Factors Released from Adipose Tissue and their Physiological Relevance Vidya Mohamed-Ali Adipokines and Metabolism Research Group Department of Medicine.

Factors Released from Adipose Tissue and their Physiological Relevance

Vidya Mohamed-Ali

Adipokines and Metabolism Research Group

Department of Medicine

University College London

Physiological Role of White Adipose Tissue

• Energy storage organ - triacylglycerols - efficient energy reserve

• Subcutaneous adipose tissue depots act as thermal insulation

• Endocrine organ - secreting a key hormone, leptin• Essential for normal glucose homeostasis -

lipodystrophy/transgenics with no WAT are markedly diabetic

Study of Human Adipose Tissue

• Ex vivo by biopsy

Adipose tissue consists of several cell types

Mature white adipocytes

Stromal-vascular cells - fibroblasts and macrophages

• In vivo by microdialysis (Lonroth et al, 1987)

Limited by the pore size of traditional microdialysis probes

• In vivo by the Fick principle (Frayn et al 1989)

Arterio-venous difference studies

• Cannulation of superficial epigastric vein draining abdominal sub-cutaneous adipose tissue

• Cannulation of radial artery - systemic circulation• Simultaneous sampling from the two sites• Blood flow measurement - Xenon washout technique• Calculate adipose tissue production or clearance

Secretory Products of Adipose Tissue

• Leptin• Interleukin-6• TNF soluble receptors• Adipsin/ASP• Adiponectin/ACRP30• Resistin• NEFA

Autocrine/Paracrine signals from Adipose Tissue

• Tumour necrosis factor-• PAI-1 and tPA• Angiotensinogen• Soluble receptors to IL-6 and leptin• Metallothionien

PAI-1

Adiponectin/AdipoQ

Monobutyrin

Resistin

Schematic of adipose tissue derived molecules

Leptin

• Circulating product of the ob gene - Friedman et al 1994 • 16 kDa glycoprotein• Central actions:

Has a feedback effect on hypothalamic energy regulation - ‘satiety signal’

Maturation of reproductive function - signals to the hypothalamus when sufficient energy has been stored to embark on energy-expensive reproductive cycle

Leptin - peripheral actions

• Receptors for leptin also present in:

Adipose Tissue, Liver, Skeletal Muscle, Islet Cells and T Lymphocytes

• Impairs insulin signalling in skeletal muscle and adipocytes

• Impairs insulin mediated glucose uptake• Inhibits phosphorylation of IRS-1• Inhibits lipogenesis, stimulates lipolysis and activates

protein kinase A

Adiponectin

• Collagen-like plasma protein - Takahashi et al 1999• Significant homology to complement factor C1q• Accumulates in vascular walls in response to

endothelial injury• Modulates endothelial inflammatory response• Reduced in obesity and weight loss causes an increase

in levels• Reduced in patients with coronary artery disease• Inhibits mature macrophage functions - phagocytosis• Inhibits TNFinduced release of adhesion molecules

Resistin

• Steppan et al 2001• Over-expressed in obesity• Neutralisation improves blood glucose levels and

insulin action• Down-regulated by thiozolidinediones - improves insulin

sensitivity• Decreases in response to fasting and increases in

response to insulin and feeding• ? effect on insulin resistance in muscle and liver

Adipsin/ASP

• ASP - Acylation Stimulation Protein/ C3adesArg - Cianflone et al 1992

• A-V studies demonstrated in vivo release of ASP basally and after ingestion of food

• Role in the uptake and esterification of fatty acids to make triacylglycerols to facilitate fatty acid storage

• Stimulates triacylglycerol synthesis via diacylglycerol acyltransferase (DGAT)

• Stimulates translocation of glucose transporters to cell surface

• ASP release induced by VLDL, LDL and HDL

Non-esterified fatty acids

• Elevated levels associated with impaired insulin sensitivity• Major determinant of carbohydrate storage and oxidation• Impairs insulin-stimulated glucose uptake and glycogen

synthase activity in skeletal muscle• Stimulates liver gluconeogenesis • Stimulates -cell insulin secretion• Thus contributes to insulin resistance in both skeltal muscle

and liver

Interleukin-6

• Released by adipose tissue and increases with increasing fat mass

• Studies in tumour cells and in IL-6 knockout animals:

Impairs appetite

Lost fat tissue with no effect on lean mass

Inhibits gluconeogensis

Increases hepatic de novo synthesis of fatty acid and cholesterol

Body fat (%)

IL-6

con

cent

rati

on (

pg/m

l)

0 10 20 30 40 50 60 7020

30

40

50

60

70

Association of IL-6 levels and body fat

IL-6 concentrations in murine obesity

• IL-6 levels (pg/ml):

wt: 2.8(2.5-5.9)

obese: 8.6(4.6-24.5)

p=0.0001

• Weight (gms):

wt:27.1(24.8-38.1)

obese:55.6(48.9-60.9)

p<0.0001

Age: 12 weeks

Data shown as median (interquartile range)

Means compared by Mann-Whitney

wt = wild-type

ob = obese1945N =

ob

Genotype

wt

IL-6

con

cen

trat

ion

(pg/

ml)

30

20

10

0

IL-6 in Adipocytes

• IL-6 mRNA and protein were expressed in preadipocytes and downregulated in mature adipocytes

• IL-6 is expressed constitutively in preadipocytes, but is induced in mature adipocytes in response to 2 or 3-adrenergic stimulation

• Exogenous IL-6 promotes adipogenesis, increases basal glucose uptake and inhibits lipolysis

INTERLEUKIN-6

SMOKING OBESITY

(CENTRAL)POLLUTION

MIGRATION

INFECTION

PSYCHOSOCIAL

STRESS

CHD

HYPERTENSIONINSULIN

RESISTANCEDYSLIPIDAEMIA ENDOTHELIAL

DYSFUNCTIONCOAGULATION

CRP

-ve

+ve

GENOTYPE

PROGRAMMING

CATECOLAMINES

HPAAXIS

Arterial and venous concentrations of cytokine soluble receptors

pg.ml-1

sTNF RI sTNF RII IL6sR

Arterial

Venous

p

971 (872-1323)

1091 (894-1495)

0.002

2174 (1830-2618)

2246 (1885-2928)

0.18

36.8 (30.1-43.2)

36.8 (31.9-43.5)

0.18

Correlation of measures of obesity with basal concentrations of cytokine soluble receptors

BMI

rs

p

sTNFRI venous 0.64 <0.001

arterial 0.62 <0.001

sTNFRII venous 0.39 0.033

arterial 0.61 <0.001

IL-6sR venous 0.19 0.32

arterial 0.25 0.18

4000

3000

2000

1000

00 10 20 30 40 50 60

Body fat (%)

RII

RI

TN

FsR

co

nce

ntr

atio

n (

pg

/ml)

Association of TNF soluble receptors and body fat

Summary

• Leptin, resistin, TNF soluble receptors and NEFA - elevated in obesity, along with insulin resistance

• Weight loss often leads to decrease in their levels and improves insulin sensitivity

• Adiponectin - decreased in obesity and increases with weight loss

• Levels directly correlates with insulin sensitivity• IL-6 - increased in obesity - facilitates storage of energy,

? Adipocyte growth factor, ? Effect on food intake• ASP - increased in obesity - facilitates storage