Adipose tissue as an endocrine organ

Farshad Mirzavi
Ph.D candidata of clinical biochernistry

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 Outline

o lntroduction
o Leptin
o Adiponecti11
· o Resistin
o Visfatin
o Omentin

.
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.••• . www.fppt.inf

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•
 lntroduction

o Adipose tissue:
• White adipose tissue (WAT): stores
energy
• Brown adipose tissue (BAT: generates body heat

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 WA v s BAT
T '
Vv'hi Brow
te n
Brown
adiposa
ussue Parivascular
adiposa
tissue

Bona marrow Epicardial

Function adiposa tlssue i---.i[I adipose
nssue

L.tpl
d

:s.
dropJ Subcutanaous
et adiposa tíssue ~~----Ji Visceral
·..=::::2:.....t._+-- adiposa

•• •• =:::P- tíssue

UCP
4
>t.info
 The m111 siiggnniiffiiccaanntt oo WAA
o0stt
ysiioolloCoagulation
pphhyVascular oggiiccaall f TT
tone control lmmuníty

ffuunnccttiioonns
Appetite
Others regulatío
n

~ Glucose
and lipid
metabolís
m

Fibrinolysis
Reproduction
•
Angiogenesis
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 AAddii ttiissu as a31 en11ddocCJ oor·g
ppose n1 r"i.ne gan11
e FF
A Leptin
IL-6

TNF-a

Angiotensin
WAT Se

x
steroids
Adiponectin
• Omentin

•• Resistin
Visfarin
G1 u
cocorticoids
6
.. www.fppt.info
 Leptin
o Discovery in 1994.

o Derived from the Greek word “λεπτός” )LLeeppttooss) “tthhiin

( meaning n“.

o Aexpressed
o Is small peptide
by the (16LkDa)
LEEPPwith)also
167 known
amino as
acids.
the ob(.

ggiseen
o Ob gene (Ob for obese) nee, on chromosome 7q31.
located

• Is expressed mainly by adipose tissue, but also found in the

o•• skeletal muscle, gastric and mammary epithelium and the
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brain. www.fppt.info
 Leptin ...

o II iinnccrreeaasseedd bbyy::

o ss
Food intake, insulin, glucocorticoids and
 proinflammatory cytokines.

o
Is decreased by:

 Fasting, cold exposure, exercise, adrenergic

stimulation,
growth hormone, thyroid hormone, melatonin, smoking,
..

.• .. thiazolidinediones and with increasing age. 8

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 Leptin..
o Its levels aarree hhiigg.hheerr in females
males, partly as a result

than
 Inhibition by androgens, stimulation by
of:
estrogen.
 Females have a higher proportion of subcutaneous fat
(Leptin synthesis is greater in subcutaneous than in visceral
adipose tissue).

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 Leptin unctions
Helps regulate the synthesís
of thyroid hormones Decreases
• glucose-stimul ated
o Signals to the insulin secretion
brain about body fat stores.
o
Regulation of appetite and energy expenditure.
pressure

f lncreased
o And wide variety of physiological functions: heart rate

• Modulation ofcellt he reward circuitry for feeding, glucose metabolism,

Activation of
s
immune

lipid oxidation, substrate partitioning, and adipocyte apoptosis.

•
l Regulate
bone mass

•
•
.
Regulating the
menstrual cycle 10
. www.fppt.info
 Leptin vs ghrelin
Lept\n
Ghre\\n~- Ghrelin Leptin
~~
Hu
nger Satiety

•
BEFO EATIN AFTER
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 Leptin..
o Mutation in the:
 Leptin gene (ob / .ob)
or Obesity
 Leptin receptor (db / db)

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 Analytical aspects of leptin

o Serum
leptin concentrations show a moderate circadian
variation:

A peak during the night at 02: 00.

 The leptin concentrations at this time are 30–100% higher than in
the
morning or early afternoon.

o There is
no alteration in measured leptin concentrations in samples
20 °C over a 2-year period.
stored at 13
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 Measurement of leptin

o Radioimmunoassay (RIA) and ELISA procedures:

o suitable
for the measurement of leptin in fluids plasma or in serum from

patients with anorexia nervosa, which have much lower leptin concentrations.

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 Anorexi nervosa vs nervos
a bulimia a
Anorexia Bulimia
nervosa nervosa
Weight
•
•
Eating Signif1cantly Normal weight or
habit underweight • overweight
• Eat httle food/íew
purges by vomiting usi
Eat farge amount off ng
and/or
calories ood, then
laxanves.
Body • Too concern on weight • Too concern on &
' image & weight
4
• appearance. appearance.
Dangerously thin but
has false irnage that
Medica! the body fatigue
Weakne rs still fat Weakness, fat1gue
sympto • ss, •
.ms
defícien Oehvdranon 15
Nutnuon
ces • Mouth and throat suc www.fppt.info
o
Also known as:
 AdipoQ,
 Gelatin-Binding Protein of 28 kDa (GBP28),
 Adipose most abundant gene transcript 1 (apM1),
 Adipocyte Complement-Related Protein of 30 kDa
(ACRP30).
o
Is a protein hormone with 224444

o
The adiponectin gene on chromosome
aa1m11ii1n1o3q27
0 was described in 1995.
aacciidds..
.
.
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 Adiponectin ...

o This adipokine circulates in three isoforms:

 A trimer, low molecular weight (LMW),

 A hexamer (trimer-dimer) of medium molecular weight (MMW),

 A multimeric high molecular weight of (HMW).

o Circulating adiponectin concentrations are high (500 –30000

μg/L).
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 Adiponectin ...

o Adiponectin exists as a:

oo ffuullll--lleennggtthh

AAddiippoonneecctitnin
 Circulates in trimeric, hexameric and higher order complexes.
((ffAAddpp))::
oo gglloobbuullaarr AAddiippoonneecctitnin ((ggAAddpp))::
 Mw=30 kDa

• A fragment containing the globular domain of

adiponectin
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which has potent metabolic effects in various tissues. www.fppt.info
 Adípenectln receptors

o They contain 7 transmembrane domains:

./ AAddiippoo RR1l::

 Is expressed mainly in s k e l e t a l but also found in the
s ke l c t a l
hypothalamus, liver andmmu
other tissues.
ussccllee
 Works with high affinity with gAdp and low affinity
with
fAdp.

./ AAddiippoo RR22::

• Is expressed primarily in the liver, but is also found in

skeletal
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 Adiponectin functions

o Is involved in rreegguullaattiinngg
and f a t t y a c i d
f at t y a ci d

gglluuccoosand
o May play anti-atherogenic see anti-inflammatory
lleevveells bbrreeaakkddoowwnn.
roles.

 Plasma adiponectin concentrations are decreased in patients with

CAD.
 It is conceivable that the use of recombinant adiponectin may become
beneficial in the prevention of cardiovascular disease.

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 Adiponectin fi

Adiponectin

t inflammation
-l- glucose output t glucose uptake -l- endothel ial adhesion
t fat accumulation r-l-energy expenditure
fat accumulation '1, foam cel 1
formation
t inflammation
Protection from:
• Insul in-resistance
• Type 2 diabetes 21
• Coronary artery disease 1pt.info
 Adiponectin ...

o Neeggaattiiv ccoorrrreell wwiitt o PPoosiittiivveellyy wwiitt

veellyy aattees hh: o ccoorrrreellaatteess hh::

 Obesity,
Percentage of body fat,  HDL-C,
BMI, insulin
 Fasting  Type I diabetes,
concentration,  Anorexia nervosa
 Coronary artery disease,
 Type II diabetes,
 plasma triglycerides.

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 Analytical aspects of adiponectin

o TNFα
produced by WAT in obesity and suppresses
adiponectin. effect of TNFα.
o Thiazolidinediones prevent this inhibitory
o Both insulin and IGF-1 increase adiponectin synthesis in WAT.

o Serum adiponectin concentrations were high

in thin individuals and low in
obese individuals.
o Moreover, surgical treatment of morbid obesity by gastric partition surgery
leads to an increase in plasma adiponectin concentration, which is
significantly correlated with body weight reduction.

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 Measurement of adiponectin

o Competitive RIAs and sandwich ELISAs:

 RIA has a lower limit of detection of 1

μg/L.
 ELISA has lower limits of detection of 0.079 –0.891
μg/L.

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 Resistin

o Discovered in 2001.

rreesii sttaa
in mice injected
o Is called “resistin”: because of
insulin with resistin. nnccee

o Is a 12.5-kDa protein, contains 110088 aa1m1 aacciid

o Contains high quantities of cysteine. 1iin11 ds. •

o Is encoded by the RREET

gene. oo

TN N
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 Res1. s tin...

o
Is secreted not only by aaddiippooc but also by a large number of
cells, in particular i1111111u11oco111¡Jete11t
•

cyyttees,
mmunocompetent cceelllls.
o
Circulates in human blood as a dimeric protein consisting of two
92 amino acid polypeptides that are linked by a disulfide bridge
at Cys-26.

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 Resistin ...

o
Release of resistin stimulated by:
 Inflammation,
 LPS (Lipopolysaccharide),
 Il-6,
 TNF α,
 Hyperglycemia,
 Growth and gonadal hormones.

.• . Thiazoladinedione drugs suppress the production of resistin.

•

•• ..
o
. ..
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 s of resistin in pa hophysío ogical conditions

o
Very little is known about the potential function of resistin.

Rtesí•·stl.

n ( Hypertensio )
n

1 Atlh e rogen
nsulln ic
1

resísta dysl i :pi d

nce em ia
( Heart ]
faílure 28
. www.fppt.info
 Analytical aspects of resistin

o There is n11 ccoorrrreella

between resistin mRNA expression and:

 Body weight,
o0 attiioonn
 Obesity,

 Insulin resistance.

o Resistin concentrations in persons with type 2 diabetes do not

differ from concentrations in the general population .

o Plasma resistin concentrations are decreased in anorectic patients.

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 Visfatin
o
Was first described in 2005.
Is a 52 kDa protein with 491 amino acids.
o
Also known as:
o
 pre-B-cell colony-enhancing factor 1(PBEF1),
 Nicotinamide phosphoribosyltransferase (NAmPRTase or
Nampt).
Is encoded by the
o
N AAMMPPTproduced
IsTprincipally T gene. by visceral adipose tissue, so is called visfatin.
o
adipose tissue, and in small
o Also produced by mmaaccrroopphhaaggees of the

.
•.
. quantities
visceral
by ssuubbccuuttaanneeoouus 30
• www.fppt.info
 v· sfat as a drug target

o
Nampt i
is a rraattee--
in the NAD+ salvage pathway that
converts nicotinamide to nicotinamide
l1ii1m11ii ttiinngg
mononucleotide (NMN).

o
APO866 is an
ee1nexperimental
1zzyy1m11 ee drug that inhibits this enzyme.

 It is being tested for treatment of advanced mmeellaannoommaa,

ly m p h(C T
and r e f r a c t o r y o r ccuButt-aacnnhcer ooounuissc TT--
l y mp h ( CT r ef r a c t o r y or B- c h r o n i c
5-phosphoribosyl-t-
oommaa LL)), rrecllaappsecdd PP.
pyrophosphate cccATP
lleylym
lll mpphhooccPP.
yytitcic
1

lleeuukke Nicotinamide ~ NMN

emmiiaa,. Nampt
_¿ Nmnat
NAO
31
•
•
•
T
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 Visf atin as a Cytokine
o Visfatin (PBEF):
 Promotes B cell maturation and inhibits neutrophil apoptosis.
 Plays an important role in the progression of arthritis.
 Induces the production of IL-1, IL-6 and TNF-α.

o Visfatin can therefore be referred to as a cytokine because

its
plasma level increases in inflammatory conditions such as
psoriasis, arthritis and obesity.

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 Physiologic effect of visf
al atin
o
Visfatin have insulino-mimetic action:

-
 Because it bind insul in receptors at a site that differs from

_¿
that of insulin an d reduces blood glucose level.
~

--
-
Visaatin -- lnstJlin

•
7··
lnsulin

-~
receptor

e
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 o/
/~
.
ah
. Inducer of vísfarín expression

Hypoxi
lnhibitor of visfatín

1
xpressr•on

a nsulin
H Somat
yperglyc Iauy acid ( e. oleare)
Monounsaturated ostatin
aem in g.
Statins
Inflammatio
IL
n
-
beta
1.\F-alpha
IL-1
Chroni Kidney Disease
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• •
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 Analytical aspects of visfatin

o There is aa pJJoOsiittiivvee ccoorrrreellaattiioonn between obesity

and visfatin.was significantly elevated in the serum of type

o Visfatin
2 DM

patient compared to controls.

o Visfatin
plasma levels significantly correlates to BBM

MII..

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 Omentin

o Is a novel hydrophilic adipokine of 313 amino acids (35 kDa).

o It was initially identified in inlttestinal Paneth cells and

c e l with the name Intelectin-1.
endothelial
enteroc y t e

lss crypt
o In 2005, omentin was officially depicted
in an omental fat. sebcueeneees

Stem O m e n tin-1 and omentin-2 are two highly homologous isoforms.

c e lls - -
o  Omentin-1 is the major circulating form with a concentration of 100
Paneth ng/mL
cells ---1
to 1 g/mL in human plasma.
36
 Ome ntin...

o
Are inversely related to obesity and positively to adiponectin levels.
Serum levels of omentin were low in patients with:
o
 Impaired glucose regulation
 T2DM
 Polycystic ovary syndrome (PCOS)
 Atherosclerosis
 Coronary artery disease (CAD)
 Heart failure
 Psoriasis
• . •

 Rheumatoid arthritis.
... •
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.
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 Ome ntin...

o
Omentin levels were elevated in:
 Nonalcoholic fatty liver disease (NAFLD)

 Hepatic carcinoma

 Prostate cancer

 Colon and colorectal cancer

 Gastric cancer

• •
 And pancreatic adenocarcinoma
•• .
. .o Omentin may have an anti-cancer effects. 38
.• www.fppt.info
 Omentin functions

o Omentin can regulate:

Inflammation status
Vasomotor and function

i
endothelium
 P
p38/JNK

K/N F-

tApoptosis
ER
e NOS AMPK/eNOS

r oliferatio n
/
Differen tiation of ce ll typesl.JKN
1 \8
t t
Monocyte
Vasodllatton i Dlfferentiation ¡ lnflammation J Monocyte adheslon
adheslon
Survival 1' . .l.

.
Endothelial Smooth-muscle cell 39
ceU www.fppt.info
 Conclusions

 Adipose tissue is the primary storage site for excess energy but
it is also recognized as an endocrine organ. Adipocytes
are now generally accepted to be a complex cell type
involved in generating a number of signals which include
cytokines, hormones and growth factors that not only
affect the neighboring cells but also impact target tissu
es
involved in energy metabolism and influencing physiologic and
40
pathologic processes. www.fppt.info
 Energ Glucos Cardiovascul Antioxidativ
y e ar e
homeo metabo protectio stres
Adiponectin
stasis Adiponecti
lism (+ Adiponectin
n (+) Adiponectin Adiponectin
s
(+) n
Omentin-1 ) Omentin-1 (+) (+) (+)
Omentin (+) (+) Vaspin {+) Omentin-1 Omentin-1
Leptin (+) Vaspin (+) Chemerin (+) Vaspin (+)
Chemerin ( + / -) {+) Vaspin (+)
(+/-) Leptin (+/-) Chemerin Chemerin
Leptin (+/-) (+) Leptin (-) (·)
 LEAN AOIPOSE TISSUE

OBESE ADIPOSE rrssus

~
f\11.acro~n age
~ infit•rat~on
... "nflarnmatron
..
sec.retion
~

- J
' Adiponecrin
"' -- ~

-~------------
Lept·n .-.. F.ree fa tty aceds i rr.r-« t
.. ~L-6 ..,
i
'" Resistin ._

~----
G1ycogeno1}rsis t

-
G1uconeogenesis Glucose up take

----~-----
...
ºla sMa gl t.:cose i .. FA oxioa ion J.

1 nfla mmation lr"9ammat-on

Ecropic liipid accumulation (sceato'sts)
Dysregulated adtpo klne Fc-opic lipid accu mu'at.on

•
Liver insulin re srst.an ce
42
SYSTEMIC INSUUN RESISTANCE
l\'luscle ins ulin re sist.ance
1pt.info
 lllCnaed .... Dec........... •••tll
• • Typo-D
"'••teda:
•
Ancnlldanervma
•diabetea
Caronary &:
• 1}po-l di.... artaycliwle
Cbnmic...tfililm
e

Normal Obesity

Adiponectin
Adiponectin ~ F . Fat tissue /' J,
"'-.... " at tíssue Leptin t
t Leptin ~ PP AR y -\-' _ /
J,
TNF-a!
....
@ hypertro
phy
~'i
(
! ---.
~)
Resisti ~ "-<'.._. ~ Resistin r
n !
Free fatty r
TNF-a Free fatty acicls
acicls ! i
Insulin sensitive Insulin resistant

Liver
Blood Skeletal muscle

•
• Lipid synthesis J
• Glucose J,
• Free fatty acids J,
• Triglyceride production J,
• Free fatty acid oxidation i
43
•• •
. . J,
• Glucose production
•
Energy dissipation i www.fppt.info
 References

Endocrine Regulation of Energy Metabolism: Review of Pathobiochemical and

o
Clinical Chemical Aspects of Leptin, Ghrelin, Adiponectin, and Resistin.
DOI: 10.1373/clinchem.2004.032482

o Biochemistry of adipose tissue: an endocrine organ. DOI:

10.5114/aoms.2013.33181.
Visfatin: Structure, Function and Relation to Diabetes Mellitus and Other
o
Dysfunctions. https://doi.org/10.2174/092986708785133004.
..
.
o. Omentin-A Novel Adipokine in Respiratory Diseases. doi:10.3390/ijms19010073
.
www.fppt.info