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

2. 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

3. 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)

4. 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

5. Secretory Products of Adipose Tissue
Leptin
Interleukin-6
TNF soluble receptors
Adipsin/ASP
Adiponectin/ACRP30
Resistin
NEFA

6. Autocrine/Paracrine signals from Adipose Tissue
Tumour necrosis factor-a
PAI-1 and tPA
Angiotensinogen
Soluble receptors to IL-6 and leptin
Metallothionien

7. Schematic of adipose tissue derived molecules
PAI-1
Monobutyrin
Adiponectin/AdipoQ
Resistin

8. 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

9. 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

10. 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 TNFa induced release of adhesion molecules

11. 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

12. 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

13. 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 b-cell insulin secretion
Thus contributes to insulin resistance in both skeltal muscle and liver

14. 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

15. IL-6 concentration (pg/ml)
Association of IL-6 levels and body fat 70 60 50
IL-6 concentration (pg/ml) 40 30 20 10 20 30 40 50 60 70
Body fat (%)

16. IL-6 concentrations in murine obesity
IL-6 levels (pg/ml):
wt: 2.8( )
obese: 8.6( )
p=0.0001
Weight (gms):
wt:27.1( )
obese:55.6( )
p<0.0001
Age: 12 weeks
Data shown as median (interquartile range)
Means compared by Mann-Whitney
wt = wild-type
ob = obese 30 20
IL-6 concentration (pg/ml) 10 N = 45 19 wt ob
Genotype

17. 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 b2 or b3-adrenergic stimulation
Exogenous IL-6 promotes adipogenesis, increases basal glucose uptake and inhibits lipolysis

18. -ve INTERLEUKIN-6 +ve PSYCHOSOCIAL STRESS CHD SMOKING OBESITY
CATECOLAMINES
SMOKING
OBESITY
(CENTRAL)
POLLUTION
MIGRATION
INFECTION
STRESS
GENOTYPE
PROGRAMMING
HPA
AXIS
-ve
INTERLEUKIN-6
CRP
+ve
INSULIN
RESISTANCE
DYSLIPIDAEMIA
ENDOTHELIAL
DYSFUNCTION
HYPERTENSION
COAGULATION
CHD

19. Arterial and venous concentrations of cytokine soluble receptors-1
pg.ml
sTNF RI
sTNF RII
IL6sR
Arterial
Venous p
971 ( )
1091 ( )
0.002
2174 ( )
2246 ( )
0.18
36.8 ( )
36.8 ( )

20. Correlation of measures of obesity with basal concentrations of cytokine soluble receptors
BMI r s p
sTNFRI
venous
0.64
<0.001
arterial
0.62
sTNFRII
0.39
0.033
0.61
IL-6sR
0.19
0.32
0.25
0.18

21. TNFsR concentration (pg/ml)
Association of TNF soluble receptors
and body fat
4000
RII
3000
TNFsR concentration (pg/ml)
2000 RI
1000 10 20 30 40 50 60
Body fat (%)

22. 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