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:H Macrophages Endocrine inflammatory signals Paracrine and autocrine inflammatory signals Fat insulin resistance Muscle insulin resistance Liver insulin resistance Overnutrition and genetics Hypertension, dyslipidemia, hyperglycemia, hyperinsulinemia ATHEROSCLEROSIS Systemic insulin resistance

Elevated FFA contribute to hypertension, dyslipidemia, and insulin resistance Eckel RH et al. Lancet. 2005;365: VLDL = very low density lipoproteins Hypertension Triglyceride (intramuscular droplet) Sympathetic nervous system Glycogen Insulin FFA Glucose VLDL  HDL-C  Small dense LDL FFA Insulin Triglyceride C-II C-III B-100 and CO 2

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: Optimal nutrition Normal immune function

Weight gain induces inflammatory changes in adipose tissue Wellen KE, Hotamisligil GS. J Clin Invest. 2003;112: Adipocyte Preadipocyte Weight gain TNF-α MCP-1 Macrophage recruitment Macrophage Leptin VEGF Endothelial cell Angiogenesis Physical stress/oxidative damage to endothelium? FFA Weight gain Insulin resistance JNK NF-κB IL-6 IL-1β TNF-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:H Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115: AtherogenicAntiatherogenic Adipocytokines (adipokines)

Adiponectin associated with decreased risk of MI Pischon T et al. JAMA. 2004;291: Plasma level (mg/L) N = 18,225 men; 6-year follow-up Relative risk 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 cells VCAM = vascular cell adhesion molecule Goldstein BJ, Scalia R. J Clin Endocrinol Metab. 2004;89: Hopkins TA et al. Cardiovasc Res Anti-atherogenic features

P < Low adiponectin in visceral adiposity Manigrasso MR et al. J Clin Endocrinol Metab. 2005;90: Median plasma adiponectin, interquartile range (  g/mL) Normal weight (n = 20) Abdominal adiposity (n = 64) Lower body adiposity (n = 20) P < P < 0.01 N = 104 women Mean BMI (kg/m 2 )

Even moderate weight loss may improve cardiometabolic risk Moderate weight loss ~10% Body weight, which includes ~30% Visceral adipose tissue  Cardiometabolic risk  Systolic/Diastolic BP  Inflammation  Endothelial function  Thrombosis susceptibility  Glycemia  Insulin resistance  A1C  IFG  IGT  Total-C  LDL -C  HDL-C  TG  non-HDL-C Manson JE et al. Arch Intern Med. 2004;164: Després J-P et al. BMJ. 2001;322: Blood pressureGlucoseLipids

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