“Sick Fat,” Metabolic Disease, and Atherosclerosis

Article Outline

• Abstract
• Metabolic diseases and atherosclerosis
  • High Blood Sugar
  • High Blood Pressure
  • Dyslipidemia
• Metabolic syndrome and atherosclerosis
• Integrative and comprehensive approach for reducing coronary heart disease risk
  • Limitations/Impairments of the Liver
  • Limitations/Impairments of Skeletal Muscle
  • Limitations/Impairments of the Pancreas
  • Limitations/Impairments of Other Organs
• Summary
• Pearls for clinical guidance
• Author disclosures
• Acknowledgments
• Supplementary data
• Supplementary data
• References
• Copyright

Abstract 

Atherosclerotic coronary heart disease (CHD) is the most common cause of morbidity and mortality among men and women in developed nations. The obesity epidemic contributes to the increasing prevalence of high blood sugar (as may be found in patients with diabetes mellitus and metabolic syndrome), high blood pressure, and dyslipidemia—all CHD risk factors. Metabolic syndrome describes the common clinical finding wherein component CHD risk factors cluster within a single patient, but this term does not identify any unified pathophysiologic process. However, a component of the metabolic syndrome is abdominal obesity, which does reflect an anatomic manifestation of a “common-soil” pathophysiologic process that promotes the onset of CHD risk factors, and thus increases CHD risk. Adiposopathy (“sick fat”) is anatomically characterized by visceral adiposity and adipocyte hypertrophy; it is manifested physiologically by a net increase in release of free fatty acids and by pathogenic adipose tissue metabolic/immune responses that promote metabolic disease and increase CHD risk. Understanding the relation of adiposopathy to CHD risk factors and recognizing the importance of treating both the “cause and effect” of metabolic diseases are critical toward a comprehensive approach in reducing CHD risk. Regarding the “cause,” clinicians and their patients should be diligent regarding appropriate nutritional and lifestyle interventions that may favorably affect health. Regarding the “effect,” clinicians and their patients should be equally diligent toward appropriate pharmaceutical interventions that reduce CHD risk factors when nutritional and lifestyle interventions do not sufficiently achieve desired metabolic treatment goals.

Keywords: Abdominal obesity, Adiposopathy, Atherosclerosis, Coronary heart disease, Metabolic syndrome

The purpose of this report is to review components of the metabolic syndrome, and thus atherosclerosis risk, with an emphasis on the central role of adipose tissue pathophysiology (often exacerbated by obesity) and its relation to the more usual atherosclerotic coronary heart disease (CHD) risk factors. For the practicing clinician, this review (1) outlines the metabolic interrelationships of CHD risk factors in a proposed unified process, (2) shows how current treatments of these CHD risk factors may affect CHD outcomes, and (3) provides a rational basis for clinician evaluation of unresolved issues and debates related to emerging details of these complex relationships. A glossary of terms used in this article is provided in Table 1.

Table 1. Glossary of terms

Apo C-II = apolipoprotein C-II; CHD = coronary heart disease; FFA = free fatty acid; HDL = high-density lipoprotein; IL-6 = interleukin-6; LDL = low-density lipoprotein; PPAR-γ = peroxisome proliferator–activated receptor-γ; TG = triglyceride; VLDL = very-low-density lipoprotein.

Most major CHD risk factors are modifiable¹; these include metabolic disorders such as type 2 diabetes mellitus, hypertension, and dyslipidemia² (Table 2). These common metabolic abnormalities often cluster together, and analyses support that their genesis is due to a common underlying pathophysiologic process.³, ⁴, ⁵, ⁶, ⁷ Treatments of these CHD risk factors vary in the degree by which they reduce CHD risk. However, as effective as drug treatments may be in treating metabolic disease once diagnosed, it is the predominant mindset and inclination of many primary care clinicians to be proactive in treating the source of disease. Many clinicians have the philosophical belief that treating both the cause and the effect of disease (including atherosclerosis) represents the most practical and perhaps the most cost-effective approach, which is ultimately in the best interest of their patients. Still more desirable are earlier interventions that remedy underlying pathophysiologic processes, potentially preventing metabolic diseases before they even occur.

Table 2. Major risk factors for future atherosclerotic coronary heart disease (CHD) events

It might be reasonably argued that in developed nations, the single most common contributor to the rising prevalence of metabolic diseases—such as type 2 diabetes, hypertension, and dyslipidemia—is excessive body fat, which often results in pathogenic adipose tissue, called adiposopathy.⁸, ⁹ Adiposopathy is defined as pathogenic adipose tissue that is promoted by positive caloric balance and sedentary lifestyle in genetically and environmentally susceptible patients; it may be anatomically manifested by adipocyte hypertrophy, visceral adipose tissue accumulation, adipose tissue growth that exceeds vascular supply, and ectopic fat deposition. Physiologically, adiposopathy causes adverse metabolic and immune consequences that result in clinical metabolic disease.⁸ It is true that not everyone appreciates adipose tissue as both an active endocrine and active immune organ.⁸ Nor is the profound pathogenic potential of adipose tissue universally accepted.⁴ As with many areas of medical science, much research and education are needed. But perhaps a good place to start is recognizing that CHD risk is much greater in developed nations than in leaner populations. This understanding may be critical toward crafting the most effective public health management plan, implementing the best preventive measures, and reducing the prevalence of CHD risk factors, thus decreasing CHD risk.

Among hunter-gatherer populations who follow their indigenous lifestyles, CHD is a rarity. This is in large measure due to a striking reduction in major CHD risk factors, such as markedly reduced cholesterol levels, in these populations (Figure 1).¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵ A significant contributor to the increased prevalence of CHD risk factors and CHD risk in many developed nations is an increase in body fat (as may be reflected by an increase in body mass index) (Figure 2, Figure 3).²⁶ This has been a disturbing and continuing trend for the past several decades, and it has advanced to the point that obesity and its metabolic consequences are now characterized as epidemics.²⁷

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• Figure 1. 

  Comparison of cholesterol levels among humans and animals.¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵ Atherosclerotic coronary heart disease (CHD) is rare among hunter-gatherers; CHD is the most common cause of mortality in adult Americans. 1 mg/dL = 0.02586 mmol/L. (Adapted with permission from J Am Coll Cardiol.¹⁰)

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• Figure 2. 

  Relation 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.²⁶ The chart data are derived from the National Health and Nutritional Examination Surveys (NHANES), 1999 to 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. (Adapted with permission from Int J Clin Pract.²⁶ Copyright 2007 Wiley Blackwell.)

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• 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 for 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. (Adapted with permission from Int J Clin Pract.²⁶ Copyright 2007 Wiley Blackwell.)

Unfortunately, current public health initiatives have failed to reverse the obesity epidemic. As a result, the onset of metabolic disease continues to increase, and clinical trials have focused on the development of pharmaceuticals that are used to treat patients with type 2 diabetes, hypertension, and dyslipidemia, which often are consequences of the obesity epidemic.

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Metabolic diseases and atherosclerosis 

High Blood Sugar 

High blood sugar is a risk factor for CHD²⁸, ²⁹ and is the single diagnostic criterion for diabetes mellitus, a major CHD risk factor. Even at ranges of glucose levels that do not define diabetes (100 to 125 mg/dL [1 mg/dL = 0.05551 mmol/L]), high blood sugar is an important diagnostic component of the metabolic syndrome, which is a constellation of risk factors thought to increase CHD risk. Poor glycemic control in patients with type 1 diabetes is an important predictor of CHD.³⁰ In patients with type 2 diabetes, hyperglycemia increases CHD risk, with a 10-year cumulative incidence of CHD events >20%—a rate equivalent to that of patients with diagnosed CHD, especially when accompanied by other CHD risk factors. Thus, type 2 diabetes is often considered a “CHD risk equivalent.”³¹ Years of intensive management of glucose levels in patients with type 1 diabetes may reduce long-term CHD risk.³² Decreased glucose levels in patients with type 2 diabetes may reduce CHD in overweight patients if anti-diabetes agents are used that have favorable effects on weight reduction and other metabolic parameters (such as metformin),³³ or that have favorable lipid effects (such as pioglitazone).³⁴ In other words, it is unclear whether reducing glucose levels alone reduces CHD risk.

Although glucose lowering may reduce CHD risk, and even though aggressive glucose lowering reduces microvascular disease in patients with diabetes, questions have arisen as to whether intensive glucose lowering is beneficial in reducing macrovascular disease. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is an ongoing study designed to evaluate usual versus intensive glycemic control, as well as usual versus intensive lipid and blood pressure control. In February 2008, the diabetes portion of ACCORD was stopped 18 months early because of an increased death rate in the intensive glucose treatment group—a difference of 3 participants per 1,000 each year over an average of almost 4 years of treatment.³⁵ Although this does not negate the potential CHD benefit of glucose lowering in patients with diabetes, it does suggest that aggressive hemoglobin A_1c (HbA_1c) reduction to <6% is potentially less favorable than attainment of HbA_1c of ∼7.5%. The reason for this finding is unclear. In contrast, preliminary findings from the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial provided no evidence that intensive treatment to lower blood glucose levels in patients with type 2 diabetes increased mortality risk, and the trial is continuing.³⁶

High Blood Pressure 

High blood pressure increases CHD risk. Large-scale observational data show a doubling of mortality from ischemic heart disease and stroke for every 20 mm Hg increase in systolic blood pressure or 10 mm Hg increase in diastolic blood pressure.³⁷ The Framingham Heart Study has shown that blood pressure values in the 130/85 to 139/89 mm Hg range are associated with a >2-fold increase in relative risk for cardiovascular disease compared with levels <120/80 mm Hg.³⁸ Reducing blood pressure in patients with hypertension definitely reduces the risk of stroke and generally is reported to decrease CHD risk.³⁹

Dyslipidemia 

The single dyslipidemia most often associated with increased CHD risk is an elevation in low-density lipoprotein (LDL) cholesterol levels.² Reducing LDL cholesterol levels reduces CHD risk (morbidity and mortality),² which, in contrast to treatment of glucose levels and blood pressure, often yields CHD outcomes benefits within months.⁴⁰ Reduced levels of high-density lipoprotein (HDL) cholesterol are also associated with an increased risk for CHD. However, raising HDL cholesterol does not always reduce CHD; such CHD effects are dependent on the mechanisms by which HDL cholesterol levels are raised.⁴¹, ⁴² Elevated triglyceride (TG) levels are a risk factor for CHD. However, it is unclear whether hypertriglyceridemia is always an independent risk factor for CHD, because not all cases of elevated TG levels increase CHD risk (such as apolipoprotein CII deficiency). Furthermore, high TG levels often are associated with abnormalities in glucose metabolism, obesity, low HDL cholesterol levels, increased lipoprotein remnants, and abnormalities of lipoprotein particle size and subclass distribution, making it even more difficult to establish that high TG levels independently increase CHD risk. Finally, no prospective clinical trial has yet demonstrated that specifically lowering TG levels in patients with significant hypertriglyceridemia reduces CHD events as a primary end point.

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Metabolic syndrome and atherosclerosis 

Metabolic syndrome is a term that is commonly used to describe the associations of abdominal obesity, elevated glucose levels, high blood pressure, hypertriglyceridemia, and low HDL cholesterol levels,² all of which are CHD risk factors (Table 3).⁴³, ⁴⁴, ⁴⁵ However, the metabolic syndrome may not be a better predictor of CHD risk when compared with assessment of its individual components, prompting some to question the utility of this term.⁴⁶ Furthermore, lipid abnormality criteria for the diagnosis of metabolic syndrome include elevated TG and low HDL cholesterol levels. However, it is an elevation in LDL cholesterol levels that represents the lipid abnormality that is most consistently associated with increased CHD risk and whose correction is best proved to decrease CHD risk. LDL cholesterol levels are not considered as part of the metabolic syndrome diagnostic criteria.

Table 3. National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) diagnostic criteria for the metabolic syndrome^⁎

Risk Factor	Defining Level
Abdominal obesity (waist circumference)
Men	>102cm(>40in)
Women	>88cm(>35in)
Triglycerides†	≥150mg/dL
HDL cholesterol‡
Men	<40mg/dL
Women	<50mg/dL
Blood pressure	≥130/≥85mmHg
Fasting glucose	≥100mg/dL§

HDL = high-density lipoprotein.

Adapted with permission from JAMA.⁴³

Abdominal obesity (Figure 4), which is a component of the metabolic syndrome, does reflect an important pathogenic finding that contributes to metabolic diseases such as type 2 diabetes, hypertension, and dyslipidemia.⁹, ⁴⁷, ⁴⁸, ⁴⁹ An increase in visceral fat is just one anatomic abnormality of the very active metabolic and immune organ that is adipose tissue.

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• 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 Expert Rev Cardiovasc Ther.⁴⁹ Copyright 2006 Future Drugs Ltd.)

Excessive body fat generally increases the prevalence of metabolic diseases (Figure 2, Figure 3),²⁶ and reduction in body weight generally improves metabolic diseases. Many metabolic diseases are important CHD risk factors.⁴⁹ If positive caloric balance causes excessive fat cell hypertrophy, this may result in “sick fat” (pathogenic adipose tissue),⁴⁸ especially if it occurs in the visceral region, and particularly if it occurs in genetically or otherwise susceptible patients.⁴⁷, ⁴⁸ The ensuing pathogenic metabolic and immune responses promote metabolic diseases, many of which are important CHD risk factors. An example of the importance of adipose tissue to metabolic health is the finding that mice with lipoatrophy (virtually no white adipose tissue) often develop diabetes. Surgical transplantation of functional adipose tissue into these lipoatrophic mice reduces hyperglycemia, lowers insulin levels, and improves muscle insulin sensitivity.⁵⁰ This illustrates that adipose tissue is far from simply an energy storage organ but is rather an important metabolic organ whose functionality is important for metabolic health.⁹ Therapeutically, improvement in adipose tissue functionality²⁵ can be achieved by adding functional adipocytes (such as through peroxisome proliferator–activated receptor-γ agonists)⁵¹ or by providing weight reduction interventions (which reduce adipocyte hypertrophy and diminish visceral adiposity) (Table 4).³ These interventions are often effective in the treatment of patients with metabolic disease.

Table 4. Various adiposopathy treatments and examples of their effects upon parameters that affect metabolic disease

FFAs = free fatty acids; PPAR-γ = peroxisome proliferator–activated receptor-γ; TNF-α = tumor necrosis factor–α; ↑ = increased; ↓ = decreased; ? = unknown; – = neutral effect.

Adapted with permission from Curr Treat Options Cardiovasc Med.³

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Integrative and comprehensive approach for reducing coronary heart disease risk 

As most primary care clinicians are acutely aware, one of the most basic interventions for treating and/or preventing the most common diseases found in medical practice, including CHD, is encouraging patients to adopt favorable nutritional and lifestyle habits. It is true that some patients may be able to respond to positive caloric balance with functional adipocyte proliferation and without generation of pathogenic adipose tissue, thus allowing them to avoid the development of metabolic disease despite weight gain. In fact, mild increases in body fat may be associated with reduced CHD risk.⁵² However, entirely too many other patients will respond to positive caloric balance with the accumulation of pathogenic adipose tissue and metabolic and immune responses that promote ill health. Furthermore, even without the development of metabolic disease, adiposity alone can lead to a number of diseases related to a mass effect alone.⁵³ Thus, clinicians often advise overweight patients of the need to reduce body weight for the purposes of improving metabolic disease and reducing important CHD risk factors (Table 4).³

Unfortunately, many patients do not adhere to clinician-directed nutritional and lifestyle recommendations. In these cases, if positive caloric balance occurs in an environment of impaired or insufficient adipogenesis (generation of additional functional adipocytes), then in order to continue to store energy, adipocyte hypertrophy and visceral adiposity, which are among the anatomic manifestations of adiposopathy, may ensue. This often results in the net release of circulating free fatty acids and other pathogenic adipose tissue metabolic and immune responses that directly contribute to type 2 diabetes, hypertension, and dyslipidemia (Figure 5).⁹ In addition to generation of these metabolic diseases, which are major CHD risk factors, evidence suggests that pathogenic responses from pericardiac and perivascular adipose tissue may directly contribute to an increased risk for CHD events through an “outside to inside” mechanistic model of increased atherogenic plaque vulnerability (see the text below).⁵⁴ However, an important concept is that adiposopathy does not act alone in promoting metabolic disease. Limitation and/or impairment of other body organs is integral toward revealing the full pathogenic potential of adipose tissue (Figure 6).

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• Figure 5. 

  Relation between adiposopathy and major atherosclerotic coronary heart disease risk factors leading to atherosclerosis. FFA = free fatty acid; HDL = high-density lipoprotein; LDL = low-density lipoprotein. (Reprinted with permission from Future Lipidology.⁹ Copyright 2006 Future Drugs Ltd.)

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• 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.

Limitations/Impairments of the Liver 

One example of how adipocyte hypertrophy and visceral adiposity may result in pathogenic metabolic responses is the net increased release into the circulation of free fatty acids (Figure 6), which then are delivered to body organs such as the liver. A limitation or impairment in the liver's ability to sufficiently oxidize these free fatty acids may contribute to increased intrahepatic lipid deposition. Increased hepatic fat promotes insulin resistance (Figure 5),⁹, ⁵⁵ contributes to dyslipidemia, and accounts for the hepatosteatosis (“fatty liver”) so commonly found in overweight, insulin-resistant patients with dyslipidemia (Figure 7).⁹ Finally, adiposopathy is associated with abnormal immune responses, such as increased release of interleukin-6 (IL-6). Although C-reactive protein (CRP) has been described to be directly released from adipose tissue, it is likely that most of the increase in CRP often seen in obese patients (particularly those with increased visceral adipose tissue) is due to IL-6−induced hepatic synthesis of CRP.⁹ CRP is often considered a CHD risk factor.

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• Figure 7. 

  Relation between pathogenic adipose tissue and the characteristic lipid pattern described by the metabolic syndrome: hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol levels, and small, dense low-density lipoprotein (LDL) particles. CETP = cholesterol ester transfer protein; FFA = free fatty acid; TG = triglyceride; VLDL = very-low-density lipoprotein. (Reprinted with permission from Future Lipidology.⁹ Copyright 2006 Future Drugs Ltd.)

Limitations/Impairments of Skeletal Muscle 

Similar to limitations in liver function, some patients have an inherent or acquired limitation or impairment in their ability to metabolize intramuscular fat.⁵⁵ If adiposopathy results in an increased net release of free fatty acids into the circulation, then lack of “flexibility” on the part of muscle to oxidize these fatty acids may result in ectopic free fatty acid storage in muscle and accumulation of intramyocellular lipids such as diacylglycerol, fatty acyl CoA, and ceramides. Because the deposition of fatty acids in nonadipose organs is potentially pathogenic, this has been described as representing “lipotoxicity” (Figure 5),⁹, ⁵¹ which may promote insulin resistance in muscle.⁵⁵, ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹ Fat weight loss through hypocaloric nutritional intervention may not necessarily improve the inherent ability of “inflexible” muscle to metabolize free fatty acids. However, such intervention is nonetheless therapeutic if fat weight loss reduces the free fatty acid and/or TG content of skeletal muscle, which, in turn, improves insulin sensitivity.⁵⁸

Limitations/Impairments of the Pancreas 

Patients with a familial limitation or impairment of pancreatic insulin secretion are at increased risk for developing type 2 diabetes when accompanied by obesity.⁶⁰ The chronic net increased release of free fatty acids into the circulation that accompanies adiposopathy may be lipotoxic to the pancreas, thereby decreasing pancreatic insulin secretion (Figure 5).⁹, ⁴⁸

Limitations/Impairments of Other Organs 

Adiposopathy adversely affects the immune system, potentially resulting in pathogenic immune responses. An enhanced net inflammatory response that results from an increase in proinflammatory factors (e.g., interleukins, tumor necrosis factor–α) and limitations or impairment of anti-inflammatory factors (e.g., adiponectin) is being increasingly recognized as an important potential contributor to pathologic processes leading to type 2 diabetes, hypertension, and dyslipidemia.⁹ The vasculature also may play a role in adiposopathy-induced CHD. Atherosclerosis most often is characterized as the interaction of intraluminal pathology with arterial subendothelia. However, pathogenic pericardial and perivascular adipose tissue may directly contribute to atherosclerotic plaque vulnerability through “outside to inside” (from the outside of the vessel to the endothelium) metabolic and immunologic pathogenic effects in susceptible patients.⁹, ⁶¹ Adipose tissue and the brain are intimately connected in multiple processes involving energy balance, with the brain affecting adipose tissue function and vice versa, all of which may directly influence metabolic and immune responses, leading to metabolic disease.⁶², ⁶³ Abnormalities of glucocorticoid and sex hormone production from endocrine organs are common with excessive body fat; these may promote metabolic disease and increase CHD risk.⁹ Various factors in the proximal intestine may work together with excessive body fat in the pathophysiology of many cases of diabetes.⁶⁴ Not only might increased adipose tissue mass contribute to hypertension by compressing the kidneys,⁹ but in predisposed patients, adiposopathy may promote high blood pressure, such as through the increased release of constituents of the renin-angiotensin system, which, in turn, may contribute to high blood pressure.⁸

The point is that the pathogenic potential of adipocyte hypertrophy and visceral adiposity most often requires a pathologic partnership between adiposopathy and inherited or acquired limitation and/or impairment of other body organs in predisposed patients.

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Summary 

The most effective way to manage metabolic diseases that increase CHD risk is by recognizing their underlying causes and treating their adverse metabolic consequences. Clinical trials have proved that available drugs effectively reduce blood sugar levels in patients with hyperglycemia, reduce blood pressure in patients with hypertension, and improve lipid levels in patients with dyslipidemia. Many of these interventions may also reduce CHD risk, and lipid-altering drug therapy may provide the most efficacious pharmaceutical approach to reducing CHD events.

In addition to drug treatments directed toward these CHD risk factors once they have already occurred, many clinicians prefer to implement interventions that help to correct the underlying pathophysiologic processes (“causes”) that lead to metabolic disorders, with the most appealing benefit being the potential to prevent or delay the onset of metabolic disease. Perhaps the most important promoter of metabolic disease in developed nations today is excessive body fat, which, in some individuals, may cause adipose tissue to become dysfunctional or “sick.”

One way in which clinicians can best focus on correcting a common underlying pathophysiologic process of metabolic disease by recognizing the profound importance of adipose tissue to human health, and by understanding the pathogenic potential for adiposopathy to contribute to metabolic disease—even as they may be implementing drug therapy directed toward improving individual metabolic parameters (e.g., “effects” such as blood sugar, blood pressure, and lipid levels). Adipose tissue must be acknowledged as far more than simply a storage organ; this may facilitate discussion with patients regarding nutritional and lifestyle measures that improve health. Specifically, clinicians and patients alike may find it simpler and more productive to engage in a conversation about how too much body fat causes fat to become “sick,” which then leads to metabolic disease (including CHD). By addressing a specific underlying pathophysiologic process and explaining its multifactorial consequences, clinicians may improve their ability to engage patients in effective management programs. If such an approach does improve physician and patient understanding, and if patients then become empowered with the knowledge of what lifestyle habits are required to “cure” their “sick fat” (as may often be achieved through appropriate nutritional and lifestyle interventions), this may represent the best example of a comprehensive management plan for the treatment and prevention of many metabolic diseases and CHD.

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Pearls for clinical guidance 

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Author disclosures 

The author of this article has disclosed the following industry relationships:

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Acknowledgments 

I thank Michael Theisen, Dolores Matthews, and Judy Fallon from Scientific Connexions, Newtown, Pennsylvania, who provided editorial assistance funded by AstraZeneca Pharmaceuticals LP.

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Supplementary data 

Supplementary material cited in this article is available online.

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Supplementary data 

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