1 / 20

How Does Fat Drive Disease? Where does the Liver Fit In?

How Does Fat Drive Disease? Where does the Liver Fit In?. Metabolic pathophysiology of obesity Effect of weight (fat) loss on metabolic function. Metabolic Complications of Obesity. Coronary heart disease. Nonalcoholic fatty liver disease. Insulin resistance Diabetes. Dyslipidemia

celine
Download Presentation

How Does Fat Drive Disease? Where does the Liver Fit In?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. How Does Fat Drive Disease? Where does the Liver Fit In? Metabolic pathophysiology of obesity Effect of weight (fat) loss on metabolic function

  2. Metabolic Complications of Obesity Coronary heart disease Nonalcoholic fatty liver disease Insulin resistance Diabetes Dyslipidemia (Increased TG-rich lipoproteins)

  3. Pathogenesis of Obesity-related Metabolic Dysfunction Glucose production Glucose Adipokines FFA β-Oxid ChREBP Subcutaneous fat SREBP-1c DNL FFA Visceral fat TG Insulin TG FFA Adipokines VLDL Plasma TG Glucose uptake

  4. Fatty Acid Induced Insulin Resistance acylcarnitine FA fatty acyl-CoA TG β-oxidation acetyl-CoA FA CO2 ketones acylcarnitines fatty acyl-CoA ceramide G-3-P Akt LPA ? NFkB PKC mTOR fatty acyl-CoA PA Insulin Resistance DAG TG fatty acyl-CoA Fabbrini E et al. Hepatology 2010

  5. Relationship Between FFA Kinetics and Body Fat FFA Ra (umol/kg FM/min) FFA Ra (umol/min) Men 45 800 Women 40 700 35 600 2 R =0.61 30 500 P<0.05 25 2 = 0.6601 R 400 20 P<0.05 300 15 200 10 100 5 0 40 60 80 0 20 0 20 40 60 80 Fat mass (kg) Fat mass (kg) Mittendorfer B et al. Obesity 17:1872, 2009.

  6. Relationship between HepaticInsulin Sensitivity andIntrahepatic Fat Content 20 15 Hepatic Insulin Sensitivity Index r = -0.62 P <0.001 10 5 0 5 10 15 20 25 30 35 40 45 50 Intrahepatic fat (%) Korenblat K et al. Gastroenterology 87:3023, 2008

  7. Relationship Between Skeletal Muscle Insulin Sensitivity and Intrahepatic Fat Content 500 400 r = -0.61 P <0.001 300 Increase in Glucose Uptake(% change from basal) 200 100 0 0 5 10 15 20 25 30 35 40 Intrahepatic fat (%) Korenblat K et al. Gastroenterology 87:3023, 2008

  8. VLDL-TG Secretion Rate in NAFLD Subcutaneous fat FFA DNL TG Visceral fat IHTG 12 * 10 VLDL 8 μmol·L plasma-1·min-1 6 * Non-systemic FA 4 SystemicFFA 2 0 Normal Liver Fat Increased Liver Fat Fabbrini E et al. Gastroenterology 134:424, 2008

  9. 150 100 50 0 Before 15 2.5–6.9 0–2.4 7.0–14.0 Insulin Sensitivity Improves With Weight Loss in Patients With Type 2 Diabetes Insulin (pmol/L) Weight Loss at 1 Year (%) Wing R et al. Arch Intern Med 1987;147: 1749

  10. Effect of Liposuction on Insulin Sensitivity Glucose production (µmol/min) 1000 1000 800 800 T2DM before Obese before 600 600 Obese after T2DM after 400 400 200 200 0 0 Basal Stage 1 Stage 2 Basal Stage 2 Stage 1 Glucose uptake (µmol/min) 4000 4000 Obese before T2DM before 3000 3000 Obese after T2DM after 2000 2000 1000 1000 0 0 Basal Stage 1 Stage 2 Basal Stage 1 Stage 2 Klein S et al. N Engl J Med 350:2549 2004

  11. Effect of liposuction on CHD risk factors Obese normal OGT Obese diabetes Before After Before After Waist circumference 108±5 94±3* 119±4 107±3* 119±5 124±4 132±4 137±6 Systolic BP 70±3 65±4 73±3 68±4 Diastolic BP 89 ±1 90±2 121±15 123±15 Plasma glucose 11±3 9±2 15±2 14±3 Plasma insulin 151±28 121±21 162±19 173±24 Triglycerides 189±12 174±13 160±9 157±10 Total cholesterol 113±9 110±11 82±7 80±11 LDL cholesterol 45±8 41±9 44 ±3 43±3 HDL cholesterol Klein S et al. N Engl J Med 350:2549 2004

  12. Effect of Negative Energy Balance on Body Fat Energy Expenditure Energy Intake

  13. Effect of Short- and Long- term Calorie Restriction on Intrahepatic TG Content and Insulin Sensitivity * 48 hours CR 100 * 7% weight loss 75 ** 50 % Change 25 IHTG content 0 Insulin mediated glucose uptake Hepatic insulin sensitivity -25 * -50 ** E. Kirk et al Gastroenterology 136:1552, 2009

  14. Intracellular Insulin Signaling Cascade Insulin glucose Cell Membrane GLUT4 Tyr - P IRS1 Tyr 183-P JNK GLUT4 Akt Ser 473-P

  15. Effect of Short-term and Long-term CR on Skeletal Muscle Insulin Signaling * 50 48 hour 40 7% Weight Loss 30 * 20 10 Change from Baseline (%) 0 -10 -20 *p<0.05 vs. baseline -30 -40 * -50 Ser 473 Akt-P Tyr IRS1-P Tyr 183 JNK-P E. Kirk et al Gastroenterology 136:1552, 2009

  16. Effect of Gastric Bypass Surgery-Induced Weight Loss on FFA and Glucose Kinetics Palmitate Ra (µmol·min-1) Glucose Ra (µmol·min-1) 200 1200 1000 160 * 800 * 120 600 80 400 40 200 0 0 Before GBS 1 year after BMI (kg/m2) 61 ± 4 45 ± 4* Glucose (mg/dL) 119 ± 14 83 ± 4* Insulin (mU/L) 42 ± 7 11 ± 2* Klein et al. Gastroenterology 130:1564, 2006

  17. Effect of 10% Weight Loss on VLDL-TG Kinetics Subcutaneous fat VLDL-TG secretion rate (µmol·L plasma-1·min-1) FFA DNL TG Visceral fat IHTG 12 VLDL 10 8 * 6 4 Non-systemic fatty acids 2 Systemic plasma fatty acids 0 After Before

  18. Effect of GBS-induced Weight Loss on Hepatic Inflammation and Fibrogenesis -SMA MCP-1 Before GBS 0.06 0.0020 0.0015 0.04 * * 0.0010 1 Yr after GBS 0.02 0.0005 0.00 0.0000 Collagen-I1 IL-8 0.0003 0.02 Data are expressed relative to 18s mRNA 0.0002 0.01 * * 0.0001 0.0000 0.00 Klein et al. Gastroenterology 130:1564, 2006

  19. Metabolically-normal and Metabolically-abnormal Obesity Adipose Tissue FFA Release Tissue FFA Trafficking (delivery, uptake, disposition) NAFLD Increased serum TG Insulin resistance

More Related