It is noteworthy
that inhibition of Ang II activity by targeted disruption of the
Agtr1a gene (encoding AT1AR) in mice translates into marked prolongation
of life span. The absence of AT1AR protected multiple organs
from oxidative damage and the alleviation of aging-like
phenotype associated with increased number of mitochondria
and upregulation of the pro-survival gene sirtuin 3 (Cassis et al.,
2010). Interaction between age and the evolution of obesity with
respect to fat Ang II is also suggested by the observation that
Ang II -induced facilitation of sympathetic neurotransmission in
brown fat is decreased in adult obese rats relative to young lean
rats (Cassis 1994).
4. Effect of fat tissue RAAS on systemic/circulating RAAS
4.1. Fat AGT contributes to circulating and non-fat tissue AGT
There is evidence that adipocyte-endogenous AGT contributes
to the systemic RAAS and to blood pressure control (Yiannikouris
et al., 2012). Selective adipocyte AGT deficiency lowered plasma
concentrations of AGT by 24–28%, compared with controls; this
was in association with reduced systolic blood pressure. Mice
whose AGT expression is restricted to adipose tissue have increased
AGT circulating in the blood stream whereas mice that
overexpress adipose AGT do not only have increased circulating
AGT levels but are also hypertensive, attesting to the functional
importance of the spillover of fat AGT to the systemic circulation
(Massiera et al., 2001a). In one report with hypertensive mice,
the adipocyte-specific AGT overexpression was linked to a parallel
increase in kidney AGT expression (Kim et al., 2006), thus suggesting
that fat cell RAAS contributes to RAAS beyond the local adipocyte
environment.
4.2. Fat-tissue derived Ang II may be released to the circulation under
increased sympathetic drive
In obese, but not in lean, human subjects AGT was shown to be
released from adipose tissue and skeletal muscle during b–adrenergic
stimulation, which likely contributes a concomitant increase
in plasma Ang II concentrations under these conditions. Thus,
increased sympathetic system activity in obese subjects can contribute
to the release of RAAS components from the excessive fat
tissue to the circulation, thereby supporting a systemic rise in
blood pressure (Goossens et al., 2006, 2007b).
5. RAAS, Ang II and fat tissue metabolism
5.1. Rate of TG storage and blood flow
The uptake of meal fatty acids depends on the expression of adipocyte
lipoprotein lipase (LPL). LPL mRNA expression is higher in
abdominal than in gluteal adipose cells. LPL activity is also higher
in abdominal adipocytes from men and in gluteal adipocytes from
women when compared with the other depots respectively (Arner
et al., 1991; Pouliot et al., 1991). Ang II causes vasoconstriction and
catecholamine secretion, which can jointly decrease blood flow
(Matsubara 1998; Moan et al., 1996). Chronic exposure to the
non-specific b-adrenergic agonist isoproterenol leads to tissue specific
alterations in LPL activity (Deshaies et al., 1993; Saranteas
et al., 2003). Ang II was shown to suppress adipocyte LPL expression
(Saiki et al., 2008), whereas AR1R antagonism can increase
fat cell LPL (Saiki et al., 2006).
5.2. Lipolysis
Lipolysis involves the hydrolysis of triglycerides (TG) into FFAs
followed by degradation to acetyl units via beta oxidation. Adipocytes
from upper-body obese women are less responsive to the
insulin induced inhibition of lipolysis compared with lower-body
obese women (Dowling et al., 1995; Hosain et al., 2010). Moreover,
higher expression of b-adrenoceptors in the abdominal adipocytes
results in a four- to fivefold increase in lipolysis of abdominal compared
to gluteal adipocytes in response to noradrenaline stimulation
(Arner et al., 1990; Wahrenberg et al., 1989). Most published
reports are consistent with a predominantly antilipolytic effect of
Ang II, with the exception of one report that Ang II has an AT1Rdependent
lipolytic effect (Ahima and Flier 2000). The rate of lipolysis
is determined predominantly by insulin and b-adrenoceptors,
both of which are negatively regulated by RAAS over-activation in
an Ang II-dependent manner (Boschmann et al., 2001; Kalupahana
et al., 2012). Accordingly, lipolysis was dose-dependently and
strongly inhibited by physiological Ang II concentrations in human
subcutaneous adipocytes of normal-weight and obese subjects,
suggesting a tonic suppression of lipolysis in vivo (Goossens
et al., 2007a). Femoral fat depots seem to be more sensitive to
the inhibitory effect of Ang II on lipolysis (Boschmann et al., 2001).
Ang II dose-dependently reduced the perfusion to-, and inhibited
basal, but not isoproterenol-stimulated lipolysis in- gluteofemoral
adipose tissue (Boschmann et al., 2001). Excess secretion
of Ang II in obesity can reduce adipose-tissue blood flow, directly
and possibly via stimulation of a2-adrenoceptors (English and Cassis
1999). This may impact fat by promoting FFA accumulation,
which along with inhibition of lipolysis shifts the balance towards
re-esterification (Lonnroth and Smith 1992) and also by reducing
oxygen delivery, favoring fat tissue hypoxia. Ang II can also enhance
lipogenesis by directly increasing the activity and expression
of key lipogenic enzymes, leading to increased TG synthesis and
storage, ultimately resulting in ‘‘fatter’’ and hence larger fat cells.
Finally, Ang II can interfere with lipid metabolism as evidenced
by its ability to reduce high density lipoprotein (HDL) and increase
cholesterol storage in association with the translocation of scavenger
receptor type B1 (SR-B1) proteins to the plasma membrane in
adipose tissue. This was also documented in transgenic mice overexpressing
AGT in their adipose tissue (Tondu et al., 2005;
Yvan-Charvet et al., 2007).
6. Adipose RAAS, Ang II and preadipocyte differentiation
Adipose mass can increase via adipocyte hypertrophy and
through enhanced adipocyte proliferation and differentiation.
Ang II was reported to either inhibit or accelerate preadipocyte
differentiation in vitro, apparently reflecting variation in the
experimental setting. Most published data, however, support the
notion that Ang II inhibits preadipocyte differentiation (Brucher
et al., 2007; Darimont et al., 1994; Fuentes et al., 2010; Janke
et al., 2002; Sarzani et al., 2008a; Tomono et al., 2008). The observation
that visceral fat preadipocytes are more sensitive to the
6 Y. Marcus et al. / Molecular and Cellular Endocrinology 378 (2013) 1–14
AT1R-dependent inhibition of differentiation and that this effect is
directly related to BMI in obese subjects is particularly significant
for the development of dysfunctional visceral fat (Brucher et al.,
2007). Concordant with this notion is the finding that AT1R antagonism
appears to accelerate adipocyte differentiation (reviewed in
Iwai and Horiuchi 2009). Adipocyte differentiation is inversely correlated
with insulin sensitivity, and RAAS blockade may delay the
onset of T2D by promoting the differentiation of adipocytes into
mature adipocytes (Sharma et al., 2002). This allows proper eutopic
storage sites for fat derived from overnutrition and minimizes
the deposition of toxic ectopic fat in non-adipose tissues such as
skeletal muscle, liver, heart and even the pancreatic islets. The latter
effect might also protect b-cells from being functionally and
structurally disabled by adjacent ectopic fat cells.
Not only can circulating or exogenous RAAS components (e.g.,
Ang II in cultured preadipocyte) affect adipose tissue differentiation
but the expression level of endogenous fat RAAS per se appears
to depend on the differentiation process and/or phase, thus indirectly
suggesting that it very likely plays a role in the progression
of differentiation. In one report, renin mRNA expression and protein
enzymatic activity were un-detectable in preadipocytes, but
became rather evident upon differentiation (Fowler et al., 2009a).
TNF-a, a naturally occurring product in adipose tissue, which is
apparently upregulated in dysfunctional adipocytes (reviewed in
Stern et al., 2007), markedly increased renin protein secretion in
cultured 3T3 cells (Fowler et al., 2009a). In human preadipocytes,
the differentiation process involves auto-generation of Ang II
through both the renin system and non RAAS pathways, and the
latter may be a more important contributor. In parallel, AT1R and
AT2R gene expression increases transiently during early differentiation
and then rapidly declines (Ye et al., 2009). Further, AT2R deficiency
reportedly retards fat cell differentiation (Iwai et al., 2009).
It has been reported that overexpression of AGT in mice leads to
a slight but significant decrease in adipose cell number, thus
revealing an inhibitory effect of Ang II on preadipocyte differentiation
in vivo (Yvan-Charvet et al., 2009). On the other hand, despite
the reduced adipose cell number, local production of AGT in adipose
tissue clearly promotes fat mass enlargement. Moreover,
Ang II was found to increase differentiation of human preadipocytes
isolated from both visceral and perirenal adipose tissue
(Sarzani et al., 2008a). The latter view is supported by the study
of Crandall et al. who showed that Ang II is able to induce cell cycle
G1 phase progression of human preadipocytes through AT1Rs by
increasing cyclin D1-dependent kinase (Crandall et al., 1999). Probably
Ang II, acting through the AT1 receptors, has a proliferative effect
on preadipocytes coupled with a differentiating activity that
results in an increased number of smaller, healthier, adipocytes
(Sarzani et al., 2008b). Since this is discordant with other reports
(Brucher et al., 2007; Darimont et al., 1994; Janke et al., 2002;
Sarzani et al., 2008a; Tomono et al., 2008), such effects could be depot-specific
or relate to time/site dependent differential expression
of AT1R/AT2R expression.
7. RAAS, Ang II and adipocyte volume and hypertrophy: Ang II
and fat mass
RAAS integrity is important for the development of fat tissue and
also for the ability of adipose tissue to properly expand in response
to caloric excess. Experimental maneuvers which either block or
accentuate RAAS are generally in line with this concept. Negative
regulation of Ang II production appears to diminish fat tissue accumulation.
For example, mice lacking AGT were protected from highfat-diet
induced obesity and featured adipose tissue hypotrophy
(Massiera et al., 2001b). Fat mass expansion was also not seen in
mice lacking the renin gene and fed on high fat diet (Takahashi
et al., 2007). Similarly, the absence of ACE expression in mice prevented
diet-induced obesity (Jayasooriya et al., 2008). At least a permissive
role for adipose tissue expansion in response to dietary
challenge was also shown for both AT1R and AT2R as mice lacking
either of these receptors were resistant to obesity-induced by high
fat intake (Kouyama et al., 2005; Yvan-Charvet et al., 2005). Obviously,
while these findings underscore the role of RAAS in fat expansion,
systemic negative manipulations of RAAS components neither
exclusively nor directly implicates local fat tissue RAAS in this process.
More specific fat RAAS targeting was achieved in transgenic
mice overexpressing adipose tissue AGT, which resulted in higher
fat mass than wild-type mice (Massiera et al., 2001a). Apparent
excessive/anomalous/imbalanced activation of AT1R through
immunization of pregnant rats against the second extracellular loop
of the AT1R resulted in increased visceral adipose tissue, increased
fatty liver, increased TGs, decreased HDL cholesterol, and decreased
adiponectin levels in the first generation offspring. This highlighted
the role of normal AT1R function for balanced adipose disuse evolution
and distribution (Zhang et al., 2012). These data provide some
direct evidence for the role of adipose AGT in adipose tissue growth
(Massiera et al., 2001a). Finally, mice lacking the Mas receptor
exhibited increased abdominal fat mass associated with higher
adipose tissue AGT expression (Santos et al., 2008).
An important extension to the role of RAAS in fat mass expansion
is the understanding that it could play a role in the deposition
of ectopic fat as well (Sui et al., 2010). Redistribution of fat, renal
fat deposition and hyperlipidemia can accompany chronic renal
failure (CRF). While uni-nephrectomized rats showed increased renal
adipogenesis with AGT and Ang I/II in renal tubular cells and
adipocytes, treatment with ACE inhibitor restored normolipidemia
and normalized renal adipogenesis and lipid deposition. Thus, not
only eutopic, but also ectopic fat deposition apparently requires intact
local RAAS function.
8. Central involvement of RAAS in adipose tissue homeostasis
Complex interactions link central RAAS with adipose tissue
RAAS. Chronic intracerebroventicular (icv) Ang II infusion reduced
body and adipose tissue mass (de Kloet et al., 2011). This could mimic
a putative effect of centrally generated Ang II response to central
or peripheral cues. Additionally, this effect could serve a
negative feedback through which Ang II spillover from excessive
adipose tissue to the circulation becomes sufficiently high to access
the brain, thus potentially counteracting the peripheral fat building
effect of adipose-derived Ang II. Centrally mediated Ang II-dependent
reduction in energy storage is consequent to both a decrease
in food intake and an increase in energy expenditure. Moreover,
with centrally administered Ang II, indices of sympathetic activation
are elevated in both brown and white adipose tissues (BAT
and WAT). This implies that Ang II acts centrally to enhance BAT
thermogenesis and WAT lipolysis, presumably contributing to the
state of negative energy balance. Moreover, central Ang II administration
increased hypothalamic expression of corticotropin-releasing
hormone (CRH) and thyrotropin-releasing hormone (TRH),
both of which can elicit anorixogenic effects (de Kloet et al.,
2011). On the other hand, AGT- and AT2-deficient mice show increased
energy expenditure, apparently resulting from increased
locomotor activity and whole-body lipid oxidation (Massiera
et al., 2001b; Yvan-Charvet et al., 2005). These findings could be related
in part to the regulatory effect of Ang II on adiponectin secretion,
which controls muscle fatty acid oxidative capacity (Clasen
et al., 2005; Furuhashi et al., 2003). Taken together, these studies
suggest that reduced Ang II signaling might provide some protection
from fat mass enlargement in mice by increasing peripheral
energy expenditure and whole-body lipid oxidation.
Y. Marcus et al. / Molecular and Cellular Endocrinology 378 (2013) 1–14 7
9. Adipocyte dysfunction and systemic RAAS
Adipocytes are not a merely energy reservoirs but rather a major
endocrine tissue that synthesizes and secretes adipokines such
as proinflammatory cytokines, acute-phase response proteins, chemotactic/chemoattractants,
eicosanoids, prostaglandins; as well as
potential anti-inflammatory effectors such as adiponectin and IL-
10 (Bays et al., 2007). ‘‘Dysfunctional adipocytes’’ or ‘‘angry fat’’
is a relatively loose term used to describe fat cells which, due caloric
excess, accumulate excessive fat and undergo marked increase
in size. Dysfunctional/mutated proteins/enzymes or incitement by
surrounding factors such as M1 macrophages, not only produce increased
amounts of adipokines, but sustain unregulated excessive
lipolysis leading to an increase in circulating FFAs. Insulin resistance
and/or insufficiency jointly with increased sympathetic
activity, which is associated with obesity, further accelerate lipolysis.
The ensuing rise in circulating FFA levels leads to the ectopic
deposition of fat which in organs such as the liver, skeletal muscle,
and heart further aggravates insulin resistance and induces mitochondrial
dysfunction and tissue injury. Such injury to pancreatic
b-cells can result in reduction in the ability to secrete insulin and
eventually induce b-cell apoptosis. This vicious cycle accentuates
insulin resistance and can lead to T2D. Improvement of adipocyte
function and/or replacement of poorly functioning adipocytes by
younger, fully functional, recently differentiated and yet unimpaired
fat cells could retard unwanted metabolic sequels of the
‘‘angry fat’’ or ‘‘adiposities’’. Preadipocytes are fibroblast-like cells
comprising a sizable fraction of the cell population in fat tissue
(e.g., 15–50% according to one report), which, in response to appropriate
cues, differentiate into adipocytes. Differentiation is initiated
through signaling pathways activated by fatty acids, IGF-1,
glucocorticoids, and other stimuli and is followed by a cascade of
transcription factors that underlies acquisition and maintenance
of the fat cell phenotype (Rosen 2005). Normal fat cell turnover, involves
differentiation of preadipocytes into adipocytes and apoptosis
of large, old adipocytes (Boney et al., 2001).
Circulatory RAAS component levels are clearly affected by adipose
tissue mass. Visceral obesity is associated with inappropriate
or even elevated levels of plasma renin activity and/or aldosterone
despite increased sodium intake, sodium/water retention, central
blood volume, and blood pressure (Goodfriend et al., 1999). Additionally,
compared to lean women, obese women have higher circulating
AGT, renin, aldosterone, ACE and lower AGT gene
expression in adipose tissue but higher fat-derived secreted AGT
(Yasue et al., 2010). Such non-suppressed activity of RAAS could
play a key role in hypertension and subsequent cardiovascular
complications in obese subjects. Weight reduction (approximately
5%), on the other hand, reduced AGT, renin and aldosterone levels
and decreased ACE expression (Engeli et al., 2005).
10. Ang II and adipose tissue inflammation
Obesity is often associated with low-grade inflammation, predominantly
of the adipose tissue itself. As fat mass expands to
other sites, this inflammation is also seen at ectopic fat depots,
e.g., the perivascular tissue, muscle, liver and the pancreas as well
as fat-free sites, such as the hypothalamus. Inflammation may, in
fact, have a significant role in the onset of obesity (Hotamisligil
2006). Ang II can promote inflammation through the stimulation
of chemokine secretion and the induction of increased oxidative
stress (Daugherty et al., 2000; Harrison et al., 2003). For example,
in preadipocytes extracted from rat adipose tissue Ang II increased
mRNA and protein of monocyte chemoattractant protein-1 (MCP-
1). Similarly, Ang II infusion to rats increased mRNA expression
of MCP-1 in adipose tissue (Tsuchiya et al., 2006). Conversely,
blockade of AT1 receptors in mice fed with diet-induced obesity
and genetically obese mice reduced the reactive oxygen species
(ROS) originating from adipose tissue (Kurata et al., 2006).
Ang II can also recruit macrophages to fat tissue, thus further
enhancing local inflammation. Indeed, infusion of Ang II to obese
mice increased macrophage infiltration into periaortic and visceral
adipose tissue. Infiltration of periaortic fat was further associated
with increased tendency to develop abdominal aortic aneurysms
(Police et al., 2009). Diet induced obesity per se reportedly not only
increases the population of macrophages in the adipose tissue, but
leads to ‘‘macrophage polarization’’, i.e., a phenotypic switch in
adipose tissue macrophages from an anti-inflammatory M2 state
to a proinflammatory M1 state (see Fig. 1). A role for endogenous
fat tissue Ang II in this process is suggested by the observation that
the AT1R blocker telmisartan reduced the mRNA expression of
CD11c and TNF-a, M1 macrophage markers, and significantly increased
the expressions of M2 markers, such as CD163, CD209,
and macrophage galactose N-acetyl-galactosamine specific lectin
(Mgl2) in adipose tissue of high-fat fed mice (Fujisaka et al.,
2011). This concept has been further refined by a very recent report
indicating that whereas AT1aR knockout mice subjected to high fat
diet can still develop a proinflammatory visceral and renal macrophage
population, further treatment with an AT1R blocker, which
affects both AT1aR and AT1bR, abolished renal macrophage infiltration
with inhibition of renal M1 and upregulation of M2 macrophage
markers in obese wild type mice. Thus, endogenous Ang II
may modulate fat tissue macrophage polarization through subtle
differential interaction with the AT1aR and AT1bR subtypes (Ma
et al., 2011). Mast cells can also infiltrate fat tissue and are more
densely found in fat depots of obese subjects (Tanaka et al.,
2011). Since mast cells contain both renin and chymase, a family
of serine proteases that convert Ang I to Ang II (Zheng et al.,
2012), their presence in adipocytes can provide an additional
source for angiotensin peptides, including Ang II. Collectively, fat
infiltration by inflammation-related cells may contribute to the increased
systemic inflammation which apparently contributes to
the development of insulin resistance and eventually T2D.
Ang II was shown to inhibit the secretion of adiponectin, an adipocyte
specific peptide hormone that exerts anti-inflammatory
and insulin sensitizing effects (Kadowaki et al., 2006). Concordantly,
adiponectin secretion is enhanced by RAAS inhibition in
human subjects (Furuhashi et al., 2003). In obese mice the ARB
olmesartan ameliorated dysregulation of adipocytokines and lowered
TNF-a, plasminogen activator inhibitor-1 (PAI-1), MCP1, and
serum amyloid A3 (Kurata et al., 2006).
A critical facet of adipose tissue inflammation is the increased
oxidative stress, typical of dysfunctional fat. In addition to the oxidative
effect exerted by inflammatory cells and cytokines, fatty
acids per se that are continuously released in the adipose milieu
due to lipolysis, especially under insulin resistance/insufficiency,
are potent instigators of oxidative stress, acting through activation
of NADPH oxidase (Furukawa et al., 2004). Pro-lipolytic mechanisms,
then, indirectly enhance adipose tissue oxidative stress.
Ang II increases oxidative stress via AT1R activation which leads
to increased generation of ROS, partly through activation of NADPH
oxidase. Released ROS can oxidize lipids, protein, and DNA which
collectively leads to cellular injury. ROS can also induce and/or perpetuate
inflammation via activation of transcription factors such as
TNF-a, MCP-1, IL-6 (reviewed in Cooper et al., 2007), thereby fostering
insulin resistance, which at the fat cell level, is conducive
of further lipolysis and release FFAs. In inhibiting pre-adipocyte
differentiation, Ang II also indirectly induces shifting of fat formed
due to caloric excess from storage in newly formed small adipocytes
to large adipocytes, whose further enlargement elicits
increases cell oxidative stress and mitochondrial dysfunction
(Stern et al., 2007). It is only expected, then, that in mice with
8 Y. Marcus et al. / Molecular and Cellular Endocrinology 378 (2013) 1–14
diet-induced or genetic obesity AT1R blockade reduces adipose tissue
ROS formation (Kurata et al., 2006). In several systems, Ang II
induced insulin resistance, which is attributed, in part, to increased
oxidative stress, possibly through impaired insulin signaling located
downstream to PI3-kinase activation, inhibition of GLUT-4
or alternative pathways (Ogihara et al., 2002; Townsend 2003).
AT2R may also affect glucose homeostasis in adipocytes: whereas
AT1R blocker increases insulin-induced glucose uptake in both
white and brown adipose tissue, uptake is impaired in white adipocytes
of transgenic AT2R-null mice, thus suggesting that AT1R
and AT2R activation is mutually antagonistic in terms of glucose
uptake in fat tissue (Shiuchi et al., 2004). Recent large-scale clinical
trials showed that RAAS blockade with either ACE inhibitors or
ARBs consistently prevented new-onset T2D, probably reflecting
improved insulin sensitivity (Jandeleit-Dahm et al., 2005). These
data are consistent with this experimental background in fat cells,
particularly since ARBs favorably modulate fat cell size and inflammatory
gene expression (Munoz et al., 2009).
11. Fat RAAS, fibrosis and hypoxia/hyperoxia
11.1. Fibrosis
Adipocytes are embedded in an extracellular matrix which
functions as a skeleton of mechanical support, but has in addition,
important emerging role in fat tissue expansion, function, susceptibility
to inflammation and response to attempted weight loss.
Collagen 6 appears to be a dominant player in the fibrous element
of fat (Khan et al., 2009). Extracellular matrix remodeling is likely
an important process during weight gain, as collagen 6 a3-subunit
(COL6A3) is increased in visceral fat of obese subjects and increased
during overfeeding, suggesting that it is important in adipose
tissue expansion (Khan et al., 2009; Pasarica et al., 2009a).
Further, recent evidence indicates that subcutaneous fat from obese
children displays significant increase of interstitial fibrosis
(Sbarbati et al., 2006). This was further confirmed in adult obese
subjects, in whom the fibrotic matrix was localized to the periadipcyte
milieu (Henegar et al., 2008). Rather significantly,
3 months following bariatric surgery fat tissue fibrosis did not regress
along with fat mass shrinkage. Furthermore, overfeeding results
in concomitant increase in microvascular density and
intercellular matrix and perivascular connective sheaths in human
subcutaneous fat, noted even prior to changes in adipocyte size
(Tam et al., 2011). In rodents, the absence of collagen 6 results in
the uninhibited expansion of individual adipocytes and was paradoxically
associated with substantial improvements in whole-body
energy homeostasis (Khan et al., 2009). Hence, it is possible that
subtle phenotypic alterations of human pre-adipocytes, adipocytes
and other cell types residing in fat tissue of obese subjects lead to
excessive synthesis of ECM components, such as collagen 6, which
can later persist. It is likely that RAAS plays a role in this process,
given the pro-fibrotic effects of Ang II as well as aldosterone in
other tissues and the stimulation of fat RAAS with overfeeding.
Adipose tissue fibrosis may also result from hypoxia (see below).
11.2. Hypoxia and fibrosis
Adipose tissue oxygen content/tension is regulated by adipose
tissue blood flow and the rate of fat cell oxygen consumption. Adipose
tissue hypoxia may evolve secondary to insufficient rise in
blood supply when fat cell mass increases rapidly or during excessive
local arterial vasoconstriction which limits oxygen supply to
fat cells, such as potentially inducible by excess locally produced
Ang II in fat tissue. In rodents, adipose tissue hypoxia was reported
in both genetic (ob/ob) and diet-induced obese mouse models
(Rausch et al., 2008; Ye et al., 2007). However, studies with human
adipose tissue showed either decreased or increased oxygen tension
(Goossens et al., 2011; Hosogai et al., 2007; Pasarica et al.,
2009b). Reduced oxygen utilization for fat oxidation in adipocytes
Fig. 1. The role of Ang II in macrophage polarization and adipocyte dysfunction. Ang II, a major product of the RAAS, retards preadipocyte differentiation, thereby affording
the channeling of caloric excess to storage in existing adipocytes. Large adipocytes form and tend to become dysfunctional, exhibit increased lipolytic activity, secrete proinflammatory
adipokines and attract inflammatory cells. Ang II also plays a role in ‘‘macrophage polarization’’ by inducing an increase in the mRNA expression of CD11c and
TNF-a, M1 macrophage markers in adipose tissue, and inhibits the secretion of adiponectin, an anti-inflammatory adipocyte specific peptide hormone.
Y. Marcus et al. / Molecular and Cellular Endocrinology 378 (2013) 1–14 9
of some obese subjects apparently underlies the finding of hyperoxia,
rather than hypoxia, despite lesser capillarization of the adipose
tissue in obese subjects (Goossens et al., 2011). When hypoxia
does evolve in fat tissue of obese animals, however, it induces the
expression of hypoxia-inducible factor 1a (HIF1a), which in turn,
elicits fibrosis, inflammation and insulin resistance, rather than
the expected vascularization (He et al., 2011). Although not specifically
shown in adipose tissue, Ang II can increase HIF1a in renal
tissue (Zhu et al., 2011), thereby providing yet another mechanism
by which RAAS activation may be linked to fat tissue fibrosis and
insulin resistance and dysfunction. As suggested by Hayden et al.
(2011), fat tissue fibrosis could result in loss of the normal cell–cell
and cell-matrix communication, which may in turn disrupt normal
paracrine control of adipogenic and metabolic functions and even
impede attempted weight loss in the obese.
12. Disruption of RAAS protects from obesity
Overall, experimental and clinical data support the concept that
disruption of the RAAS can protect from obesity and/or its sequels.
Mice lacking renin showed reduced production of renin-driven
peptides of the RAAS such as Ang II and were also protected from
obesity (Takahashi et al., 2007). Likewise, mice lacking AGT, AT2R
or AT1R were protected from high-fat-diet induced obesity and
featured adipose tissue hypotrophy (Massiera et al., 2001b; YvanCharvet
et al., 2005; Kouyama et al., 2005). Collectively these results
suggest a synergistic contribution of AT1 and AT2 in mediating
the in vivo effect of Ang II on adipose tissue development. The
notion of systemic trophic/permissive effect of Ang II on adipose
tissue development was further supported by the finding that
ACE KO-mice had less body fat, particularly abdominal fat, than
wild type controls. The mechanisms implicated in protection from
obesity in this model also involved increased energy expenditure
and enhanced lipolysis in adipose depots (Jayasooriya et al.,
2008). Finally, RAAS blockade via ACEI, ARBS or a renin inhibitor
prevented fat mass enlargement (de Kloet et al., 2009; Lee et al.,
2008; Mathai et al., 2008; Stucchi et al., 2009). In humans, RAAS
inhibition through ACEI or ARBs is known to reduce the incidence
of T2D (Tocci et al., 2011). Complementary to these data is the evidence
that one of the countering arms of Ang II driven effects, that
of the Ang1–7/Mas receptor system, acts in the opposite direction:
mice lacking the Mas receptor exhibited increased abdominal fat
mass associated with higher adipose tissue AGT expression, thereby
suggesting a tight regulation of Ang II production by Ang (1–7)
in adipose tissue (Santos et al., 2008).
13. Fat RAAS and insulin resistance: an integrated overview
Fat tissue RAAS induces and aggravates insulin resistance
through both local and systemic mechanisms. As schematically
shown in Fig. 1, local the expression of the key components of
RAAS in adipose tissue increases along with fat cell differentiation
(Fowler et al., 2009a). In fact, fat mass enlargement in response to
caloric excess requires the presence of the full cascade of fat RAAS.
Yet, Ang II, a major product of this system, retards differentiation,
thereby affording the channeling of caloric excess to storage in
existing adipocytes. Large, ‘‘fatter’’ adipocytes thus form and tend
to become dysfunctional to exhibit increased lipolytic activity, secrete
pro-inflammatory adipokines and to attract inflammatory
cells such as M1 macrophages to adipose tissue. A state of ‘‘adiposities’’
evolves, leading to the increased release FFA, adipokines such
as resistin, cytokines such as IL6 and TNF-a, and chemoattractants
such as MCP-1. Local insulin resistance is jointly enhanced by compounds,
which translates into further enhancement of lipolysis.
The latter increases oxidative stress, such that adipocyte dysfunction
and insulin resistance are further augmented. As caloric excess
persists, active RAAS is required for fat mass enlargement and ectopic
fat deposition, both of which increase the resistance to insulin’s
actions. Locally produced Ang II can reduce blood supply to
adipose depots thereby enhancing local inflammation. Such reduction
in local perfusion will also reduce the clearance of released
FFA which not only stimulate ROS formation via induction of
NADPH oxidase activity, but are shifted back to esterification, a
process that increases local fat deposition and adipocyte cell size.
Spillage of fat tissue-derived angiotensinogen and Ang II in
obesity contributes to systemic effects of RAAS, as schematically
shown in Fig. 2. Ang II inhibits insulin-dependent glucose uptake
by multiple mechanisms including the induction of endothelial
dysfunction, which diminishes insulin-dependent glucose transport
to target cells (e.g., skeletal muscle cells) and disruption of
insulin cell signaling by increasing ROS formation and direct interference
with multiple insulin signaling elements in skeletal muscle,
such as inhibition of insulin-mediated GLUT4 translocation
through transient activation of ERK1/2 which inhibit IRS-1/2 and
a direct inhibitory nitration of Akt (Csibi et al., 2010). Ang II also increases
the secretion of aldosterone and this effect is synergistic
with adipose tissue-derived aldosterone stimulating factor (Krug
et al., 2007). Aldosterone is yet another enhancer of insulin resistance,
whose secretion is stimulated by fat derived compounds
including Ang II itself and adipocyte-derived aldosterone stimulating
factor(s). Aldosterone increases oxidative stress (Lastra et al.,
2008), which leads to insulin receptor substrate 1 degradation, reduced
downstream phosphorylation of Akt which translates into
diminished translocation of GLUT-4 translocation to the plasma
membrane, resulting in reduced glucose uptake. Recent evidence
also indicates that aldosterone increases oxidative stress in cultured
fat cells, acting through both MR and GR, thereby assisting
in the shift of adipose tissue into a dysfunctional state, which
aggravates local and systemic insulin resistance (Limor et al.,
2012).
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