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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