3/20/2011. Body Mass Index (kg/[m 2 ]) Age at Issue (*BMI > 30, or ~ 30 lbs overweight for 5 4 woman) Mokdad A.H.

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1 U.S. Adults: 1988 Nineteen states with 10-14% 14% Prevalence of Obesity (*BMI > 30, or ~ 30 lbs overweight for 5 4 woman) Metabolic John P. Cello, MD Professor of Medicine and Surgery, University of California, San Francisco Mokdad A.H., CDC U.S. Adults: 2000 Twenty-two two states with > 20 % of obese adults, 27 states with 15-19% 19% obesity, one state with 10-14% 14% obesity (*BMI > 30, or ~ 30 lbs overweight for 5 4 woman) Relationship of BMI to Excess Mortality Age at Issue Body Mass Index (kg/[m 2 ]) Mokdad A H, et al. J Am Med Assoc 2001; 286:10 Bray GA. Overweight is risking fate. Definition, classification, prevalence and risks. Ann NY Acad Sci 1987;499:

2 But doctor why am I so fat? I just eat like a bird. The Answer: First Law of Thermodynamics Matter and energy are interchangeable. They are neither created nor destroyed Calories Ingested minus Calories Expended = Excess or Deficit. Energy (caloric) excess is conserved and stored principally as fat. Basal Energy Requirements 70 kg. (est. total 1940 kcal) Tissue Weight % B Weight Kcal/day Liver Brain Kidneys Heart Skeletal muscle Adipose Factors Used to Estimate Thermal Effect of Physical Activity Resting (academic bench research) 1.0 Very light activity (attending medicine) Light activity (medical residents) Moderate activity (surgery residents) Heavy activity (surgery faculty)

3 Endogenous Fuel Stores in a 70 Kg. Man Tissue Adipose Liver Muscle Blood Fuel Source Grams Kcal. Triglyceride (60 d) Glycogen Protein Triglyceride Protein (12 d) Glycogen Triglyceride Glucose Triglyceride 4 35 Free fatty acids Non-adipose/muscle energy stores equivalent to 2 days!! Historical Background Metabolic Vague (France) 1947 first noted that upper body obesity predisposed to diabetes, atherosclerosis, gout Avogaro & Crepaldi (Italy) 1967 describes 6 obese patients with DM, elevated chol. & TG all responding to dieting with low carbohydrates Haller (Germany) coined term Metabolic in patients with obesity, DM, atherosclerosis, elevated TG & chol. Associated with hepatic steatosis Reaven (England) 1988 proposed insulin resistance as the underlying factor for X Metabolic Definition Clustering of Multiple Metabolic Risk Factors Atherogenic dyslipidemia Elevated blood pressure Elevated plasma glucose Prothrombotic state Proinflammatory state Components of the Metabolic Abdominal Obesity increased visceral fat (premier feature) Insulin Resistance with glucose intolerance and diabetes mellitus Dyslipidemia (consequential) Hypertension (consequential) 3

4 Morbid Obesity and the Metabolic Abdominal obesity (visceral fat accumulation) is the core feature of the metabolic syndrome The key aspect of the metabolic syndrome is insulin resistance Prevalence of Metabolic Worldwide (over 50 years old) United States 40% of population Europe 30 % of population Developing world not immune from the entity India now 27% of population Racial predisposition Hispanics>African- Americans>Caucasians>Asians Sex predisposition none: males = females Younger Age Populations ( years old) Increased Prevalence World Wide: Not just an American and European Problem Saudi Arabia 39% Turkey 33% USA 28% Venezuela 31% Brazil 25% India 24% Pathophysiology of the Metabolic Adipose tissue plays an important role in energy regulation endocrine, paracrine and autocrine signals Adipokines released by visceral fat cause insulin resistance. Insulin antagonists TNF-alpha, IL-6, resistin (decrease insulin action) Insulin sensitizers leptin, adiponectin Adiponectin only adipokine with decreased levels Leptin resistance noted 4

5 Genetic factors How Does Abdominal Obesity Cause Insulin Resistance Reduced Physical Activity Excessive food intake IL-6 TNF-α adiponectin leptin Inflammation various cytokines insulin receptor Substrate (IRS-1 & IRS-2) Metabolic Concomitants of Insulin Resistance Per Se Atherogenic dyslipidemia High TC/HDL-C C ratio Higher blood pressure Hyperinsulinemia and dysglycemia Prothrombotic and proinflammatory states Endothelial dysfunction and microalbuminuria Fatty liver (i.e. NAFL) blood FFA 2005 Revised ATP III Clinical Screening Criteria to Identify Metabolic (AHA and NHLBI) Parameter (any 3/5 diagnostic) Elevated waist circumference Elevated triglycerides Reduced HDL-cholesterol Elevated blood pressure Elevated fasting glucose Categorical cutpoints 40 inches in men 35 inches in women 150 mg/dl at baseline <40 mg/dl in men <50 mg/dl in women Or on drug treatment for reduced HDL-C 130 mmhg systolic blood pressure or 85 mmhg diastolic blood pressure or on antihypertensive drug treatment in a patient with a history of hypertension 100 mg/dl at baseline What is NAFLD (Non- Alcoholic Fatty Liver)? How does it occur? Why is it important? 5

6 Fat Inflammation/Necrosis Normal Liver gross and micro. Fatty Liver gross and micro. Mallory s Hyaline Ballooning/Fibrosis Obesity & Pathogenesis of NAFLD/NASH Circulating FFA IRS-1(insulin receptor substrate [intracellular adapter protein]) signaling Impaired insulin responsiveness Low grade, chronic inflammatory state Inflammatory cytokines, chemokines & adipokines ( IL-6, TNFα, leptin, resistin adiponectin) = Insulin resistance Hyperinsulinemia SREBP 1c Oxidative Stress NASH Steatosis 6