“Sick Fat,” Metabolic Disease, and Atherosclerosis Harold E. Bays, MD Medical Director and President, Louisville Metabolic and Atherosclerosis Research Center (L-MARC), Louisville, KY Graphical support by Scientific Connexions Sponsored by AstraZeneca
“Average” Cholesterol Is Not Necessarily Normal Text Figure 1 HUNTER-GATHERER HUMANS WILD PRIMATES WILD MAMMALS URBANIZED HUMANS Mean Total Cholesterol, mg/dL Figure 1 Comparison of cholesterol levels among humans and animals. Atherosclerotic coronary heart disease (CHD) is rare among hunter-gatherers; CHD is the most common cause of mortality in adult Americans. (Modified with permission from O’Keefe JH Jr, Cordain L, Harris WH, et al. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43:2142–2146.) Modified with permission from O’Keefe JH Jr et al. J Am Coll Cardiol. 2004;43:2142–2146. Bays HE. Am J Med. 2009;122:S26S37.
BMI and Prevalence of Metabolic Disease NHANES 1999-2002 Text Figure 2 70 68 67.5 Diabetes Mellitus 62.2 62.5 Hypertension 60 Dyslipidemia 53.1 51.3 52.9 50 44 38.2 39.3 40 % of Patients 30.8 28.9 30 27.3 24 25.3 22.3 20 17.6 16.4 12.2 10.1 9 10 Figure 2 Relationship of body mass index (BMI) to prevalence of metabolic diseases, which are major atherosclerotic coronary heart disease risk factors. The BMI intervals do not represent equal quintiles; rather, they represent established obesity diagnostic and treatment cutoff points. The chart data are derived from the National Health and Nutritional Examination Surveys (NHANES; 1999-2002) and are based on the following definitions: (1) diabetes mellitus = diagnosed and previously undiagnosed type 1 or type 2 diabetes mellitus; (2) hypertension = administration of antihypertensive medication or systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg; and (3) dyslipidemia = any of the following: total cholesterol 240 mg/dL, triglycerides 200 mg/dL, low-density lipoprotein cholesterol 160 mg/dL, or high-density lipoprotein cholesterol 40 mg/dL. (Modified with permission from Bays HE, Chapman RH, Grandy S. The relationship of body mass index to diabetes mellitus, hypertension and dyslipidaemia: comparison of data from two national surveys. Int J Clin Pract. 2007;61:737–747, © 2007 Wiley Blackwell.) 5.7 4.2 1.7 <18.5 18.5-24.9 25-26.9 27-29.9 30-34.9 35-39.9 40 OVERALL Lean Normal Overweight Obese Body Mass Index (BMI) Modified with permission from Bays HE et al. Int J Clin Pract. 2007;61:737–747; © 2007 Wiley Blackwell. Bays HE. Am J Med. 2009;122:S26S37.
BMI Among Patients With Metabolic Disease NHANES 1999-2002 Text Figure 3 Figure 3 Body mass index (BMI) distribution among patients with metabolic diseases. In general, metabolic disease definitions are based on measurements whose abnormalities significantly increase the risk of adverse clinical outcomes. The fact that these metabolic diseases often have a unified underlying pathophysiologic process may help to explain why the distributions of BMI for diabetes mellitus, hypertension, and dyslipidemia are generally similar. (Modified with permission from Bays HE, Chapman RH, Grandy S. The relationship of body mass index to diabetes mellitus, hypertension and dyslipidaemia: comparison of data from two national surveys. Int J Clin Pract. 2007;61:737–747, © 2007 Wiley Blackwell.) Body Mass Index (BMI) 18.5 18.5-24.9 25-26.9 27-29.9 30-34.9 35-39.9 40 Lean Normal Overweight Obese Modified with permission from Bays HE et al. Int J Clin Pract. 2007;61:737–747; © Wiley Blackwell. Bays HE. Am J Med. 2009;122:S26S37.
Adipocyte Size and Body Fat Distribution Help to Define “Sick” Versus “Healthy” Adipose Tissue Text Figure 4 Figure 4 Adipocyte size and body fat distribution influence whether increased fat weight gain results in “sick” versus “healthy” adipose tissue. (Reprinted with permission from Bays H, Blonde L, Rosenson R. Adiposopathy: how do diet, exercise, weight loss and drug therapies improve metabolic disease? Expert Rev Cardiovasc Ther. 2006;4:871–895, © 2006 Future Drugs Ltd.) Reprinted with permission from Bays H et al. Expert Rev Cardiovasc Ther, 2006;4:871–895; © 2006 Future Drugs Ltd. Bays HE. Am J Med. 2009;122:S26S37.
Contributors and Consequences of Pathogenic Adipose Tissue (Adiposopathy) Text Figure 5 FFA = free fatty acid; HDL = high-density lipoprotein; LDL = low-density lipoprotein Figure 5 Relationship between adiposopathy and major atherosclerotic coronary heart disease risk factors leading to atherosclerosis. (Reprinted with permission from Bays H, Ballantyne C. Adiposopathy: why do adiposity and obesity cause metabolic disease? Future Lipidology. 2006;1:389–420, © 2006 Future Drugs Ltd.) Reprinted with permission from Bays H et al. Future Lipidology. 2006;1:389–420, © 2006 Future Drugs Ltd. Bays HE. Am J Med. 2009;122:S26S37.
Navigating the Consequences of “Sick Fat” Text Figure 6 Figure 6 Navigating the consequences of adipocyte hypertrophy and visceral adiposity. Fat cell enlargement and accumulation of adipose tissue in the visceral area often result in pathogenic adipose tissue metabolic and immune responses, including the net release of free fatty acids, which may be lipotoxic to peripheral organs. The potential of pathogenic adipose tissue to cause metabolic disease is largely dependent on cross-talk and interactions with, as well as responses of, other body tissues. Bays HE. Am J Med. 2009;122:S26S37.
NCEP Definition of Metabolic Syndrome* Text Table 3 Risk factor Defining level Abdominal obesity (waist circumference) 102 cm (40 in) for men 88 cm (35 in) for women Triglycerides 150 mg/dL HDL-C 40 mg/dL (men) 50 mg/dL (women) Blood pressure 130/85 mm Hg Fasting glucose 100 mg/dL *Presence of 3 of these components. Modified with permission from NCEP. JAMA. 2001;285:2496–2497. Grundy SM et al Circulation. 2005;112:2735-2752. Bays HE. Am J Med. 2009;122:S26S37.
Genesis of the Metabolic Syndrome Lipid Profile Text Figure 7 Figure 7 Relationship between pathogenic adipose tissue and the characteristic lipid pattern described by the metabolic syndrome: hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C) levels, and small, dense low-density lipoprotein (LDL) particles. CETP = cholesteryl ester transfer protein; FFA = free fatty acids; HDL = high-density lipoprotein particles; LDL = low-density lipoprotein particles; TG = triglycerides; VLDL = very low density lipoprotein particles. (Reprinted with permission from Bays H, Ballantyne C. Adiposopathy: why do adiposity and obesity cause metabolic disease? Future Lipidology. 2006;1:389–420, © 2006 Future Drugs Ltd.) Reprinted with permission from Bays H et al. Future Lipidology. 2006;1:389–420, © 2006 Future Drugs Ltd. Bays HE. Am J Med. 2009;122:S26S37.
Examples of CHD Risk Factors Text Table 2 History Prior diagnosis of CHD Carotid artery disease Peripheral artery disease Abdominal aortic aneurysm Nonmodifiable factors Age: Men 45 years, women 55 years Family history: CHD in a 1st-degree relative aged 55 years (male) or 65 years (female) Metabolic disease Type 2 diabetes mellitus Hypertension Dyslipidemia Modifiable factors Cigarette smoking Pathogenic adipose tissue (adiposopathy)* *The potential of adipose tissue to be an active endocrine, immune, and pathogenic organ is not universally accepted. Bays HE. Am J Med. 2009;122:S26S37.
Treatments for Adiposopathy Text Table 4 (part 1) May Affect Glucose Metabolism, Blood Pressure, and Lipid Metabolism May Affect Glucose Metabolism Intervention Visceral Adipose Tissue Free Fatty Acids Leptin Adiponectin Tumor Necrosis Factor-Alpha Nutrition and physical activity PPAR-γ agonists (pioglitazone, rosiglitazone) or ― Orlistat Sibutramine or ― ? Cannabinoid receptor antagonists* Peroxisome proliferator–activated receptor gamma (PPAR-γ) is a regulator of adipocyte function and differentiation. Thus, PPAR-γ activators such as thiazolidinediones are plausible candidates for the treatment of adiposopathy. TNF-α = tumor necrosis factor-alpha. (Modified with permission from Bays HE, Rodbard RW, Schorr AB, González-Campoy JM. Adiposopathy: treating pathogenic adipose tissue [adiposopathy] to reduce cardiovascular disease risk. Curr Treat Options Cardiovasc Med. 2007;9:259–271.) *Not currently available in the United States. = Increased; = decreased;? = unknown; ― = neutral effect; PPAR-γ = peroxisome proliferator–activated receptor gamma. Modified with permission from Bays et al. Curr Treat Options Cardiovasc Med. 2007;9:259-271. Bays HE. Am J Med. 2009;122:S26S37. 11
Treatments for Adiposopathy Text Table 4 (part 2) May Affect Blood Pressure May Affect Lipid Metabolism Intervention Renin-Angiotensin-Aldosterone Enzymes Androgens Estrogens Nutrition and physical activity (women) (men) or ― (men) PPAR-γ agonists (pioglitazone, rosiglitazone) ― Orlistat ? (women) Sibutramine Cannabinoid receptor antagonists* Peroxisome proliferator–activated receptor gamma (PPAR-γ) is a regulator of adipocyte function and differentiation. Thus, PPAR-γ activators such as thiazolidinediones are plausible candidates for the treatment of adiposopathy. TNF-α = tumor necrosis factor-alpha. (Modified with permission from Bays HE, Rodbard RW, Schorr AB, González-Campoy JM. Adiposopathy: treating pathogenic adipose tissue [adiposopathy] to reduce cardiovascular disease risk. Curr Treat Options Cardiovasc Med. 2007;9:259–271.) *Not currently available in the United States. = Increased; = decreased;? = unknown; ― = neutral effect; PPAR-γ = peroxisome proliferator–activated receptor gamma. Modified with permission from Bays et al. Curr Treat Options Cardiovasc Med. 2007;9:259-271. Bays HE. Am J Med. 2009;122:S26S37. 12
PEARLS FOR CLINICAL GUIDANCE To reduce coronary heart disease (CHD) risk, encourage appropriate nutrition and healthy lifestyle habits, and, if needed, recommend pharmaceutical agents that improve modifiable risk factors. Even if a metabolic parameter is a risk factor for CHD, an isolated improvement in this CHD risk factor may not always reduce CHD events. Therapies that improve glucose metabolism in hyperglycemic patients, reduce blood pressure in hypertensive patients, and improve lipid levels in dyslipidemic patients may reduce CHD risk, although it is unclear whether isolated improvements in some of these CHD risk factors independently reduce CHD risk. Furthermore, the degree to which therapies that improve CHD risk factors actually reduce CHD risk may depend on how these CHD risk factors are improved. Adipose tissue functions as an active endocrine and immune organ that, when “sick” (as often occurs with weight gain) may contribute to metabolic disease. Adipocyte hypertrophy and visceral adiposity (adiposopathy) may result in adverse metabolic and immune consequences that contribute to major CHD risk factors (e.g., high glucose levels, high blood pressure, dyslipidemia). Reducing adipocyte hypertrophy and visceral adiposity through appropriate nutritional measures and lifestyle interventions may improve the metabolic health of patients and thus reduce CHD risk. Bays HE. Am J Med. 2009;122:S26S37.