State of the art paper

Biochemistry of adipose tissue: an endocrine organ

Marisa Coelho1,2, Teresa Oliveira2, Ruben Fernandes1,2

1
Ciencias Químicas e das Biomoléculas e Unidade de Mecanismos Moleculares da Doença
^
Corresponding author:
do Centro de Investigaça~ o em Saúde e Ambiente, Escola Superior de Tecnologia da Prof. Ruben Fernandes
Saúde do Porto, Instituto Politécnico do Porto, Portugal ESTSP
2
Centro de Farmacologia e Biopatologia Química (U38-FCT), Faculdade de Medicina da Rua Valente Perfeito 322
Universidade do Porto, Portugal 4400-330 Vila Nova de Gaia
Portugal
Submitted: 8 June 2012 Phone: + 351 222 061 004
Accepted: 4 July 2012 E-mail: [email protected]

Arch Med Sci 2013; 9, 2: 191-200

DOI: 10.5114/aoms.2013.33181
Copyright © 2013 Termedia & Banach

Abstract
Adipose tissue is no longer considered to be an inert tissue that stores fat. This
tissue is capable of expanding to accommodate increased lipids through hyper-
trophy of existing adipocytes and by initiating differentiation of pre-adipocytes.
Adipose tissue metabolism exerts an impact on whole-body metabolism. As an
endocrine organ, adipose tissue is responsible for the synthesis and secretion
of several hormones. These are active in a range of processes, such as control

inflammatory process mediators (tumor necrosis factor α (TNF-α), interleukin-6

of nutritional intake (leptin, angiotensin), control of sensitivity to insulin and

(IL-6), resistin, visfatin, adiponectin, among others) and pathways (plasminogen

activator inhibitor 1 (PAI-1) and acylation stimulating protein (ASP) for example).
This paper reviews some of the biochemical and metabolic aspects of adipose
tissue and its relationship to inflammatory disease and insulin resistance.

Key words: adipose tissue, adipocytes, adipokines.

Adipose tissue
Originally considered as simply a storage organ for triacylglycerol, inter-
est in the biology of adipose tissue has increased substantially. Over the
last decades there has been considerable accumulation of experimental
data about the biology and biochemistry of adipose tissue. This tissue is
no longer considered to be an inert tissue that just stores fat [1]. Adipose
tissue is a metabolically dynamic organ that is the primary site of storage
for excess energy but it serves as an endocrine organ capable of synthe-
sizing a number of biologically active compounds that regulate metabolic
homeostasis. This dynamic tissue is composed not only of adipocytes, but
also of other cell types called the stroma-vascular fraction, comprising
blood cells, endothelial cells, pericytes and adipose precursor cells among
others [2-5]. Several studies have evidenced that adipose tissue is not uni-
form. Depending on the location in the body, they differ in their capacity
to secrete adipocytokines, as well as cellular composition with varied phe-
notype, as well as the quantity and proportion of adipocytes forming it,
blood vessel stromal cells and immune system cells [6]. It is now generally
recognized that adipose tissue is an important organ of a complex network
that participates in the regulation of a variety of quite diverse biological
functions (Figure 1) [7-10].
Marisa Coelho, Teresa Oliveira, Ruben Fernandes

Coagulation its color from extensive vascularization and the

Vascular
tone control Immunity presence of many densely packed mitochondria. It
is traversed by many more blood vessels than white
fat. These blood vessels assist in delivering fuel for
Appetite
Others regulation storage and oxidation, and in dispersing heat gen-
erated by the numerous mitochondria to other
parts of the body [8, 9].
Body
weight Glucose
Although its participation in thermogenesis is
homeostasis and lipid irrelevant, white adipose tissue’s functional capac-
metabolism ity is much broader and more comprehensive. It has
extensive distribution in the body, involving, or infil-
Fibrinolysis
Reproduction
trating, almost the entire region subcutaneously by
organs and hollow viscera of the abdominal cavity
Angiogenesis or mediastinum and several muscle groups, for
which it offers mechanical protection, softening the
Figure 1. The most significant physiological functions
impact of shocks and allowing appropriate sliding
of white adipose tissue such as coagulation, appetite
regulation, immunity, glucose and lipid metabolism, of muscle bundles, one on the other, without com-
reproduction, angiogenesis, fibrinolysis, body weight promising their functional integrity [2, 4]. Because
homeostasis and vascular tone control it is an excellent thermal insulator and has a wide
distribution, including the dermis and subcutaneous
Adipogenesis refers to the differentiation of pre- tissue, it plays an important role maintaining body
adipocytes into mature fat cells, i.e. the development temperature [5]. By this ability to accumulate and
of adipose tissue, which varies according to sex and provide energy when necessary, it assumes the sta-
age. Adipocytes differentiate from stellate or fusiform tus of the most important buffering system for lipid
precursor cells of mesenchymal origin. The mor- energy balance, particularly fatty acids, which are
phological and functional changes that take place an exceptionally efficient fuel storage species. The
in the course of adipogenesis correspond to a shift highly reduced hydrocarbon tail can be readily oxi-
in transcription factor expression and activity lead- dized to produce large quantities of ATP (adenosine
ing from a primitive, multipotent state to a final triphosphate) [9].
phenotype characterized by alterations in cell shape
and lipid accumulation [4, 5]. Lipogenesis and lipolysis
Pre-adipocytes within adipose tissue can diffe- Fat accumulation is determined by the balance be-
rentiate into mature adipocytes throughout life, thus tween fat synthesis (lipogenesis) and fat breakdown
enabling hyperplastic expansion of adipose tissue (lipolysis/fatty acid oxidation).
when increased storage requirements are needed. Lipogenesis is a process that occurs preferentially
In addition, the mature adipocytes can expand in size in adipose tissue (Figure 2), but it also happens in
to accommodate increased storage needs and in liver, and it is the synthesis of fatty acids, which are
situations of overnutrition become hypertrophic. As used as energy reserves. This process is responsive
a result, adipocyte number and morphology trans- to changes in the diet [12]. It is stimulated by a high
form in response to energy balance via the bioche- carbohydrate diet leading to elevated postprandial
mical processes involved in lipid uptake, esterifica- plasma triglyceride levels, whereas lipogenesis is
tion, lipolysis and differentiation of pre-adipocytes [11]. inhibited by polyunsaturated fatty acids and by fast-
In mammals, there are two types of adipose tis- ing. Fasting is related to a decrease in plasma glu-
sue: white and brown. The adipocytes in these two cose and an increase in plasma-free fatty acids.
types exhibit different morphology and function. These effects are partly mediated by hormones,
Brown adipose tissue specialized in heat produc- which inhibit (leptin) or stimulate (angiotensin, acy-
tion (thermogenesis) is almost absent in adult hu- lation stimulating protein) lipogenesis. Glucose itself
mans, but is found at birth. Brown adipocytes, with is a substrate for lipogenesis. It increases the process
an average diameter, are smaller than adipocytes of by stimulating the release of insulin and inhibiting
white adipose tissue. They have a number of cyto- the release of glucagon from the pancreas [12].
plasmic lipid droplets of different sizes, cytoplasm Lipolysis occurs in adipose tissue and is the break-
relatively abundant, a spherical core and slightly down of fat, in other words, from energy reserves (tri-
eccentric and numerous mitochondria that release glycerides) for energy production by which triacyl-
heat by oxidation of fatty acids. Brown adipose tis- glycerol molecules are hydrolyzed to free fatty acids
sue also stores energy in lipid form, but more regu- and glycerol (Figure 2). During times of metabolic
larly produces heat by oxidizing fatty acids within stress (i.e. during fasting or prolonged arduous exer-
the adipocyte, rather than supplying free fatty acids cise when the body’s energy needs exceed the cir-
for use by other cell types [2, 4, 5]. Brown fat derives culating nutrient levels), the adipocyte’s triacylglyce-

192 Arch Med Sci 2, April / 2013

 Biochemistry of adipose tissue: an endocrine organ

rol droplet is degraded to provide free fatty acids to GLUT-4

VLDL Fatty acids
be used as an energy source by other tissues. Nume-
(liver)
rous stimuli are able to elicit the lipolytic response
Chylomicrons
in adipocytes. However, ultimately the same pair of (intestine)
enzymes, hormone-sensitive lipase and monoacyl-
glycerol lipase, is responsible for catalyzing the hy- Fatty acids
drolysis of the triacylglycerol ester bonds. Complete
hydrolysis of triacylglycerol involves the breakage of Insulin Free fatty
3 ester bonds to release free fatty acids and a glyc- Glucagon, acids
erol moiety. The same enzyme, hormone-sensitive catecholamines, (albumin)
lipase, is responsible for facilitating hydrolysis of adrenocorticotropic
hormone (ACTH),
the esters at positions 1 and 3 of the triacylglycerol.
serotonin
A second enzyme, 2-monoacylglycerol lipase, cata-
lyzes hydrolysis of the remaining ester to yield Figure 2. Primary metabolic role of adipose tissue. In
a third free fatty acid and glycerol. Hormone-sen- the feeding state, insulin-dependent glucose trans-
sitive lipase is inhibited by insulin and is favored port 4 (GLUT 4) allows the uptake of glucose from the
by the presence of glucagon and epinephrine [9, 10, bloodstream to adipocytes. Glycolysis occurs, produ-
cing glycerol-3-phosphate (glycerol-3-P), a substrate
12]. Glycerol is effluxed out of adipocytes via an
required for lipogenesis. Fatty acids from liver carried
aquaporin type of transport molecule and must be by very low-density lipoproteins (VLDL) and chylomi-
shuttled back to the liver for use in oxidation or glu- crons from the intestine are esterified with glyce -
coneogenesis. However, under maximal lipolytic rol-3-P to form lipid droplets of triacylglycerols (TAGs).
conditions, substantial recycling of fatty acids In the fasting state and in stress conditions, hormone-
occurs such that on average about two fatty acid sensitive lipase is activated for lipolysis. Some steps
are required to produce glycerol, which travels to the
molecules are released per glycerol molecule. Out- liver, and fatty acids. These free fatty acids will travel
side the adipocyte, fatty acids are immediately bound in the bloodstream to the liver, muscle and to other
to albumin and carried in the bloodstream to the organs to be oxidized. In the bloodstream fatty acids

β-Oxidation is a catabolic process in which the free

liver, muscle and other tissues for oxidation [10]. are immediately bound to albumin

fatty acids resulting from lipolysis are used by the It is commonly assumed that under normal
body as a source of energy. The fatty acid molecules physiological circumstances adult humans are prac-
are converted into acetyl coenzyme A molecules [2]. tically devoid of functional brown adipose tissue
[14]. However, it has been recently shown that hu-
Secretory organ man white adipose tissue can be infiltrated with
Through the discovery of the ability to secrete brown adipocytes expressing uncoupling protein 1
hormones, great importance has been attributed to (UCP-1). This protein is found in the mitochondria
of brown adipose tissue and it generates heat by
the role of adipose tissue [3].
non-shivering thermogenesis.
White adipose tissue may represent the largest
Experimental data suggest that there are some
endocrine tissue of humans. Its pleiotropic nature
differences, in respect to adipokine synthesis and
is based on the ability of fat cells to secrete nume-
secretion, between visceral fat and subcutaneous
rous hormones, growth factors, enzymes, cytokines,
adipose tissue, as visceral fat appears to be more
complement factors and matrix proteins. Adipose
active. Both types of this tissue are characterized
tissue also expresses receptors for most of these by production of a unique profile of adipocytokines.
factors that are implicated in the regulation of many In the visceral tissue, for example, higher concen-
processes including food intake, energy expendi- trations of IL-6 (interleukin-6) and PAI-1 (plasmino-
ture, metabolism homeostasis, immunity and blood gen activator inhibitor 1) are observed. In turn, in the
pressure homeostasis [7, 13]. subcutaneous tissue, there is a higher concentra-
Adipose tissue is dynamically involved in cell tion of leptin and adiponectin [6].
function regulation through a complex network of The endocrine activity of white adipose tissue
endocrine (signals travel through the circulatory sys- was postulated when its capacity for steroid hor-
tem to reach all parts of the body), paracrine (sig- mone interconversion was alluded to. Particularly
nals sent only to cells in the vicinity of the cell sta- since the discovery of leptin, in 1994, the list of adi-
tion), and autocrine (only affecting cells that are the pocyte-derived factors has been increasing at an
same type) signals that influence the response of extraordinary pace. The discovery of leptin opened
many tissues, including hypothalamus, pancreas, up a whole field of studies into the biology of adi-
liver, skeletal muscle, kidneys, endothelium, and the pocytes, their metabolic and endocrine functions,
immune system, among others. This secretory nature and the functional relationships between secretions
has prompted the view of white adipose tissue as an of adipocytes and peripheral metabolic functions.
extremely active endocrine tissue [5]. A different way of addressing the production of adi-

Arch Med Sci 2, April / 2013 193

Marisa Coelho, Teresa Oliveira, Ruben Fernandes

Leptin cial adipocytokines, such as adiponectin, might be

FFA IL-6 major mechanisms involved in lifestyle-related di-
seases, including diabetes mellitus, hyperlipidemia,
hypertension and atherosclerosis, comprising the so-
Others
TNF-α called MetS [15, 16]. The reduction of visceral fat the-
refore might be an essential preventive measure for
MetS and its consequence, cardiovascular disease.
Sex The regulation of key adipocytokines such as adipo-
Angiotensin steroids nectin might be considered as an efficient therapeutic
procedure, but needs to be studied carefully [13].
Adiponectin
Obesity is now viewed as a state of systemic,
PAI-I chronic low-grade inflammation [17]. It has been
recognized by recent studies that obesity (waist cir-
Glucocorticoids cumference) has a strong impact on adipokine se-
Resistin Visfatin
cretion and insulin resistance [18]. More recently it
Figure 3. Some of the factors secreted by white adi- has been recognized that macrophages are an
pose tissue, which underlie the multifunctional important part of the secretory function of adipose
nature of this endocrine organ: adiponectin, leptin,
tissue and the main source of inflammatory cytoki-
angiotensin, resistin, visfatin, acylation stimulating
nes, such as TNF-α and IL-6. As a secretory organ,
necrosis factor α (TNF-α), interleukin-6 (IL-6), and
protein (ASP), sex steroids, glucocorticoids, tumor
adipose tissue presents several particularities and its
free fatty acids (FFA), among others secretory activity is regulated by humoral and hor-
monal mechanisms (Table I).
pose-derived factors is by focusing on the function
Leptin
they perform [4, 5].
The adipose tissue secretes a number of bioac- Leptin is a small peptide (16 kDa), considered as
tive substances (Figure 3), such as adipocytokines a pre-inflammatory cytokine that indicates com-
among others. Unbalanced production of pro- and mon structural and functional properties, belong-
anti-inflammatory adipocytokines in obese adipose ing to the IL-6 family of cytokines [17, 19, 20]. The
tissue may contribute to many aspects of the meta- ob gene expressed by adipocytes encodes it. It is
bolic syndrome (MetS). an anorexigenic peptide that increases energy ex-
Oversecretion of potentially harmful adipocyto- penditure, and is primarily cleared from plasma by
kines, such as PAI-1, tumor necrosis factor-α (TNF-α) the kidney through glomerular filtration followed by
or visfatin, and hyposecretion of potentially benefi- proteolytic degradation in the renal tubules. The lep-

Table I. Factors secreted by adipose tissue into the bloodstream and respective function/effect in their targets
Molecule Function/effect
Leptin Signals to the brain about body fat stores. Regulation of appetite and energy expenditure.
Wide variety of physiological functions
Adiponectin Plays a protective role in the pathogenesis of type 2 diabetes and cardiovascular disease
Resistin Hypothetical role in insulin resistance
TNF-α Affects insulin receptor signaling, possible cause of the development of insulin resistance in obesity
IL-6 Pro-inflammatory, lipid and glucose metabolism, regulation of body weight
PAI-1 Inhibitor of the fibrinolytic system by inhibition of activation of plasminogen
Angiotensinogen Precursor of angiotensin II; regulator of blood pressure and electrolyte homeostasis
FFA Oxidized in tissues to produce local energy. Serve as a substrate for triglyceride and structural
molecular synthesis. Involved in the development of insulin resistance
ASP Influences the rate of triacylglycerol synthesis in adipose tissue
VEGF Stimulation of angiogenesis
Adipsin Potential relation between the complement pathway and adipose tissue metabolism
Glycerol Structural component of the major classes of biological lipids and gluconeogenic precursor
IGF-1 Stimulates proliferation of a wide variety of cells and mediates many cells and many of the effects
of growth hormone
TNF-α – tumor necrosis factor α, IL-6 – interleukin-6, PAI-1 – plasminogen activator inhibitor 1, FFA – free fatty acids, ASP – acylation stimulating pro-
tein, VEGF – vascular endothelial growth factor, IGF-1 – insulin-like growth factor 1

194 Arch Med Sci 2, April / 2013

 Biochemistry of adipose tissue: an endocrine organ

tin receptor is expressed not only in the central negative correlation between plasma adiponectin
nervous system, but also in some peripheral tissues concentration in humans and fat mass, with the
(hematopoietic and immune cells), suggesting that exception of severe cases of undernutrition and in
leptin may have functions other than food intake the newborn [24]. Adiponectin is associated with
and energy expenditure regulation [17, 19]. Adipose type 2 diabetes (T2D), but is almost exclusively due
tissue and plasma leptin concentrations are depen- to a decrease in levels of the circulating HMW iso-
dent on the amount of energy stored as fat as well form, without an accompanying reduction in levels
as the status of energy balance. Therefore, leptin of the other two oligomeric forms. The distribution
levels are higher in obese individuals and increase of circulating adiponectin oligomers is thought to
with overfeeding. Conversely, lean individuals have be primarily regulated at the stage of secretion from
lower leptin levels and fasting results in reduction adipocytes, since interconversion between the dif-
of circulating leptin. Nutritional regulation of leptin ferent isoforms does not occur once they have been
is mediated at least in part by insulin, as leptin released from the cell [24]. In models of genetic and
decreases in response to low insulin levels and diet-induced obesity, adiponectin was shown to
increases with feeding or in response to insulin improve whole-body insulin sensitivity. Another role
stimulation [10]. of adiponectin is to stimulate fatty acid oxidation
Leptin is expressed mainly by adipose tissue, alt- and glucose uptake in skeletal muscle and adipose
hough low levels have been detected in the placen- tissue; this effect is dependent on AMP-activated
ta, skeletal muscle, gastric and mammary epithelium protein kinase (AMPK) signaling. Adiponectin is also
and the brain. Leptin is increased by glucocorticoids, involved in the suppression of hepatic glucose out-
acute infection and proinflammatory cytokines. In put through activation of AMPK [19].
contrast, cold exposure, adrenergic stimulation, growth Two receptors of adiponectin have been identi-
hormone (GH), thyroid hormone, melatonin, smo- fied: AdipoR1 and AdipoR2. They contain 7 transmem-
king and thiazolidinediones decrease leptin [12, 13]. brane domains, but differ structurally and func-
Its levels are higher in females than males, partly as tionally. Recent studies have shown that the skeletal
a result of inhibition by androgens, stimulation by muscle contains abundant levels of both AdipoR1 and
estrogen and depot-related differences in leptin ex- AdipoR2 but the liver primarily expresses AdipoR2.
pression. Leptin synthesis is greater in subcutaneous AdipoR1 works with high affinity with gAdp and low
than in visceral adipose tissue, and the higher cir- affinity with fAdp, whereas AdipoR2 works with
culating concentration of leptin in females is likely intermediate affinity with gAdp and fAdp. The bio-
to be due, in part, to a higher proportion of subcuta- logical effects of these receptors depend not only on
neous fat. Leptin has been implicated in other roles, blood concentrations of adiponectin but also tissue
including modulation of the reward circuitry for specificity [17, 25]. Adiponectin displays no great
feeding, glucose metabolism, lipid oxidation, sub- fluctuations in the bloodstream, which means that
strate partitioning, and adipocyte apoptosis [17, 19]. its release is not acute but regulated by long-term
metabolic changes [25]. Adiponectin regulates ener-
Adiponectin gy expenditure through activation of AMPK in the
The adiponectin gene on chromosome 3q27 was hypothalamus, where AdipoR1 and AdipoR2 co-loca-
described in 1995. From the structural point of view, lize with the leptin receptor, ObR [17]. It has been de-
adiponectin is related to the complement 1q fami- monstrated that adiponectin stimulated appetite
ly and contains a carboxyl-terminal globular domain and reduced energy expenditure and that these
effects were eliminated following the ablation of
and an amino-terminal collagenous domain and
AdipoR1 (siRNA) or AMPK signaling (AMPK domi-
also shares extensive sequence homology with col-
nant negative) [26].
lagen VIII and X [21]. Each monomer of adiponectin
In contrast to leptin, which has been suggested
region, an α-helical collagenous ‘stalk’ composed
is composed of 3 domains: a variable N-terminal
to enter the brain via endocytosis through the leptin
receptor, the mechanism by which adiponectin is able
of multiple G–X–X repeats, and a distinctive C-ter-
to reach the hypothalamus is unknown. This study
minal globular domain of approximately 140 amino
also showed an important finding: adipo–/– mice
acids [19]. This adipokine circulates in three isoforms:
show markedly increased leptin sensitivity. This fact
a trimer, of low-molecular weight (LMW), a hexamer
led to the proposal that the central actions of leptin
(trimer-dimer) of medium molecular weight (MMW)
and adiponectin have reciprocal functions for pro-
and a multimeric high molecular weight (HMW) iso-
viding a homeostatic mechanism to maintain fat
form [22]. Adiponectin exists as a full-length pro-
levels and energy stores through the suppression or
tein (fAdp) of 30 kDa, which circulates in trimeric,
stimulation of appetite and energy expenditure [19].
hexameric and higher order complexes. A fragment
Tumor necrosis factor α
containing the globular domain of adiponectin (gAdp)
has also been shown to exhibit potent metabolic
effects in various tissues. Adiponectin is secreted ex- Tumor necrosis factor, TNF-α, is synthesized as
clusively from adipose tissue [23]. There is a strong a 26 kDa transmembrane protein that undergoes

Arch Med Sci 2, April / 2013 195

Marisa Coelho, Teresa Oliveira, Ruben Fernandes

cleavage by a metalloproteinase to be released into from the circulatory system is contributed by adi-
the circulation as a 17 kDa soluble TNF-α molecule [10]. pocytes, which by secreting monocyte chemotactic
Adipocytes (isolated and differentiated) are capa- protein (MCP-1), macrophage migration inhibition
ble of producing TNF-α. For some years it was sug- factor (MIF-1), macrophage inflammatory proteins
gested that adipocytes are the principal source of (MIP-1α), chemokine CCL5 (RANTES) and macro-
elevated TNF-α levels in obesity [21]. Nevertheless, phage colony stimulating factor (M-CSF), support
more recently it has been recognized that adipo- diversification and maturation of monocytes [27, 28].
cytes are not the major source of inflammatory The first adipose derived factor suggested to rep-
cytokine but that macrophages from the stromal resent a link between obesity, inflammation and
vascular fraction are the primary source of adipose diabetes was TNF-α. Studies show that mRNA ex-
derived TNF-α. Macrophages, which constitute pression levels of TNF-α in adipose tissue in obesity
about 10% of the stromal vascular fraction, are pre- is strongly implicated in the pathogenesis of insulin
sent in larger quantities in visceral adipose tissue resistance; this is because it has been demonstrated
than in subcutaneous adipose tissue [6]. These that TNF-α can impair insulin signaling in hepato-
studies also postulate that the increased levels of cytes and adipose tissue [29]. Other studies demon-
this TNF-α in obesity are due to the increased infil- strated that chronic treatment with TNF-α decrea-
tration of adipose tissue with M1 macrophages [21]. sed insulin-stimulated glucose uptake in rat skeletal
Some studies showed that the macrophages are muscle, and targeted deletion of TNF-α or its recep-
formed as a result of transformation from mono- tors increased insulin sensitivity and glucose tole-
cytes that infiltrated the adipose tissue from the rance in obese rodents in some, but not all, studies
circulatory system [27]. It was also evidenced that, (Figure 4) [19].
both in humans and in mice, the quantity of macro- TNF-α neutralization in obese T2D humans does
phages in the adipose tissue correlates with the fat not appear to improve glucose tolerance or insulin
mass. It was observed that infiltration of monocytes sensitivity. However, in individuals without establi-

LEAN ADIPOSE TISSUE

OBESE ADIPOSE TISSUE

Macrophage
infiltration
inflammation
Dysregulated adipokine secretion

↓ ↓
↓ ↓
↓
Adiponectin
Leptin ↓
TNF-α
Free fatty acids
IL-6
Resistin

↓
↓
Glucose uptake ↓
Glycogenolysis
Gluconeogenesis↓
Plasma glucose FA oxidation ↓
Inflammation Inflammation
Ectopic lipid accumulation (steatosis) Ectopic lipid accumulation
Liver insulin resistance Muscle insulin resistance

SYSTEMIC INSULIN RESISTANCE

Figure 4. The expansion of adipose tissue leads to adipocyte hypertrophy in obesity. The release of chemokines that

duction of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α) and IL-6. This is accomplished by
induce recruitment of macrophages from the bloodstream increases infiltration and inflammation with enhanced pro-

increased release of FFA and dysregulated secretion of leptin, adiponectin and resistin. The macrophage and adipose
tissue-derived adipokines acts in a paracrine or autocrine way, which exacerbates adipose tissue inflammation. Altered
adipokine secretion, at the systemic level, can lead to decreased muscle and liver insulin sensitivity through enhanced
ectopic lipid deposition and inflammation. These effects lead to increased liver glucose production (by means of glu-
coneogenesis and glycogenolysis). In contrast, muscle metabolism is reshuffled to a pattern of low glucose uptake
and low FFA oxidation (with increases in levels of glycerol substrate for liver gluconeogenesis). These events lead to
an increase of plasma glucose and, subsequently, an increase of insulin resistance. Adapted from: Galic S et al., 2010

196 Arch Med Sci 2, April / 2013

 Biochemistry of adipose tissue: an endocrine organ

shed T2D, prolonged treatment does improve insu- demonstrated that these effects require activation
lin sensitivity [19]. The molecular mechanism for of AMPK-activated protein kinase but this mecha-
this observed impairment in insulin action involves nism is not understood [32]. In general, IL-6 inhibits
inhibition of insulin receptor substrate (IRS) sig- lipase lipoprotein, induces lipolysis and increases
naling capability through the activation of serine glucose uptake [19].
kinases such as the c-Jun-N-terminal kinase (JNK)
or inhibitor of NF-κB kinase (IKK) and through Angiotensin
increased expression of suppressor of cytokine sig-
Adipose tissue expresses all components of the
naling 3 (SOCS3). In hepatocytes TNF-α also reduces
renin-angiotensin-aldosterone system (RAAS), inclu-
fatty acid oxidation and skeletal muscle through
ding angiotensinogen (AGT), renin, angiotensin I-con-
effects mediated by the induction of protein phos-
verting enzyme, and angiotensin II type 1 receptor [3].
phatase 2C and suppression of AMPK. The reduced
Moreover, adipose tissue angiotensinogen mRNA and
rates of fatty acid oxidation are accompanied by
protein levels are regulated by nutrition, leading to
increased accumulation of bioactive lipids, such as
decreased levels with fasting and to increased le-
diacylglycerols, which in turn are known to activate
vels with refeeding. Angiotensin II stimulates prosta-
protein kinase C and inhibit IRS function [19]. In
cyclin synthesis, adipocyte differentiation and lipo-
addition, TNF-α induces pro-apoptotic and/or death
genesis. Based on these findings, it is suggested that
signals in a variety of cell types. It is therefore inter-
adipose tissue-derived angiotensin may regulate
esting to speculate that hypertrophied adipocytes,
adipocyte differentiation and growth, as is the case
which are stimulated by macrophage-derived TNF-α,
in other tissues. It is also possible that RAAS pepti-
can release saturated fatty acids as an endogen
des secreted by adipose tissue act on the vasculature
danger signal that report their diseased state to
and distant targets to regulate blood pressure and
macrophages in obese adipose tissue. Indeed, sev- cardiovascular responses in obese individuals [32].
eral lines of evidence indicate that adipocyte death Angiotensin II also has a recognized effect on
and/or the death receptor Fas signaling contribute cardiovascular function such as hypertension and
to the obesity-induced adipose tissue, particularly hemostasis. Human platelets express angiotensin II
during periods of starvation, but recent evidence receptors AT1 [34]. Some studies have described the
has suggested pathophysiological roles other than role of angiotensin II on hemostasis. It has been
the supply of nutrients in times of fasting or demonstrated that angiotensin II can induce and
increased demand. In this regard free fatty acids, potentiate shape change in human platelets [35].
when released physiologically during fasting or star-
vation via adipocyte lipolysis, may not act as a dan- Plasminogen activator inhibitor 1 (PAI-1)
ger signal [30].
Another factor involved in microvascular events
Interleukin-6 (IL-6) is the plasminogen activator inhibitor 1 (PAI-1).The
gene for PAI-1 is located on chromosome 7q21.3- q22.
In humans, approximately 30% of circulating IL-6 PAI-1 is a single chain 45-kDa glycoprotein that con-
originates from adipose tissue. Concentrations are tains from 379 to 381 amino acids. Endothelial and
higher in visceral fat as compared to subcutaneous vascular smooth muscle cells are presumably the
fat. They increase with obesity and are stimulated main sources of PAI-1 but other cells, such as plate-
by TNF and interleukin-1 (IL-1). Elevated levels are lets, hepatocytes, mesangial cells, fibroblasts, mono-
associated with increased risk of coronary artery cytes, macrophages, adipocytes, and stromal cells per-
disease, atherosclerosis, and unstable angina [31]. meating the adipose tissue, have also been shown
In T2D plasma IL-6 levels are increased and are to secrete the serpin [36].
positively correlated with body mass and plasma The greater the fat cell size and the adipose tissue
free fatty acid concentrations. As with TNF-α, the mass, the greater is the contribution of adipose pro-
largest amount of IL-6 is derived from cells of the stro- duction to circulating PAI-1. Experimental data show
mal vascular fractions, while the other part, appro- that visceral adipose tissue has a higher capacity
ximately 1/3, of IL-6 detected in plasma is attribu- to produce PAI-1 than subcutaneous adipose tissue.
ted to the production from white adipose tissue [2, Studies in human adipocytes indicate that PAI-1 syn-
19]. It has been demonstrated that IL-6 inhibits the thesis is upregulated by insulin, glucocorticoids,
insulin signaling pathway by up-regulating SOCS3 angiotensin II, some fatty acids and, most potent-
expression, which in turn is known to impair in- ly, by cytokines such as TNF-α and transforming
sulin-induced insulin receptor and IRS-1 phospho- growth factor-β, whereas catecholamines reduce
rylation in adipocytes and hepatocytes. Moreover, PAI-1 production [36, 37].
IL-6 can promote fatty acid oxidation and glucose The PAI-1 is a protein involved in fibrinolysis and
uptake in skeletal muscle findings, which are also is altered in obesity [38]. Plasma PAI-1 levels increase
observed with the IL-6 family member ciliary neu- in proportion to visceral adiposity, raising the pos-
rotrophic factor (CNTF) [32, 33]. Some studies have sibility that PAI-1 serves as the link between abdo-

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Marisa Coelho, Teresa Oliveira, Ruben Fernandes

minal/central obesity and cardiovascular disease. cytokines (IL-1, IL-6 and TNF) leads to considerable
That protein can change the balance between fib- increase in resistin production during infection [20].
rinolysis and fibrinogenesis, contributing to the re- Release of resistin appears to be stimulated by in-
modeling of vascular architecture and the athero- flammation, LPS (lipopolysaccharide), IL-6, hypergly-
sclerotic process [39]. An altered function of the cemia, growth and gonadal hormones. While released
endocrine system and an impaired auto-/paracrine within the fat tissue resistin acts on adipocytes them-
function at the fat cell levels may mediate this dis- selves, leading to insulin resistance [45].
turbance of the fibrinolytic system and thereby Effects of the administration and neutralization
increase the risk for cardiovascular disease [37]. of resistin in glucose tolerance in tissues indicate that
its action is through the negative modulation of one
Acylation stimulating protein (ASP) or more steps of insulin signaling aimed at increas-
The ASP is produced through a two-step process ing glucose uptake [44]. In addition, it promotes in-
involving three proteins of the alternate comple- sulin resistance by increasing hepatic gluconeoge-
ment system: C3, factor B and adipsin, all of which nesis. It was also observed that the expression is
are synthesized and secreted by adipocytes [40]. about 3 times higher in pre-adipocytes compared
It has an important effect on the increase of lipo- to mature adipocytes, indicating that it is a poten-
genesis by the translocation of glucose transporter tial regulator of adipogenesis [44, 47].
type 4 (GLUT4) in glycerol 3-phosphate and the Resistin also stimulates endothelial cells to secrete
activity of diacylglycerol acyltransferase (DGAT), an such substances as monocyte chemoattractant pro-
enzyme catalyzing the synthesis of triglycerides [40, tein-1 (MCP-1), vascular cell adhesion molecule 1
41]. Plasma ASP increases with meals and facilitates (VCAM-1) and intercellular adhesion molecule 1
the synthesis and storage of triglycerides. Consis- (ICAM-1), which is indicated to be an adiponectin an-
tent with its role as a mediator of lipogenesis, ASP tagonist [27].
deficiency increases postprandial fatty acid levels
and decreases weight gain and triglyceride syn- Visfatin
thesis [39].
Visfatin is a highly conserved 52 kDa protein
In humans, ASP levels are increased in obesity, T2D,
and cardiovascular disease, whereas exercise or weight prevalent in visceral adipose tissue. It is also known
loss decreases ASP levels. Postprandially, subcuta- as pre-B cell colony-enhancing factor (PBEF), is prin-
neous adipose tissue increases production of ASP, cipally produced by adipocytes, although also by
and this has been shown to correlate with local fatty macrophages of the visceral adipose tissue, and in
acid trapping. Furthermore, similar to insulin resis- small quantities by subcutaneous adipose tissue.
tance, a deleterious ASP-resistant state has been pro- Visfatin mRNA expression significantly increases
posed to also contribute to the disturbed adipose during differentiation of preadipocytes to adipocytes
tissue metabolism and dyslipidemia common to [48, 49].
diabetes and cardiovascular disease. The ASP levels It was shown that visfatin’s major function is re-
curiously are also reduced with age, a phenomenon lated to energy metabolism and innate immunity and
observed previously in humans, with children tend- it is now regarded as a pro-inflammatory adipocy-
ing to have higher ASP values than adults [41, 42]. tokine. Its properties induce activation of leukocytes
and stimulate production of TNF-α and IL-6 [49, 50].
Resistin Inside cells visfatin acts as a nicotinamide phos-
phoribosyltransferase involved in the salvage path-
Resistin, discovered in 2001, is a small peptide
(12.5 kDa) synthesized as a peptide with 108 amino way of NAD+ biosynthesis. Thus, it is able to regulate
acids, containing high quantities of cysteine [19, 20]. cellular levels of NAD+, exerting an influence on cell
The structure of resistin is strikingly similar to that energy metabolism and the activity of NAD+/NADH
of adiponectin [43]. Resistin is secreted not only by dependent enzymes [39].
adipocytes, but also by a large number of cells, in Recent studies demonstrated that visfatin exerted
particular immunocompetent cells. insulin mimetic effects in cultured adipocytes, myo-
Circulating resistin levels are increased in mouse cytes, and hepatocytes and lowered plasma glu-
models of obesity and in obese humans and are cose levels in mice by binding to and activating the
decreased by the anti-diabetic drug rosiglitazone, insulin receptor [51].
and increased in diet-induced and genetic forms of Conclusions
obesity, and administration of anti-resistin antibody
has been shown to improve blood sugar and insulin Adipose tissue is the primary storage site for ex-
action in mice with diet-induced obesity [44, 45]. cess energy but it is also recognized as an endocrine
Similarly, resistin has been implicated in the pathoge- organ. Adipocytes are now generally accepted to be
nesis of diabetic complications and diabetes [45, 46]. a complex cell type involved in generating a num-
In vitro studies evidenced that macrophage stim- ber of signals which include cytokines, hormones
ulation with lipopolysaccharide or pro-inflammatory and growth factors that not only affect the neigh-

198 Arch Med Sci 2, April / 2013

 Biochemistry of adipose tissue: an endocrine organ

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