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 resistance

Liver 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

Glucose

VLDL

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

PreadipocyteWeight gain

TNF-α

MCP-1

Macrophage recruitment

Macrophage

LeptinVEGF

Endothelial cell

Angiogenesis

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

CRP

IL-6

PAI-1

Angiotensinogen

Leptin

Resistin

MCP-1

TNF-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 5

0.0

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 < 0.0001

P < 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