Adiposity in CVD

1
Adiposity in CVD
2
Role of adipose tissue in atherogenesis
Overnutrition and genetics
Macrophages
Paracrine and autocrine inflammatory signals
Endocrine inflammatory signals
Fatinsulin resistance
Systemic insulin resistance
Muscle insulin resistance
Liver insulin resistance
Hypertension, dyslipidemia, hyperglycemia,
hyperinsulinemia
ATHEROSCLEROSIS
Adapted from de Luca C, Olefsky JM. Nat Med.
20061241-2.Lau DCW et al. Am J Physiol Heart
Circ Physiol. 2005288H2031-41.
3
Elevated FFA contribute to hypertension,
dyslipidemia, and insulin resistance
VLDL very low density lipoproteins
Eckel RH et al. Lancet. 20053651415-28.
4
Energy homeostasis is linked to immune balance
Optimal nutrition Normal immune function
Malnutrition Immunosuppression(susceptibility to
infection)
Overnutrition Immunoactivation(susceptibility to
inflammatory disease)
Adapted from Wellen KE, Hotamisligil GS. J Clin
Invest. 20051151111-9.
5
Weight gain induces inflammatory changes in
adipose tissue
Adipocyte
Insulin resistance
JNKNF-?B
TNF-a
Leptin
Preadipocyte
Weight gain
Weight gain
VEGF
Endothelial cell
IL-6IL-1ßTNF-a
Angiogenesis
Physical stress/oxidative damage to endothelium?
MCP-1
MCP-1
FFA
Macrophage recruitment
Macrophage recruitment
Macrophage
Wellen KE, Hotamisligil GS. J Clin Invest.
20031121785-8.
6
Adipose tissue An endocrine organ
Adipocytokines (adipokines)
Atherogenic
Antiatherogenic

• CRP
• IL-6
• PAI-1
• Angiotensinogen
• Leptin
• Resistin
• MCP-1
• TNF-a

• Adiponectin

Lau DCW et al. Am J Physiol Heart Circ Physiol.
2005288H2031-41. Wellen KE, Hotamisligil GS. J
Clin Invest. 20051151111-9.
7
Adiponectin associated with decreased risk of MI
N 18,225 men 6-year follow-up
1.2
1.0
0.8
Relativerisk
0.6
0.4
0.2
0.0
1
2
3
4
5
Adiponectin quintile (95 CI)
7.9
12.6
16.5
21.1
29.2
Plasma level (mg/L)
Pischon T et al. JAMA. 20042911730-7.
8
Beneficial associations of adiponectin
Anti-atherogenic features

• ?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 cells VCAM vascular cell
adhesion molecule
Goldstein BJ, Scalia R. J Clin Endocrinol Metab.
2004892563-8. Hopkins TA et al. Cardiovasc Res.
2007.
9
Low adiponectin in visceral adiposity
N 104 women
30
P lt 0.0001
P lt 0.01
25
P lt 0.0001
Median plasma adiponectin, interquartile
range(?g/mL)
20
15
10
5
0
Normal weight(n 20)
Abdominal adiposity(n 64)
Lower body adiposity(n 20)
Mean BMI (kg/m2)
25.2
33.4
37.1
Manigrasso MR et al. J Clin Endocrinol Metab.
2005905876-9.
10
Even moderate weight loss may improve
cardiometabolic risk
Moderate weight loss 10 Body weight, which
includes 30 Visceral adipose tissue


Blood pressure
Glucose
Lipids

• ?Systolic/Diastolic BP
• ?Inflammation
• ?Endothelial function
• ?Thrombosis susceptibility

?Total-C ?LDL -C ?HDL-C ?TG ?non-HDL-C
?Glycemia ?Insulin resistance ?A1C ?IFG ?IGT
?Cardiometabolic risk
Manson JE et al. Arch Intern Med.
2004164249-58.Després J-P et al. BMJ.
2001322716-20.
11
Summary
Adipose tissue is emerging as an important
endocrine organ
Expansion of visceral adipocytes leads to
macrophage infiltration, release of
pro-atherogenic adipokines, and decreased
secretion of adiponectin
Elevated free fatty acid levels act on the liver
and skeletal muscle to promote hypertension,
dyslipidemia, and insulin resistance