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Adiposity in CVD. Role of adipose tissue in atherogenesis. Overnutrition and genetics. Macrophages. Paracrine and autocrine inflammatory signals. Endocrine inflammatory signals. Fat insulin resistance. Systemic insulin resistance. Muscle insulin resistance. Liver insulin resistance. - PowerPoint PPT Presentation
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Adiposity in CVD
Role of adipose tissue in atherogenesis
Adapted from de Luca C, Olefsky JM. Nat Med. 2006;12:41-2.Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H2031-41.
Macrophages
Endocrine inflammatory
signals
Paracrine and autocrine
inflammatory signals
Fatinsulin resistance
Muscle insulin resistanceLiver insulin
resistance
Overnutrition and genetics
Hypertension, dyslipidemia, hyperglycemia, hyperinsulinemia
ATHEROSCLEROSIS
Systemicinsulin resistance
Elevated FFA contribute to hypertension, dyslipidemia, and insulin resistance
Eckel RH et al. Lancet. 2005;365:1415-28.VLDL = very low density lipoproteins
Hypertension
Triglyceride (intramuscular droplet)
Sympathetic nervous system
Glycogen
Insulin
FFAFFA
GlucoseVLDL
HDL-CSmall dense LDL
FFA InsulinTriglyceride
C-IIC-IIIB-100 and
CO2
Energy homeostasis is linked to immune balance
Malnutrition
Immunosuppression(susceptibility to infection)
Overnutrition
Immunoactivation(susceptibility to
inflammatory disease)
Adapted from Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.
Optimal nutrition
Normal immune function
Weight gain induces inflammatory changes in adipose tissue
Wellen KE, Hotamisligil GS. J Clin Invest. 2003;112:1785-8.
Adipocyte
Preadipocyte Weight gain
TNF-α
MCP-1
Macrophage recruitment
Macrophage
LeptinVEGFEndothelial
cellAngiogenesis
Physical stress/oxidative damage to endothelium?
FFA
Weight gain
Insulin resistance
JNKNF-κB
IL-6IL-1βTNF-α
MCP-1
Macrophage recruitment
Adipose tissue: An endocrine organ
CRPIL-6PAI-1AngiotensinogenLeptinResistinMCP-1TNF-α
Adiponectin
Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H2031-41.Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.
Atherogenic Antiatherogenic
Adipocytokines (adipokines)
Adiponectin associated with decreased risk of MI
Pischon T et al. JAMA. 2004;291:1730-7.
1 2 3 4 50.0
0.2
0.4
0.6
0.8
1.0
1.2
7.9 12.6 16.5 21.1 29.2Plasma level (mg/L)
N = 18,225 men; 6-year follow-up
Relativerisk
Adiponectin quintile (95% CI)
Beneficial associations of adiponectin
Endothelial vasodilation
Nitric oxide
Angiogenesis
VCAM-1
TNF- level +proinflammatory effects
Insulin sensitivity
Oxidized LDL effects on endothelial cells
Endothelial cell proliferation/migration
Growth factor effects on SMC
Neointimal thickening
SMC proliferation
SMC = smooth muscle cellsVCAM = vascular cell adhesion molecule
Goldstein BJ, Scalia R. J Clin Endocrinol Metab. 2004;89:2563-8.Hopkins TA et al. Cardiovasc Res. 2007.
Anti-atherogenic features
P < 0.0001
Low adiponectin in visceral adiposity
Manigrasso MR et al. J Clin Endocrinol Metab. 2005;90:5876-9.
Median plasma adiponectin, interquartile
range(g/mL)
30
25
20
15
10
5
0Normal weight
(n = 20) Abdominal adiposity(n = 64)
Lower body adiposity(n = 20)
P < 0.0001P < 0.01
N = 104 women
Mean BMI (kg/m2) 25.2 33.4 37.1
Even moderate weight loss may improve cardiometabolic risk
Moderate weight loss ~10% Body weight, which includes ~30% Visceral adipose tissue
Cardiometabolic risk
Systolic/Diastolic BPInflammationEndothelial functionThrombosis susceptibility
GlycemiaInsulin resistanceA1CIFGIGT
Total-CLDL -C HDL-CTGnon-HDL-C
Manson JE et al. Arch Intern Med. 2004;164:249-58.Després J-P et al. BMJ. 2001;322:716-20.
Blood pressure GlucoseLipids
Summary
Adipose tissue is emerging as an important endocrine organ
Elevated free fatty acid levels act on the liver and skeletal muscle to promote hypertension, dyslipidemia, and insulin resistance
Expansion of visceral adipocytes leads to macrophage infiltration, release of pro-atherogenic adipokines, and decreased secretion of adiponectin