Vol. 1 Issue 3, pp: (25-40), December 2016. Available online at: http://www.prudentjournals.org/IRJC

Review

Adipose tissue significance with special emphasis on

its role in regulating immune functions in mammals M. K. Vidya1, Girish Kumar1, Madiajagan Bagath2, Govindan Krishnan2, R.K.

Veeranna2, K.K. Sunil Kumar1, Veerasamy Sejian2* and Raghavendra Bhatta2

1Veterinary College, Karnataka Veterinary Animal and Fisheries Sciences University, Hebbal,

Bangalore-560024, India.

2ICAR-National Institute of Animal Nutrition and Physiology, Adugodi, Bangalore-560030, India

*Corresponding Author. E-mail: drsejian@gmail.com

Received 23 July, 2016; Accepted 13 November, 2016.

Abstract

This review attempts to cover the implication of the adipose tissue in controlling immune functions with

emphasis on the structure and properties of adipose tissue, adipokines produced by adipose tissue,

immune cells in adipose tissue and molecular mediators of adipose tissue inflammation. Adipose tissue

(AT) in mammals is a complex, multi-depot, anatomically dissectible discrete structure with high

metabolic activity. Both excess and deficiency of adipose tissue affect the normal homeostasis of the

body. The AT comprises of two types of adipocytes, white adipocytes which store lipids whereas brown

adipocytes which oxidize these lipids to produce heat. Further, to serving as a fat depot, AT also serves

as endocrine adipose organ producing many bioactive molecules, called adipokines. These adipokines

include leptin, adiponectin, visfatin, apelin, vaspin, omentin, resistin, hepacidin, monocyte

chemoattractant protein (MCP), interleukin 6 (IL-6), tumor necrosis factor (TNF-α), plasminogen activator

inhibitor (PAI-1) and other cytokines. Leptin is by far the most important endocrine parameter produced

which regulates feed intake and considered as nutritional signal in mammals. In addition, leptin also was

also found to be associated with controlling puberty, immunity, and autoimmune disorders. Adiponectin

was found to be another noteworthy molecule produced from AT which increases fatty acid oxidation

and reduces the synthesis of glucose in the liver. Further, adiponectin was found to have an anti-diabetic,

anti-inflammatory and anti-atherogenic effect. A strong interplay between AT and immunity was

established in mammals. Recently it was established that AT plays a huge role in controlling the immune

functions in mammals through its close association with lymphoid organs; secreting inflammatory

cytokines and adipokines; and through its anti-microbial and phagocytic activities. The involvement of

AT in controlling immunity and autoimmune disorder was reported to be a significant breakthrough in

cancer biology. Hence, it may be concluded that apart from acting as a fat depot to control energy

metabolism, AT was also found to be associated with several other important biological functions

signifying its role as an important endocrine organ in mammals.

Keywords: Adipose tissue, Auto-immune disorder, Leptin, Adipokines, Immunity, Interleukins.

International Research Journal of Chemistry Article Number: PRJA13407592 Copyright ©2016 Author(s) retain the copyright of this article Author(s) agree that this article remain permanently open access under the terms of the Creative Commons

Attribution 4.0 International License.

Introduction

Anatomically adipose tissue (AT) is a

complex structure comprising two types of

adipocytes, white and brown, each of which

differs in their anatomy and physiology. White

adipocytes store lipids whereas brown

adipocytes oxidize these lipids to produce heat

(non-shivering thermogenesis).

Until very recently, AT was thought to be a mere

fat storage sink. However, the discovery of leptin

sheds new light on the involvement of AT in

immunity. Apparently, the endocrine adipose

organ produces many bioactive molecules, called

adipokines. These adipokines include leptin,

adiponectin, visfatin, apelin, vaspin, omentin,

resistin, hepacidin, which regulate metabolism

and possess immunoregulatory properties1.

Among these adipokines, leptin and adiponectin

are the most important. Increased or altered

production of these factors in obesity may lead to

insulin resistance and metabolic syndrome 2.

Excess and deficiency of AT, both affect the

normal homeostasis of the body. Excess of AT

predisposes an individual to inflammation,

autoimmune diseases, and cancer. Obesity, the

hallmark of the metabolic syndrome, which takes

its origin to the expansion of AT in the body, is a

heterogenous disorder leading to insulin

resistance and type 2 diabetes mellitus (DM2).

Obesity is characterized by chronic, low-grade

inflammation with increased infiltration of immune

cells to the AT, especially visceral adipose tissue

(VAT) and switching of macrophages towards a

pro-inflammatory phenotype.

In a new research area called

immunometabolism, the role of immune cells of

the AT in the initiation and progression of

inflammation has been highlighted. Indeed, AT is

now considered an active immune organ with a

key role in metabolic homeostasis. Adipose

tissue contains many types of resident immune

cells3. There is infiltration of many other pro-

inflammatory and anti-inflammatory cells in

obesity. The pro-inflammatory cells include

macrophages, neutrophils, mast cells, CD8+ T

cells and B cells; whose number directly

correlates to the extent of inflammatory response.

Particularly, the AT macrophages (ATM) are

increased during obesity-induced inflammation.

In contrary, the anti-inflammatory cells like

eosinophils, regulatory T cells (Tregs), helper T

cells (Th2) cells and CD4+ T cells are negatively

correlated. Along with innate immune cells, T

cells and B cells also regulate insulin resistance

through the expression of cytokines on their cell

surface. Hence, both adaptive and innate

immune cells’ role has been implicated in the

inflammatory process of obesity. Although AT

was originally thought to have associated only

with fat storage and energy metabolism, the latest

information suggests its involvement in multiple

functions4,5. Hence, an attempt has been made in

this review to collate and synthesize information

pertaining to various biomolecules synthesized

and about the multifaceted functions of AT. This

review attempts to cover the implication of the

adipose tissue in controlling immune functions

with emphasis on the structure and properties of

adipose tissue, adipokines produced by adipose

tissue, immune cells in adipose tissue and

molecular mediators of adipose tissue

inflammation.

Structure and salient properties of adipose

tissue

Adipose tissue of mammals is a complex,

multi depot, anatomically dissectible discrete

structure with a high metabolic activity. It

comprises of two types of adipocytes, white and

brown, each of which differs both in their anatomy

and physiology. White adipocytes store lipids,

whereas brown adipocytes oxidize these lipids to

produce heat (non-shivering thermogenesis).

Uncoupling protein (UCP1) is a mitochondrial

protein, which is found only in brown adipocytes

to burn the lipids6. Fig. 1 describes the white and

brown fat cells.

Vidya et al 26

Fig. 1 describing the white and brown fat cells

Besides adipocytes, the AT produces bioactive

adipokines like leptin, adiponectin, visfatin,

apelin, vaspin, omentin, resistin, hepacidin3.

Further, the AT also produces important

cytokines like monocyte chemoattractant protein-

1 (MCP-1), interleukin 6 (IL-6), tumor necrosis

factor (TNF-α) and plasminogen activator

inhibitor (PAI-1)7. The adipose tissue also

contains connective tissue matrix, nerve tissue,

stromal vascular cells, and immune cells.

Together, these components function as an

integrated unit which contributes to the

inflammatory status of the body8.

White adipocytes are spherical, unilocular

adipocytes with a diameter of 40μ to 160μm

(lean, mammary subcutaneous) and 30μm to

100μm (lean, visceral perirenal). They are

surrounded by a distinct basal membrane and

have elongated and thin mitochondria with

randomly oriented cristae whereas, brown

adipocytes are polygonal in shape with a variable

diameter (15μ to 50μm). Unlike unilocular white

adipocytes which store the triglycerides as a

single lipid droplet, brown adipocytes are

multilocular wherein the triglycerides are present

in the form of multiple small vacuoles9. The brown

adipocytes have a large and numerous numbers

of mitochondria in the cytoplasm10. Furthermore,

in comparison to white adipocytes, brown

adipocytes are supplied with a denser blood

supply and nerve supply. Brown adipocytes are

present in all the Subcutaneous Adipose Tissue

(SCAT) and VAT depots. Their numbers are more

in young ones. Adipose tissue is diffused in the

body superficially and deeply as SCAT and VAT,

respectively11

Table 1: Physiological differences between VAT and SCAT

Properties VAT SCAT

Inflammatory and immune cells More Less

Large adipocytes More Less

Glucocorticoid and androgen receptors More Less

Transdifferentiation capacity Low High

Metabolic activity highly active Low

Lipolysis more sensitive Less

Insulin resistance More Less

Capaticity to generate Free Fatty Acids (FFA) More Less

Capacity to uptake glucose More Less

Sensitivity to adrenergic stimulation More Less

27 Int. Res. J. Chem.

Fig.2. Role of adipose tissue in controlling different biological functions in mammals 4,12,13

There are regional variations in the adipose

tissue receptors density, affinity and signal

transduction11. Receptors of adipose tissue are

activated by three types of signals (i) endocrine

hormones in circulation; (ii) Paracrine mechanism

adipokines; (iii) nerve impulses from Central

Nervous System (CNS). The four kinds of

receptors in AT are (i) Glucocorticoid receptors,

(ii) Androgen receptors (iii) Estrogen receptors

(iv) Adrenergic receptors White and brown

adipocytes are often found intermingled with one

another. The relative amount of white, brown and

mixed regions are genetically determined and

depends on age, sex, environmental temperature

ADIPONECTINN

RESISTIN

VISFATIN

ADIPSIN

APELIN

Nutritional Cue Haematoposis Puberty Immunity

Anti-Diabetic Anti-Inflammatory Anti-Atherogenic

Diabetic Inflammatory Anti-Atherogenic

Glucose Chemotaxis Auto Immune Disorder

Obesity

Adipocyte Differentiation Complement Activation

Adipocyte Differentiation

ADIPOKINES CYTOKINES RESIDENT IMMUNE CELLS

INSULIN RESISTANCE & IMMUNITY

LEPTIN

ADIPOSE TISSUE

WHITE ADIPOSE TISSUE BROWN ADIPOSE TISSUE

LIPID STORAGE NON-SHIVERING THERMOGENESIS

ENDOCINE ADIPOSE ORGAN

Vidya et al 28

and nutritional status10. Fig. 2 describes the role

of adipose tissue in controlling different biological

functions in mammals.

Different adipokines produced by

Adipose tissue

Adipokines are the bioactive peptides

produced by the endocrine adipose organ which

regulates systemic metabolism and also possess

immunoregulatory properties1. These adipokines

include leptin, adiponectin, visfatin, apelin,

vaspin, omentin, resistin, hepcidin and few more.

Leptin

Leptin, the so-called “satiety hormone”

encoded by an obese (ob) gene in murines or

LEP gene located on chromosome 7 in humans;

was discovered in 1994 in the white adipose

tissue (WAT)14. This discovery hypothesized that

WAT takes part in immunity apart from its

paradigm of fat storing status15. The primary

function of leptin is to regulate fat stores by

inhibiting hunger which is in contrary to the effect

of “the hunger hormone” Ghrelin.

Leptin is a non-glycosylated peptide

hormone of 16 kDa, consisting 167 amino acids

belongs class-I cytokine superfamily. Besides

being mainly produced by WAT, leptin is also

produced by BAT, placenta, ovaries, skeletal

muscle, bone marrow16.

Leptin and its receptors

Leptin contains four antiparallel α-helices

which are interconnected. The structure and

function of leptin and its receptors closely

resembles the long-chain helical cytokines17.

When a molecule of leptin binds to its receptor, a

tetrameric complex is formed. The leptin receptor

forms homodimer to which two molecules of

leptin binds. Interestingly, it is the tetrameric

complex of ligand and receptor which induces

activation of the receptor through conformational

change and not mere the dimerization of the

receptor18. The leptin receptors (LEP-R or CD295

or OB-R) encoded by gene ‘ob’ are expressed in

the arcuate nucleus of the hypothalamus. The

leptin receptor (OB-R) has an extracellular

domain of 840-amino-acid with the signal

transducing component gp-130, which is in

common with IL-619.

Regulation of production of leptin

Leptin is found in circulation in both bound

form in association with plasma proteins and OB-

Re (leptin receptor subtype), and biologically

active free form. The levels of leptin in blood

follow the diurnal rhythm and are gender-

dependent which is slightly higher in females than

in males20. The circulating leptin levels varying

exponentially with WAT mass reflects the relative

amount of fat stored21. Increase in pro-

inflammatory cytokines like tumor necrosis factor

α (TNF-α) and IL-1, Insulin, inflammatory stimuli

like lipopolysaccharide (LPS) and turpentine

causes an acute increase in leptin expression22;

in obesity. So it also conveys that low leptin level

results in the depressed immune system with the

onset of starvation23.

Effects of leptin and its role in immunity

It stimulates satiety by promoting synthesis of α-

Melanocyte Stimulating Hormone (MSH), a

hunger suppressant24. Accumulation of fat in non-

adipose tissue in the body results in lipotoxicity

which can be prevented by stimulating fatty acid

oxidation and glucose uptake through the action

of leptin on hypothalamus25. Serum level of leptin

is increased during pregnancy whereas during

lactation an immune-reactive leptin is found,

which is transferred to the young ones through

milk3. The level of leptin controls the onset of

puberty26. Leptin deficiency is associated with

increased susceptibility to pro-inflammatory

stimuli like bacterial endotoxins and viral

infections27. Added to that, there is reduced

inflammation in models of autoimmune disease28.

Leptin has shown direct effects in both

innate and adaptive immunity. Leptin has a

pleiotropic role in innate immune cells i.e.,

antigen presenting cells (APCs) like dendritic

cells (DCs), macrophages/monocytes, and

neutrophils and natural killer (NK) cells. It

promotes the survivability and maturation of DCs.

It increases the proliferative and phagocytic

capacity of macrophages and monocytes. It also

promotes infiltration of macrophage into the

wound site29. Leptin role in adaptive immunity is

29 Int. Res. J. Chem.

to promote longevity of naive T cells by protecting

them from apoptosis, and also the production of

IFN-γ and IL-2 are also enhanced. Switching of

cytokine production from T cell towards Th1

phenotype is attributed to leptin. Also, it activates

Th1 cells and IgG2a switching of B cells while

they inhibit Th2 cells through a reduction in the

class switching of IgG1. Leptin suppresses B cell

apoptosis and hence increase their survivability30.

Leptin also plays a role in autoimmune disorders.

Production of leptin is much higher in

osteoarthritic human cartilage than in normal

cartilage. Obese individuals are protected against

osteoarthritic degeneration of cartilage as they

have high circulating level of leptin31.

Adiponectin

Encoded by the gene Adiponectin, C1Q and

Collagen Domain Containing (ADIPOQ) which is

located on chromosome 3q27, adiponectin is a

244 amino acid polypeptide. Adiponectin has a

plasma half-life of 2.5 hours in humans32. Unlike

leptin, it can cross blood brain barrier on its own33.

There are two receptors for Adiponectin

through which it acts, ADIPOR1 and ADIPOR234.

This adipokine has a wide spectrum of biological

activities and is well known for its role in the

regulation of insulin sensitivity. In humans,

adiponectin levels are positively correlated with

insulin sensitivity and inversely related to the

degree of adiposity and obesity35. Adiponectin

increases fatty acid oxidation and reduces the

synthesis of glucose in the liver. In addition to its

inhibitory effect on the phagocytic activity of the

macrophages and the production of IL-6 and

TNFα, it also reduces B-cell lymphopoiesis and

decreases T-cell response. Thus, it has a

protective role against obesity2. It induces the

production of anti-inflammatory factors IL-10 and

IL-1RA (IL-1 receptor antagonist) by human

monocytes and APCs like macrophages and

dendritic cells2. Adiponectin has the anti-diabetic,

anti-inflammatory and anti-atherogenic effect to

protect the body during adverse conditions.

Fig. 3 describes the different types of inflammatory responses of adipose tissues in mammals.

Vidya et al 30

Resistin

Resistin is a dimeric polypeptide with a

molecular weight of 12 kDa containing 114 amino

acids. It belongs to the family of cysteine-rich C-

terminal domain proteins, also called as resistin-

like molecules (RELMs). They are predominantly

found in adipocytes in mice. In contrast,

macrophages are the important source of resistin

in humans along with adipocytes, muscle, and

pancreatic cells. This polypeptide molecule has

been implicated in representing an interesting role

in the regulation of inflammatory processes36.

Expression of resistin in serum can be

increased by pro-inflammatory cytokines IL-1, IL-6

and TNF, and by LPS stimulated macrophages in

humans whereas decreased by PPARγ agonists

(eg. pliaglitazone)10. Furthermore, cytokines like

IFNγ and leptin had no effect on its expression. As

found in rodents, expression of resistin is 15-fold

greater in SCAT than in VAT37.

Visfatin

Visfatin is a peptide hormone exhibiting its

function through endocrine, autocrine and

paracrine function. It is expressed preferentially in

white adipocytes of visceral adipose tissue and

has been identified in various tissues and organs

like brain, lung, kidney, spleen, and testis. It is also

produced by neutrophils. This adipokine mimics

the action of insulin by binding and activating the

insulin receptor thereby decreasing the insulin

resistance38. Interestingly, it does not

competitively inhibit insulin, indicating that the two

proteins bind to different sites on the insulin

receptor.

Adipsin

Adipsin, also called as complement factor

D or C3 convertase activator, is derived from

adipocyte differentiation-dependent serine

protease gene. It is expressed during adipocyte

differentiation and is a rate-limiting enzyme in the

alternative pathway of complement activation.

Adipsin is primarily found in adipocytes in mice

and in both adipocytes and monocytes-

macrophages in humans39. Further, adipsin is

required for the production of acylation stimulating

protein (ASP), a complement protein that affects

lipid and glucose metabolism by cleaving the

terminal arginine of C3a by carboxypeptidase B

(CbB)40. Decreased level of adipsin has been

reported in murines during obesity. However, in

humans increased adipsin level was reported with

adiposity, insulin resistance, dyslipidemia, and

cardiovascular disease40.

Apelin

It is a bioactive peptide produced in TNFα

stimulated adipose tissue. It is expressed during

adipocyte differentiation. Similar to insulin, plasma

and circulating apelin levels are increased in

obesity41.

Vaspin

Secretion of vaspin from AT is a

compensatory mechanism for the damage caused

by obesity and its complications. It is produced

from the VAT and is known to improve glucose

tolerance and insulin sensitivity in obese mice24. It

is believed that vaspin could be regarded as a new

link between obesity and related metabolic

disorders42.

Hepcidin

Being produced by liver, hepcidin is the

master regulator of iron homeostasis. It was later

identified as an adipokine that has a role in

mediation of antimicrobial immunity also43.

Synthesis of hepcidin depends on plasma iron

level, hypoxia and inflammatory stimuli. Induction

of hepcidin represents a component of the innate

immune response to acute infection, with the

potential to affect disease pathogenesis44.

Omentin

Omentin is also called as intelectin. It is

produced from omental AT (milky spots)45.

Through recognition of pathogens and bacterial

components it has acquired importance in innate

immune response against parasitic infection.

Further, the expression of omentin gene is altered

in obesity46.

Adipose tissue role in immunity (innate

and adaptive)

There are many other pieces of evidence

that signify the interplay between AT and

immunity47,48. Firstly, a close anatomical

interaction with lymphoid organs47. Secondly,

other than adipocytes, AT also secretes

31 Int. Res. J. Chem.

inflammatory cytokines and adipokines. Thirdly,

the AT exhibits anti-microbial and phagocytic

activity through adipose resident macrophages49.

Finally, excess adiposity activates a cascade of

events like ER stress and apoptosis of

adipocytes50. So, it is important to know how the

immune functions are carried out by AT.

Immunity is the protective mechanism of

the body that comprises of two different types –

innate and adaptive immunity. Activation of innate

immune system is induced by either pathogen

associated molecular patterns (PAMPs) from

pathogens or damage associated molecular

patterns (DAMPs) from dying cells, which are

recognized by pattern recognition receptors

(PRRs) of the host. The PRRs include toll-like

receptors (TLRs), nucleotide-binding

oligomerization domain (NOD)-like receptors

(NLRs), C-type lectin receptors (CLRs), and

retinoic acid–inducible gene (RIG)-I-like receptors

(RLRs). Subsequently, these signals lead to

activation of innate immune cells like

macrophages, dendritic cells (DCs), mast cells,

neutrophils, eosinophils and natural killer (NK)

cells51.

However, adaptive immune system is

different from the innate immune system in a way

that it is extremely specific against a particular

antigen. Adaptive immune mechanisms are

mediated by B or T lymphocytes, including many

subsets of T cell population like CD4+, CD8+ T,

and NK T (NKT) cells. These cells have highly

specific receptors on their surface called B cell

receptor (BCR) and T cell receptors (TCR), which

are equipped with the ability to recognize an

enormous number of antigens specifically52.

Immune cells in adipose tissue

Macrophages

Macrophages are the most abundantly

found leukocytes in AT53 and represent 5% of the

stromal vascular fraction in lean AT which

increases up to 25-30% in obese AT54. There are

two phenotypic states, M1 (classically activated)

and M2 (alternatively activated) macrophages

which reversibly switch among themselves

depending on the metabolic status of AT.

Normally, M2 phenotype macrophages present in

the AT helps to maintain the state of insulin

sensitivity through secretion of anti-inflammatory

cytokine IL-10. In contrary to M1 macrophages,

the pro-inflammatory M2 macrophages produce

IL-6 and TNF-α which are directly involved in local

and systemic inflammation and insulin

resistance55.

Dendritic cells

The DCs are professional antigen-

presenting cells that present antigen to T cells

through major histocompatibility complex (MHC)

II. Hence they are involved in both innate and

adaptive immunity56. They produce cytokines IL-

12 and IL-15 which are involved in inducing the

differentiation of naive T cells into Th1 T cells and

proliferation and activation of CD8 T cells and NK

cells, respectively57. Their circulating numbers are

increased in obesity and also have a role in the

aggregation of macrophages around the

adipocytes58.

Neutrophils

Neutrophils, the first leukocytes to arrive at

the site of inflammation, comprises of 1.5% of the

stromal vascular fraction of AT. The inflamed

adipocytes secrete neutrophil chemoattractant

protein, IL-859. Subsequently, through the

production of MCP-1 and other cytokines, the

neutrophils recruit the monocytes which

perpetuate the inflammation. In obese individuals,

elevated plasma myeloperoxidase level is

reported which is a neutrophil marker; indicative of

inflammation60,61.

Eosinophils

Eosinophils are the sentinels of WAT that

influences metabolic regulation and represent

about 5% of stromal vascular cells of AT which is

decreased in obesity62. They are produced in bone

marrow and then recruited into AT with the help of

IL-563. Primarily, these cells are more in lean

individuals and eosinophilia is linked with insulin

sensitivity. Their population is decreased in

obesity leading to insulin resistance. Mainly,

resident eosinophils of WAT are the primary

source of IL-4 and IL-13 which is required for

activation of M2 macrophages64.

Vidya et al 32

Mast cells

Mast cells are involved in the orchestration

of immune cells and activation of DCs thereby the

adaptive immunity65. There are two types of mast

cells, MT that express only tryptase and MCTC

which express both chymase and tryptase. MCTC

are the type of mast cells present in AT66. The

activated macrophages secrete a wide range of

pro- and anti-inflammatory cytokines (TNFα, IL-1β,

IL-6, IFNγ, TGF-β, IL-4 and IL-10). IL-6 and IFNγ

promote the inflammatory processes in the AT.

Accordingly, mast cells are accumulated in the

obese AT67.

T cells

The T cells are the important lymphocytes

of adaptive immunity. Further to macrophages,

both B and T lymphocytes are the other largest

groups of immune cells present in AT68. They are

produced in the bone marrow and maturation

takes place in thymus69. Based on their function,

they are divided into T helper cells (IFNγ-

producing Th1 cells, IL-4-producing Th2 cells, IL-

17-producing Th17 cells, and IL-10-producing

regulatory T cells) and cytotoxic T cells. T helper

cells bear CD4+ surface marker and MHC II

molecules on their surface through which they

present the antigen while cytotoxic T cells bear

CD8+ marker and MHC I molecule on their surface

for antigen recognition. The regulatory T cells bear

CD4+ marker on their surface70.

Th1

The Th1 cells are increased in obesity

while Th2 cells are reduced. Th1 cells secrete

IFNγ which directly helps in the polarization of M2

macrophages and thereby acts as a pro-

inflammatory immune cell68.

Tregs

Tregs are found in more numbers in lean

AT and they are reduced in obesity71. These

regulatory T cells are required by the AT to

maintain a normal anti-inflammatory state. Indeed,

they are involved in preventing the self-destructive

immune responses in AT. Further, they enroll

themselves in sustaining the macrophages in M2

state through secretion of IL-1071. Also, they

express peroxisome proliferator-activated

receptor gamma (PPARγ) factor which is crucial

for the anti-inflammatory function of Tregs72.

Cytotoxic T cells (CTLs)

The CTLs are the CD8+ T cell population.

Their numbers in circulation are increased by 3 to

4 fold in obesity. They increase the recruitment of

macrophages and expression of TNFα and IL-6

thereby promoting the inflammatory responses73.

Invariant natural killer T cells (iNKT)

The iNKT are a type of NK cells that

recognize antigen presented even by CD1d

antigen presenting molecules expressed by DCs,

macrophages, B cells and T cells74. Interestingly,

CD1d activated iNKT cells are known for their

ability to rapidly produce Th1 and Th2 cytokines.

These iNKT cells improve the insulin sensitivity.

Their numbers are more in murine and human AT

and are reversibly reduced in obesity75.

B-cells

B-cells are synthesized from the bone

marrow in an immature form which contains IgM

BCR. After being transported to various secondary

lymphoid organs like the spleen or lymph node, the

B cell undergoes complete maturation and

differentiates into other antibodies viz., IgA, IgD,

IgG, and IgE76. In lean animals, they provide

immunity against infection. However in obesity, B-

cells undergo functional changes and influence

the AT pathologically to develop insulin

resistance77. Furthermore, they also influence the

polarization of M2 to M1 macrophages and they

are involved in downregulation of Tregs78.

Cytokines secreted by adipose tissue

Cytokines are the hormonal messengers

involved in cell-mediated immunity. Obesity-

induced insulin resistance occurs in adipocytes,

hepatocytes, myocytes and β-cells whereas,

obesity-induced inflammation occur in the tissue-

infiltrating immune cells. Obesity-inflamed immune

cells produce cytokines that mediate the insulin

resistance and recruitment of other tissue-resident

immune cells. Cytokines can be grouped into two

functional types – pro-inflammatory (TNFα, IL-6,

IL-1 β, Plasminogen activator inhibitor-1 (PAI-1),

C-reactive protein, Monocyte chemoattractant

33 Int. Res. J. Chem.

protein (MCP-1) and anti-inflammatory cytokines

(IL-13, IL-4, IL-10)7.

Molecular mediators of AT inflammation

Lipids are the essential signaling moieties

in metabolic regulation79. Besides, they are also

required for enhancing the inflammatory gene

expression in AT80. There are many mechanisms

through which lipids carry out the inflammatory

functions. For example, (Toll Like Receptors)

TLRs, inflammasomes, nuclear receptors, cell

death, endoplasmic reticulum (ER) stress,

cytokines, and hypoxia.

The IKKβ/NFκB pathway

Nuclear factor-κB (NFκB) is a molecular

mediator of inflammation81. Resting cells have

NFκB bound to IκBα in the cytoplasm; so its

nuclear localization sequence (NLS) is

unexposed. Any stimuli like growth factors,

cytokines, and foreign pathogens activate the IKK

enzyme complex which phosphorylates Ser32 and

36 of IκBα inducing the proteasome-dependent

degradation of IκBα. It causes translocation of

NFκB into the nucleus finally leading to initiation of

the gene expression of various inflammatory

mediators like TNFα, IL-6, and MCP-1.

Jun N-terminal kinases (JNKs)

The Jun N-terminal kinase/stress-

activated protein kinases (JNK/ SAPKs) plays a

major role in insulin resistance through ER stress

pathway where it directly inhibits the insulin

signaling pathway and affects insulin-responsive

cells82.

Endoplasmic Reticulum Stress

The ER is the site for the synthesis, folding,

and secretion of the membrane and secretory

proteins. Acute shortage of proteins may lead to

accumulation of misfolded proteins and hence

disrupting the ER homeostasis. Finally, to maintain

ER homeostasis the unfolded protein response

(UPR) signaling pathway is activated83. This is a

potential mechanism in the pathologic

development of obesity and types 2 diabetes. The

stressors induce the activation of ER stress sensor

Inositol-requiring-enzyme 1α (IRE1α) or ER-

resilient eukaryotic translation inhibition factor 2α

(eIF2α) kinase PERK to cause the activation of

inflammatory signaling cascades, such as the JNK

and NF-κB pathways82.

Inflammasome pathway

The inflammasome is a high-molecular-

weight multimeric intracellular complex that plays

a major role in innate immunity84. There are four

classes of inflammasomes - the NLR family, pyrin

domain–containing 1 and 3 (NLRP1 and NLRP3),

CARD domain–containing 4 (NLRC4, also known

as IPAF), and absent in melanoma 2 (AIM2)

inflammasomes. This complex is activated by

(Danger Associated Molecular Patterns) DAMPs

or (Pathogen Asscociated Molecular Patterns)

PAMPs. Since excess adiposity mimics the

danger signals mediated by DAMPs or PAMPs,

inflammasome pathway has key role pathology of

obesity and insulin resistance85.

Peroxisome Proliferator-Activated Receptors

(PPAR)

The PPARα, PPARδ, and PPARγ nuclear

receptors are transcription factors which are

expressed by macrophages and adipocytes that

mediate the effects of fatty acids and their

derivatives on gene expression. Notably, these

nuclear receptors have a role in polarization of

macrophages towards M2 phenotype and hence

improve insulin sensitivity78. They interfere with the

activity of pro-inflammatory transcription factors

NF-κB, (Activator Proteins) AP-1, and (Signal

Transducers and Activators of Transcription)

STATs, and inhibit inflammatory gene expression.

Cell Death

Pathological apoptosis of cells releases

intracellular molecules known as damage-

associated molecular patterns (DAMPs) that

activate the innate and adaptive immune

systems86. In obesity, adipocytes may die by

apoptosis87 and/or by necrosis10 which signal for

the recruitment of immune cells or activate

inflammasomes via adipocyte-associated DAMPs.

Interplay between AT and immunity

Recently, there are many pieces of

evidence suggesting that there is a cross-talk

between metabolic and immune system86,87. This

cross-talk is mediated by adipokines, cytokines

and immune cells which are expressed by the AT.

Vidya et al 34

Excess deposition of adiposity causes

dysfunction, a disorder characterized by chronic

low-grade subclinical inflammation, leading to

insulin resistance and metabolic, type 2 diabetes

mellitus, cardiovascular disease (CVD),

dyslipidemia, hepatic steatosis, cancers,

respiratory infections and other infections. These

conditions may cause morbidity and sometimes

they may also result in mortality88.

Obesity increases the number and

activation levels of pro-inflammatory cells and thus

mimicking the signals elicited by bacterial

infection. Among various pro-inflammatory cells,

adipose tissue macrophages are highly increased

in obesity.

Role of AT in Cancer:

Mechanism linking obesity and cancer is

not clear however the association of obesity with

chronic inflammation cannot be denied89.

Accumulation of AT in individuals leads to obesity

over a period of time. This increase in the AT

causes chronic hyperinsulinaemia with alteration

in peptide and steroid hormones. This alteration is

postulated for the development of cancer90.

Obesity related hormones/growth factors plays

vital role in the cross talk between adipocytes,

macrophages, and epithelial cells during cancer.

Dysfunction of adipose tissue, obesity towards

growth factor signaling and chronic inflammation

might also contribute to cancer91.

In obesity, hypertrophy of adipocyte,

hyperplasia of AT, alter the regulations within the

ATs leading to adiposopathy which actually means

promotion of pathogenic adipocytes and AT

related disorders92. It has been estimated that 20%

of all cancers are caused by excess weight gain.

Some common cancers that have increased risk

of occurrence with increased adiposity are

prostate, colon, breast, endometrial and

pancreatic cancers93. Leptin synthesized from AT

plays a vital role in autoimmune disorder by

maintaining immune suppression in individuals by

maintain a balance between metabolism and

immunity. In vitro studies of leptin on cancer cells

are indicative of proliferation of various cancers

due to leptin. The general effects of leptin in cancer

research include proliferation, cell survival,

angiogenesis, and subsequent cancer

progression94.

Adiponectin is one of the only adipocyte-

secreted protein with beneficial effects on health.

When adiponectin is decreased with obesity,

known as hypoadiponectinemia, as the result of

increased secretion of other cytokines like TNFα,

its anti-disease properties are also decreased. As

the most prolific protein secreted by adipocytes,

adiponectin is anti-inflammatory, pro-apoptotic,

and anti-proliferative under normal

circumstances95. There are two ways the hormone

can effect cancer retardation: either directly on the

tumor cells as several cancer lines express

adiponectin receptors or through its insulin-

sensitizing effects. Either way, decreases in

adiponectin have been associated with breast,

endometrial, colon, esophageal, and liver cancer

among many others96.

Cytokines are another class of molecule

that have been heavily indicated in the induction

and pathogenesis of cancer. Cytokines are

primarily linked to the development of cancers by

way of their influence on inflammation, mainly

chronic low grade inflammation associated with

many diseases such as obesity, hence

inflammation is one of the major factors that links

obesity to the development of its associated co-

morbidities97. Further, Apelin produced and

secreted by adipocytes, had been demonstrated

to play a role in lymph node metastasis and

lymphangiogenesis via binding to its receptor in

lymphatic endothelial cells that activates ERK and

PI3K pathways, leading to cell proliferation,

migration, and cell survival98. In addition, studies

on visfatin, resistin, and chemerin shown that

these adipokines enhance the progression of

cancers, while omentin shown anti-cancerous

action97.

Conclusion

Apart from its usual involvement in energy

metabolism, AT was also found to control other

important biological functions in mammals through

secretion of specialized molecules called

adipokines. Among these adipokines, leptin and

adiponectin are the predominant ones involved in

controlling additional biological functions. Further,

35 Int. Res. J. Chem.

it was also established that AT plays a huge role

in controlling the immune functions in mammals. In

addition, AT was also found to be associated with

controlling immunity and autoimmune disorders in

mammals. All these findings signify the importance

of AT in controlling various immune functions in

mammals and the most noteworthy progress

made was to elucidate its role in cancer biology.

Future research efforts are necessary to further

understand the hidden intricacies of AT in

controlling all these biological functions.

Conflict of Interest Statement

The authors declare that there is no any conflict of

interest for this manuscript

Acknowledgement

The authors extend their sincere thanks to director

NIANP for giving permission for submitting this

manuscript.

References:

Trayhurn P and Wood IS. 2005. Signalling role of

adipose tissue: adipokines and inflammation in

obesity. Biochem. Soc. Trans., 33: 1078-1081.

Tilg H and Moschen AR. 2006. Adipocytokines:

mediators linking adipose tissue, inflammation and

immunity. Nature Rev. Immunol., 6: 772-783.

Schipper HS, B Prakken, E Kalkhoven and M Boes.

2012. Adipose tissue-resident immune cells: key

players in immunometabolism. Trends Endocrinol.

Metabol., 23: 407-415.

Freedland ES. 2004. Role of critical visceral adipose

tissue threshold in metabolic syndrome: implications

for controlling dietary carbohydrates. Nutr. Metabol., 1:

12-35.

Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H,

Okamoto Y, Hotta K, Nishida M, Takahashi M,

Nakamura T. and Yamashita, S. 1999. Novel

modulator for endothelial adhesion molecules

adipocyte-derived plasma protein adiponectin.

Circulation., 100: 2473-2476.

Cannon B, Hedin A and Nedergaard J. 1982.

Exclusive occurrence of thermogenin antigen in brown

adipose tissue. FEBS Lett., 150: 129-132.

Coppack SW 2001. Pro-inflammatory cytokines and

adipose tissue. Proc. Nutr. Soc., 60: 349-356.

Kershaw EE and Flier JS. 2004. Adipose tissue as an

endocrine organ. J. Clinic. Endocrinol. Metabol., 89:

2548-2556.

Blanchette-Mackie EJ, Dwyer NK, Barber T, Coxey RA

Takeda T, Rondinone CM, Theodorakis JL,

Greenberg AS and Londos C. 1995. Perilipin is located

on the surface layer of intracellular lipid droplets in

adipocytes. J. Lipid Res., 36: 1211-1226.

Cinti S, 2009. Transdifferentiation properties of

adipocytes in the adipose organ. Am. J. Physiol.

Endocrinol. Metab., 297: E977-E986.

Rolfe EDL, Ong KK, Sleigh A, Dunger DB, Norris S A,

2015. Abdominal fat depots associated with insulin

resistance and metabolic syndrome risk factors in

black African young adults. BMC Public Health, 15:

1013

Joyner JM, Hutley LJ and Cameron DP 2000.

Glucocorticoid receptors in human preadipocytes:

regional and gender variations. J. Endocrinol., 166:

145-152.

Hellmer J, Marcus C, Sonnefeld T and Arner P. 1992.

Mechanisms for differences in lipolysis between

human subcutaneous and omental fat cells. J. Clin.

Endocrinol. Metab., 75: 15-20.

Rohner-Jeanrenaud F and Jeanrenaud B. 1996. The

discovery of leptin and its impact in the understanding

of obesity. European journal of endocrinology, 135:

649-650.

Zhang Y, Proenca R, Maffei M, Barone M, Leopold L

and Friedman JM. 1994. Positional cloning of the

mouse obese gene and its human homologue. Nature,

372: 425-432.

Bado A, Levasseur S, Attoub S, Kermorgant S,

Laigneau JP, Bortoluzzi MN, Moizo L, Lehy T and

Guerre-Millo M. 1998. The stomach is a source of

leptin. Nature, 394: 790-793.

Zhang F, Basinski MB, Beals JM, Briggs, SL, Churgay

LM, Clawson DK and DiMarchi RD. 1997. Crystal

structure of the obese protein leptin-E100. Nature,

387: 206-209.

Fong TM, Huang RR, Tota MR, Mao C, Smith T,

Varnerin J, Karpiyskiy VV, Krause JE and Van der

Ploeg LH. 1998. Localization of leptin binding domain

in the leptin receptor. Mol. Pharmacol., 53: 234-240.

Vidya et al 36

Baumann H, Symes AJ, Comeau MR, Morella KK,

Wang Y, Friend D, Ziegler SF, Fink JS and Gearing

DP 1994. Multiple regions within the cytoplasmic

domains of the leukemia inhibitory factor receptor and

gp130 cooperate in signal transduction in hepatic and

neuronal cells. Mol. Cell Biol., 14: 138-146.

Otero M, Lago Gomez R, C Dieguez, F Lago, J

Gomez-Reino and Gualillo O. 2006. Towards a pro-

inflammatory and immunomodulatory emerging role of

leptin. Rheumatology, 45: 944-950.

Madej T. 1998. Considerations in the use of lipid-

based drug products. J. Intraven. Nurs., 21: 326-329.

Sarraf P, Frederich RC, Turner EM, Ma G, Jaskowiak

NT, Rivet DJ, Flier JS and Lowell B. 1997. Multiple

cytokines and acute inflammation raise mouse leptin

levels: potential role in inflammatory anorexia. J. Exp.

Med., 185: 171-175.

Ozata M, Ozdemir IC and Licinio J. 1999. Human

leptin deficiency caused by a missense mutation:

multiple endocrine defects, decreased sympathetic

tone, and immune system dysfunction indicate new

targets for leptin action, greater central than peripheral

resistance to the effects of leptin, and spontaneous

correction of leptin-mediated defects. J. Clin.

Endocrinol. Metab., 84: 3686-3695.

Lago F, Dieguez C, Gómez-Reino J and Gualillo O

2007. Adipokines as emerging mediators of immune

response and inflammation. Nature Clinical Practice,

3: 716-724.

Minokoshi Y and Kahn BB. 2003. Role of AMP

activated protein kinase in leptininduced fatty acid

oxidation in muscle. Biochem. Soc. Trans., 31: 196-

201.

Garcia-Mayor RV, Andrade MA, Rios M, Lage M,

Dieguez C and Casanueva FF, 1997. Serum leptin

levels in normal children: Relationship to age, gender,

body mass index, pituitary-gonadal hormones, and

pubertal stage 1. J. Clin. Endocrinol. Metabol. 82(9):

2849-2855.

Takaya K, Ogawa Y, Isse N, Okazaki T, Satoh, N.,

Masuzaki H, Mori K and Tamura N. 1996. Molecular

cloning of rat leptin receptor isoform complementary

DNAs-identification of a missense mutation in Zucker

fatty (fa/fa) rats. Biochem. Biophys. Res. Commun.,

225: 75-83.

Fantuzzi G. 2005. Adipose tissue, adipokines, and

inflammation. J. Allergy Clin. Immunol., 115: 911-919.

Goren I, Kampfer H, Podda M, Pfeilschifter J and

Frank S. 2003. Leptin and wound inflammation in

diabetic ob/ob mice: differential regulation of

neutrophil and macrophage influx and a potential role

for the scab as a sink for inflammatory cells and

mediators. Diabetes, 52: 2821-2832.

Faggioni R, Feingold KR and Grunfeld C. 2001. Leptin

regulation of the immune response and the

immunodeficiency of malnutrition. FASEB J., 15:

2565-2571.

Dumond H, Presle N, Terlain B, Mainard D, Loeuille D,

Netter P and Pottie P. 2003. Evidence for a key role of

leptin in osteoarthritis. Arthritis & Rheumatism, 48(11):

3118-3129.

Yamauchi T, Iwabu M, Okada-Iwabu M and Kadowaki,

T. 2014. Adiponectin receptors: a review of their

structure, function and how they work. Best Pract. Res

Clin. Endocrinol. Metab., 28(1):15-23.

Dumond H, Presle N, Terlain B, Mainard D, Loeuille D,

Netter P and Pottie P. 2003. Evidence for a key role of

leptin in osteoarthritis. Arthritis & Rheumatism, 48(11):

3118-3129.

Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS and

Lodish HF. 2004. T-cadherin is a receptor for

hexameric and high-molecular-weight forms of

Acrp30/adiponectin. Proc. Natl. Acad. Sci. U.S.A.,

101(28): 10308-10313.

Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K,

Miyagawa J, Hotta K, Shimomura I, Nakamura T,

Miyaoka K, Kuriyama H, Nishida M, Yamashita S,

Okubo K, Matsubara K, Muraguchi M, Ohmoto Y,

Funahashi T, Matsuzawa Y. 1999. Paradoxical

decrease of an adipose-specific protein, adiponectin,

in obesity. Biochem Biophys Res Commun.,

257(1):79-83.

Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney

A and Henzel W. 2000. FIZZ1, a novel cysteine-rich

secreted protein associated with pulmonary

inflammation, defines a new gene family. EMBO J., 19:

4046-4055.

Banerjee RR and Lazar MA. 2003. Resistin: molecular

history and prognosis. J. Mol. Med., 81: 218-226.

Fukuhara A, Matsuda M, Nishizawa M., Segawa K,

Tanaka M, Kishimoto K, Matsuki Y, Murakami M,

Ichisaka T, Murakami H. and Watanabe E. 2005.

37 Int. Res. J. Chem.

Visfatin: a protein secreted by visceral fat that mimics

the effects of insulin. Science, 307: 426-30.

Gabrielsson BG, Johansson JM, Lonn M, Jernas M,

Olbers T and Peltonen M. 2003. High expression of

complement components in omental adipose tissue in

obese men. Obes. Res., 11: 699-708.

Liu Y, Gupta P, Lapointe M, Yotsapon T, Sarat S,

Cianflone K. 2014. Acylation stimulating protein,

component C3 and lipid metabolism in ketosis-prone

daiabetic subjects. Plos One 9(10): e109237.

Daviaud D, Boucher J, Gesta S, Dray C, Guigne C and

Quilliot D. 2006. TNFalpha up-regulates apelin

expression in human and mouse adipose tissue.

FASEB J., 20: 1528-1530.

Dimova R. and Tankova T. 2015. The role of vaspin in

the development of metabolic and glucose tolerance

disorders and atherosclerosis. BioMed Research

International. Article ID 823481, 7 pages.

Bekri S, Gual P, Anty R, Luciani N, Dahman M,

Ramesh, B, Iannelli A, Staccini–Myx A, Casanova D,

Amor IB. and Saint–Paul MC. 2006. Increased

adipose tissue expression of hepcidin in severe

obesity is independent from diabetes and NASH.

Gastroenterology, 131(3): 788-796.

Armitage AE, Eddowes LA, Gileadi U, Cole S,

Spottiswoode N, Selvakumar TA, Ho LP, Townsend

AR and Drakesmith H. 2011. Hepcidin regulation by

innate immune and infectious stimuli. Blood, 118:

4129-4139.

Schäffler A, Neumeier M, Herfarth H, Fürst A,

Schölmerich J and Büchler C. 2005. Genomic

structure of human omentin, a new adipocytokine

expressed in omental adipose tissue. Biochimica et

Biophysica Acta (BBA)-Gene Structure and

Expression, 1732: 96-102.

de Souza Batista CM, Yang RZ, Lee MJ, Glynn NM,

Yu DZ, Pray J, Ndubuizu K, Patil S, Schwartz A,

Kligman M. and Fried SK. 2007. Omentin plasma

levels and gene expression are decreased in obesity.

Diabetes, 56: 1655-1661.

Pond CM. 2003. Paracrine relationships between

adipose and lymphoid tissues: implications for the

mechanism of HIV-associated adipose redistribution

syndrome. Trends Immunol., 24: 13-18.

Matarese G and La Cava A. 2004. The intricate

interface between immune system and metabolism.

Trends Immunol., 25: 193-200.

Saillan-Barreau C, Cousin B, Andre M, Villena P,

Casteilla L and Penicaud L. 2003. Human adipose

cells as candidates in defense and tissue remodeling

phenomena. Biochem. Biophys. Res. Commun., 309:

502-505.

Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ,

Sole J, Nichols A, Ross JA, Tartaglia LA and Chen H.

2003. Chronic inflammation in fat plays a crucial role

in the development of obesity-related insulin

resistance. J. Clin. Invest., 112: 1821-1830.

Mills KH, 2011. TLR-dependent T cell activation in

autoimmunity. Nature Rev. Immunol., 11: 807-822.

Janeway CA and Medzhitov R. 2002. Innate immune

recognition. Annu. Rev. Immunol., 20: 197-216.

Chawla A, Nguyen KD and Goh YP. 2011.

Macrophage-mediated inflammation in metabolic

disease. Nature Rev. Immunol., 11: 738-749.

Nishimura S, Manabe I, Naqasaki M, Eto K,

Yamashita, H., Ohsuqi M and Otsu M, 2009. CD8+

effector T cells contribute to macrophage recruitment

and adipose tissue inflammation in obesity. Nature

Med., 15: 914-920.

Wentworth JM, Naselli G, Brown WA, Doyle L,

Phipson B, Smyth GK, Wabitsch M, O’Brien PE and

Harrison LC. 2010. Pro-inflammatory

CD11cCCD206C adipose tissue macrophages are

associated with insulin resistance in human obesity.

Diabetes, 59: 1648-1656.

Wu L and Liu YJ. 2007. Development of dendritic-cell

lineages. Immunity, 26: 741-750.

Hashimoto D, Miller J and Merad M. 2011. Dendritic

cell and macrophage heterogeneity in vivo. Immunity,

35: 323-335.

Dominguez PM and Ardavin C. 2011. Differentiation

and function of mouse monocytederived dendritic cells

in steady state and inflammation. Immunol. Rev., 234:

90-104.

Gerhardt CC, Romero IA, Cancello R, Camoin L and

Strosberg AD. 2001. Chemokines control fat

accumulation and leptin secretion by cultured human

adipocytes. Mol. Cell Endocrinol., 175: 81-92.

Vidya et al 38

Talukdar S, Oh DY, Bandyopadhyay, G, Li D, Xu J,

McNelis J and Liu M, 2012. Neutrophils mediate

insulin resistance in mice fed a high-fat diet through

secreted elastase. Nature Med., 18: 1407-1412.

Andrade VL, Petruceli E and Belo VA. 2012.

Evaluation of plasmatic MMP-8, MMP-9, TIMP-1 and

MPO levels in obese and lean women. Clin. Biochem.,

45: 412-415.

Gleich GJ and Adolphson CR. 1986. The eosinophilic

leukocyte: structure and function. Adv Immunol.

39:177-253.

Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ,

Cheng LE, Mohapatra A. Chawla, A. and Locksley,

R.M. 2013. Innate lymphoid type 2 cells sustain

visceral adipose tissue eosinophils and alternatively

activated macrophages. J. Exp. Med., 210: 535-549.

Wu D, Molofsky AB, Liang HE, RR Ricardo-Gonzalez,

HA Jouihan, JK Bando, A Chawla and RM Locksley,

2011. Eosinophils sustain adipose alternatively

activated macrophages associated with glucose

homeostasis. Science, 332: 243-247.

Gri G, Frossi B, D'Inca F, Betto E, Mion F, Sibilano R

and Pucillo C. 2012. Mast cell: an emerging partner in

immune interaction. Front. Immunol., 3: 120.

Xu JM, Shi GP. 2012. Emerging role of mast cells and

macrophages in cardiovascular and metabolic

diseases. Endocr. Rev., 33: 71-108.

Altintas MM, Nayer B and Walford EC, 2012. Leptin

deficiency-induced obesity affects the density of mast

cells in abdominal fat depots and lymph nodes in mice.

Lipids Health Dis., 11: 21.

Winer DA, Winer S, Shen L, Wadia PP, Paltser G,

Tsui, H. and Wu, P. 2011. B cells promote insulin

resistance through modulation of T cells and

production of pathogenic IgG antibodies. Nature Med.,

17: 610-617.

Koch, U. and Radtke, F. 2011. Mechanisms of T cell

development and transformation. Annu. Rev. Cell

Dev. Biol., 27: 539-562.

Oestreich, K.J. and Weinmann, A.S. 2012. Master

regulators or lineage-specifying. Changing views on

CD4+ T cell transcription factors. Nature Rev.

Immunol., 12: 799-804.

Feuerer, M., Herrero, L., Cipolletta, D., Naaz, A.,

Wong, J., Nayer, A., Lee, J., Goldfine, A.B., Benoist,

C. and Shoelson, S., 2009. Lean, but not obese, fat is

enriched for a unique population of regulatory T cells

that affect metabolic parameters. Nature Med., 15:

930-939.

Cipolletta, D., Feuerer, M., Li, A., Kamei, N., Lee, J.,

Shoelson, S.E., Benoist, C. and D. Mathis, 2012.

PPAR-g is a major driver of the accumulation and

phenotype of adipose tissue Treg cells. Nature, 486:

549-553.

Rausch, M.E., Weisberg, S., Vardhana, P. and

Tortoriello, D.V. 2008. Obesity in C57BL/6J mice is

characterized by adipose tissue hypoxia and cytotoxic

T-cell infiltration. Int. J. Obes., 32: 451-463.

Gumperz, JE, 2006. The ins and outs of CD1

molecules: bringing lipids under immunological

surveillance. Traffic, 7: 2-13.

Lynch L, Nowak M, Varghese B, Clark J, Hogan AE,

Toxavidis V, Balk SP, O’Shea D, O’Farrelly C and

Exley MA. 2012. Adipose tissue invariant NKT cells

protect against diet-induced obesity and metabolic

disorder through regulatory cytokine production.

Immunity, 37: 574-587.

LeBien TW and Tedder TF. 2008. B lymphocytes: how

they develop and function. Blood, 112: 1570-1580.

DeFuria J, Belkina AC, Jagannathan-Bogdan M,

Snyder-Cappione J, Carr JD, Nersesova YR,

Markham D, Strissel KJ, Watkins AA and Zhu M. 2013.

B cells promote inflammation in obesity and type 2

diabetes through regulation of T-cell function and an

inflammatory cytokine profile. PNAS, 110: 5133-5138.

Kang K., Reilly SM, Karabacak V, Gangl MR and

Fitzgerald K. 2008. Adipocyte-derived Th2 cytokines

and myeloid PPARdelta regulate macrophage

polarization and insulin sensitivity. Cell Metab., 7: 485-

495.

Dresner A, Laurent D, Marcucci M, Griffin ME and

Dufour S. 1999. Effects of free fatty acids on glucose

transport and IRS-1-associated phosphatidylinositol 3-

kinase activity. J. Clin. Invest., 103: 253-259.

Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H and

Flier JS. 2006. TLR4 links innate immunity and fatty

acid-induced insulin resistance. J. Clin. Invest., 116:

3015-3025.

Ghosh G, Wang VY, Huang DB and Fusco A. 2012.

NF-kappaB regulation: lessons from structures.

Immunol. Rev., 246: 36-58.

39 Int. Res. J. Chem.

Hotamisligil GS. 2010. Endoplasmic reticulum stress

and the inflammatory basis of metabolic disease. Cell,

140: 900-917.

Ron D and Walter P. 2007. Signal integration in the

endoplasmic reticulum unfolded protein response.

Nature Rev. Mol. Cell Biol., 8: 519-529.

Strowig T, Henao-Mejia J, Elinav E and Flavell R.

2012. Inflammasomes in health and disease. Nature,

481: 278-286.

Vandanmagsar B, Youm YH, Ravussin A, Galgani JE

and Stadler K. 2011. The NLRP3 inflammasome

instigates obesity-induced inflammation and insulin

resistance. Nature Med., 17: 179-188.

Rock KL. and Kono H. 2008. The inflammatory

response to cell death. Ann. Rev. Pathol., 3: 99–126.

Alkhouri N, Gornicka A, Berk MP, Thapaliya S and

Dixon LJ. 2010. Adipocyte apoptosis, a link between

obesity, insulin resistance, and hepatic steatosis. J.

Biol. Chem., 285: 3428-3438.

Flegal KM, Graubard BI, Williamson DF and Gail MH.

2007. Cause specific excess deaths associated with

underweight, overweight, and obesity. JAMA, 298:

2028-2037.

Hursting SD, Dunlap SM, Ford NA, Hursting MJ and

Lashinger LM. 2013. Calorie restriction and cancer

prevention: a mechanistic perspective. Cancer

Metab., 1(1):10. doi: 10.1186/2049-3002-1-10.

Calle EE and Kaaks R. 2004. Overweight, obesity and

cancer: epidemiological evidence and proposed

mechanisms. Nat. Rev. Cancer, 4: 579–591.

Harvey AE, Lashinger LM, and Hursting SD. 2011.

The growing challenge of obesity and cancer: an

inflammatory issue. Ann. N.Y. Acad. Sci. 2011, 45–52.

Booth A, Magnuson A, Fouts J and Foster M. 2015.

Adipose tissue, obesity and adipokines: role in cancer

promotion. Horm Mol Biol Clin Invest. 21: 57–74.

Rodriguez C, Freedland SJ, Deka A, Jacobs EJ,

McCullough ML, Patel AV, Thun MJ and Calle EE.

2007. Body mass index, weight change, and risk of

prostate cancer in the Cancer Prevention Study II

Nutrition Cohort. Cancer Epidemiol Biomarkers Prev.

16: 63–9.

Roberts DL, Dive C and Renehan AG. 2010. Biological

mechanisms linking obesity and cancer risk: new

perspectives. Ann Rev Med. 61: 301–16.

Dalamaga M, Diakopoulos KN and Mantzoros CS.

2012. The role of adiponectin in cancer: a review of

current evidence. Endocr Rev. 33: 547–94

Barb D, Williams CJ, Neuwirth AK and Mantzoros CS.

2007. Adiponectin in relation to malignancies: a review

of existing basic research and clinical evidence. Am J

Clin Nutr. 86: 858–66.

Taniguchi K and Karin M. 2014. IL-6 and related

cytokines as the critical lynchpins between

inflammation and cancer. Semin Immunol., 26: 54–74.

Berta J, Hoda MA, Laszlo V, Rozsas A, Garay T, Torok

S, Grusch M, Berger W, Paku S, Renyi-Vamos F,

Masri B, Tovari J, Groger M, Klepetko W, Hegedus B

and Dome B. 2014. Apelin promotes

lymphangiogenesis and lymph node metastasis.

Oncotarget. 5: 4426–37.

Vidya et al 40