Obesity. L organo adiposo, ruolo centrale nella sindrome metabolica. Medical Complications of Obesity. Claudio Pagano

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L organo adiposo, ruolo centrale nella sindrome metabolica Claudio Pagano Lab. Endocrino-Metabolico, Clinica Medica 3 Dip.

hypoventilation syndrome Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Gall bladder disease Gynecologic abnormalities abnormal

Hypertension Severe pancreatitis Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Phlebitis venous stasis Conditions Associated

1 L organo adiposo, ruolo centrale nella sindrome metabolica Claudio Pagano Lab. Endocrino-Metabolico, Clinica Medica 3 Dip. di Scienze Mediche e Chirurgiche Università di Padova Medical Complications of Obesity Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Gall bladder disease Gynecologic abnormalities abnormal menses infertility PCOS Osteoarthritis Skin Gout Idiopathic intracranial hypertension Stroke Cataracts Coronary heart disease Diabetes Dyslipidemia Hypertension Severe pancreatitis Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Phlebitis venous stasis Conditions Associated With Obesity (Relative Risk) Diabetes Mellitus (RR>>3) Gallbladder disease (RR>>3) Sleep Apnea (RR>>3) Stroke (RR -3) Obesity Hypertension (RR>>3) Coronary Artery Dis. (RR -3) Gout (RR -3) Osteoarthritis (RR -3)

2 Clinical Identification of the Metabolic Syndrome: NCEP-ATP III Diagnosis is established when >3 of these risk factors are present Risk Factor Abdominal obesity (Waist circumference) Men Women TG HDL-C Men Women Blood pressure Fasting glucose Defining Level > cm (> in) >88 cm (>35 in) >5 mg/dl < mg/dl <5 mg/dl >3 / >85 mm Hg > (>) mg/dl 3 New ADA IFG criteria (Diabetes Care) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. ;85: Percentuale di rischio popolazione-attribuibile (Par%) per diabete di tipo, per categorie di BMI vs BMI<3 Par % 7 6 6, 5 3, 9,6 -,9 3-,9 5-9,9 >3 BMI Wolf e Colditz, 996

3 Total, Oxidative, Nonoxidative Glucose Disposal and Hepatic Glucose Production in Control and Obese Subjects 9 mg / kg min Control Obese p <. basal clamp basal clamp basal clamp basal clamp Rd HGP Oxidative Glucose Disposal Non-Oxidative Glucose Disposal TC Scan 3

4 LIPOLYTIC RESPONSES TO ADRENALINE normal subjects obese subjects µmol glycerol/ 7 cells/h Omental Subcutaneus Noradrenaline (log M) -8 Hoffstedt J et al. J Lipid Res 38:795,997 CONCENTRATION OF INSULIN CAUSING HALF-MAXIMUM INHIBITION OF LIPOLYSIS Insulin ( (pmol pmol/l) 5,5 3,5 3,5,5,5 Subcutaneus Omental Zierath et al. Diabetologia :33, 998

GENETICS + ENVIRONMENT LOWER BODY OBESITY UPPER BODY VISCERAL EXCESS OBESITY FAT STORAGE GENETICS + HORMONES FFA LIVER MUSCLE INSULIN RESISTANCE FFA FFA FFA INSULIN RESISTANCE INSULIN SECRETION

5 GENETICS + ENVIRONMENT LOWER BODY OBESITY UPPER BODY VISCERAL EXCESS OBESITY FAT STORAGE GENETICS + HORMONES FFA LIVER MUSCLE INSULIN RESISTANCE FFA FFA FFA INSULIN RESISTANCE INSULIN SECRETION PANCREAS INSULIN CLEARANCE SURGICAL REMOVAL OF VISCERAL FAT REVERSES HEPATIC INSULIN RESISTANCE Increase in visceral fat (g) 6 VF+ 8 6 Visceral Fat VF- Insulin Infusion,6,,,8,6,, I I R (mu/kg/min) Barzilai et al. JCI :353,998 ADIPOSE TISSUE STORAGE PATHWAYS GLUCOSE GLUT INSULIN G- 6- P α- Glyceroḻ- Glycerol AcCoA P ACC FA FA TG TG (VLDL) LPL 5

6 Effect of h Intralipid+heparin infusion on MUSCLE and ADIPOSE TISSUE glucose utilization. G.U.I. ngmg-min- 5 5 Control Intralipid p<.5 r. gastr. SAT VAT PPARγ- AND LEPTIN mrna LEVELS IN HUMAN ADIPOSE TISSUE BEFORE AND AFTER 5h INTRALIPID PLUS HEPARIN INFUSION PPAR/Leptin 3 β-actin Relative amount,5,5,5 before after Leptin before after PPARγ- NEFA LEPTIN PPAR γ TNF α CD36 LEPTIN PPAR γ TNF α CD36? GLUT GLUT GLUCOSE UPTAKE C/EBP α ADD/SREBP INSULIN FAS GLUCOSE UPTAKE 6

7 PPARγ INSULIN INSULIN SENSITIVITY Storage capacity Metabolic fuels Oxidative capacity Adipose tissue derived peptides Resistin TNF IL-6 Sex steroids Glucocorticoids Angiotensin PAI- Adiponectin Leptin Metabolic fuels FFA Glycerol Lactate 7

% mrna target gene/ mrna β-actin THE ADIPOSE ORGAN Trayhurn P

August Volume 7 Number 8 pp 9-96 The fat-derived hormone

lipoatrophy and obesity T. Yamauchi et al.

β-actin 8 bp obese Co lean weight loss Mw 6 ADIPONECTIN #

8 % mrna target gene/ mrna β-actin THE ADIPOSE ORGAN Trayhurn P et al. Br J Nutr. August Volume 7 Number 8 pp 9-96 The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity T. Yamauchi et al. adiponectin expression in obese rats: effect of weight loss β-actin 8 bp obese Co lean weight loss Mw 6 ADIPONECTIN # resistin 36 bp adiponectin 53 bp 8 PPAR-γ 99 bp 6 TNF-α 386 bp Lean Fa/? rats Obese fa/fa rats Post- Obese rats Milan G et al. Obesity Research 8

9 % mrna target gene/ mrna β-actin % mrna target gene/ mrna β-actin Regional differences in adiponectin expression TAV TAS # 5 5 ADIPONECTIN ADIPONECTIN Lean Fa/? rats Obese fa/fa rats Milan G et al. Obesity Res Adiponectin is Reduced in Obese Humans Weyer et al JCEM 86:93; Decreased Plasma Adiponectin in Visceral Obesity Plasma adiponectin μg/ml Visceral Fat Area (cm ) 9

10 (a)effect of Acrp3 on glucose production, G6Pase flux, and glucose cycling. (b) Effect of Acrp3 on hepatic mrna expression of PEPCK. Combs TP et al. J Clin Invest ADIPONECTIN ng/ml 6 8 ADIPONECTIN ng/ml 8 6 CONTROL NAFLD FATTY LIVER NASH Serum adiponectin in NASH patients, according to fibrosis stage, and of insulin-sensitive controls Stage :absent-mild fibrosis Stage -3:moderate-severe fibrosis Musso G et al Am J Gastroent 5

11 Association of Hypoadiponectinemia With Coronary Artery Disease in Men. Kumada M et al. Arterioscler Thromb Vasc Biol 3 Adiponectin Prevents Intimal Thickening of Injured Arteries Matsuda et al JBC 77:3787;

Neutralization of resistin improves hyperglycemia and insulin resistance. Resistin impairs glucose tolerance in mice 5.

12 Adiponectin hypothesis for insulin resistance, metabolic syndrome, and atherosclerosis Hypoadiponectinemia Kadowaki T et al. Endocr Rev 5 Nature 9:37-,. Resistin expression is adipose specific. Resistin is present in blood and increased in obese mice 3. Neutralization of resistin improves hyperglycemia and insulin resistance. Resistin impairs glucose tolerance in mice 5. Resistin antagonizes insulin-stimulated glucose uptake in 3T3-L cells PPARγ INSULIN VISFATIN, RESISTIN, TNF-α, IL-6, CB-FAAH,β HSD- INSULIN SENSITIVITY ADIPONECTIN

13 Adipose tissue macrophages (F/8) in mice with varying degrees of adiposity. female lean Ay/+ Lepob/ob male lean DIO Lepob/ob Weisberg SP et al. J Clin Invest 3 Elevated CRP Levels in Obesity: NHANES Percent with CRP. mg/dl Normal Overweight Obese Visser M et al. JAMA 999 L eccesso di grasso viscerale favorisce l infiammazione sistemica Area di grasso viscerale (cm ),3,3 8 6 () () (3) () (5) Quintili di PCR Circonferenza della vita (cm),,, () () (3) () (5) Quintili di PCR I numeri sulle colonne indicano le rispettive differenze significative fra I diversi quintili Lemieux I et al. Arterioscl Thromb Vasc Biol 3

Infiammazione sistemica e prognosi cardiovascolare sfavorevole Physicians' Health Study: 9-anni di follow up Rischio relativo di IM 5

Markers of Inflammation & Thrombosis Lumen Lumen Vulnerable plaque Activated Adipocytes, T-Lymphocytes, Macrophages Endothelial Cell

14 Infiammazione sistemica e prognosi cardiovascolare sfavorevole Physicians' Health Study: 9-anni di follow up Rischio relativo di IM Basso Medio Alto Colesterolo/HDL colesterolo ratio Basso MedioAlto hs-crp Ridker PM et al. Circulation 998;97:7-. Markers of Inflammation & Thrombosis Lumen Lumen Vulnerable plaque Activated Adipocytes, T-Lymphocytes, Macrophages Endothelial Cell Activation ICAM, VCAM selectins PAI- t-pa Cytokines TNFα IL- IL6 Liver Endothelial Cells CRP SAA Gabay C, NEJM 999; Libby P, Circulation 999

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Clinical Staging for Obesity. Raj Padwal Clinical Pharmacology and General Internal Medicine University of Alberta

Clinical Staging for Obesity. Raj Padwal Clinical Pharmacology and General Internal Medicine University of Alberta Clinical Staging for Obesity Raj Padwal Clinical Pharmacology and General Internal Medicine University of Alberta Disclosures Funding: CIHR, Heart and Stroke Foundation of Canada, University Hospital Foundation.