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ORIGINAL ARTICLE

Dyslipidemia of Central Obesity and Insulin Resistance

John D. Brunzell, MD
John E. Hokanson, PHD

An association between hypertriglyceridemia, obesity, hyperinsulinemia, insulin resistance, impaired glucose tolerance, hypertension, and coronary artery disease (CAD) has been appreciated since the early 1960s (1–4). Various aspects of this syndrome have been called syndrome X (5), the metabolic syndrome (6), the insulin resistance syndrome (7), and the atherogenic lipoprotein phenotype (8). The various lipoprotein abnormalities that occur with hypertriglyceridemia in this syndrome and the potential mechanisms for this dyslipidemia are the focus of this article.

CENTRAL OBESITY— J. Vague (9) first documented central obesity as an adverse health factor in the early 1950s when he described the android and gynoid forms of obesity. Kissebah et al. (10) and Björntorp and colleagues (11) rekindled interest in abnormalities of body fat distribution when they noted that central obesity was associated with increased risk of diabetes and CAD in both men and women.

With the advent of computerized tomography, a preponderance of intra-abdominal obesity, in contrast to subcutaneous fat accumulation, was demonstrated in individuals with central fat accumulation (12–15). Although intra-abdominal fat correlated with subcutaneous fat and total body fat, when all fat stores are considered simultaneously, only intra-abdominal fat remains correlated with the other components of the central obesity–insulin resistance syndrome (16). Indeed, even in men with a normal BMI, the amount of intra-abdominal fat is correlated with the other components of this syndrome. Although adipose tissue characteristically accumulates in the hips and thighs in women, those who have increased intra-abdominal fat have metabolic abnormalities similar to those of centrally obese men (10,11,17).

CENTRAL OBESITY AND INSULIN RESISTANCE— Hyperinsulinemia, thought to be due to insulin resistance, was noted to be associated with obesity shortly after the development of the assay for insulin (2,3). This association was demonstrated to be caused by impaired insulin action (i.e., insulin resistance) shortly thereafter (18), which was shown to reverse after weight loss (19,20). These findings have been confirmed with the hyperinsulinemic-euglycemic clamp (21) and with the frequently sampled intravenous glucose tolerance test (22). Recently, intra-abdominal fat has been demonstrated to be the main fat store responsible for insulin resistance (12,18,23). Reduction of intra-abdominal fat by caloric restriction (20) or exercise (24,25) ameliorates the insulin resistance and other components of the syndrome.

DYSLIPIDEMIA OF CENTRAL OBESITY— The hypertriglyceridemia associated with obesity and insulin resistance was thought to be secondary to the effects of elevated plasma insulin levels causing increased hepatic fatty acid esterification, which forms triglyceride (26). This concept required the liver to be uniquely insulin sensitive, which appears unlikely when measured directly (27,28). It has been proposed that insulin resistance leads to elevated triglyceride levels in obesity through decreased adipose tissue lipoprotein lipase (LPL). However, kinetic studies suggest that plasma triglyceride removal is not defective in obesity (19,29), and adipose tissue LPL activity (per cell) is elevated in obesity (30). The sequential relation of increased adipose tissue LPL/cell to obesity with increased fat cell size and subsequent insulin resistance has been suggested to occur (31).

A unique explanation for the association of central obesity and insulin resistance with hypertriglyceridemia is via an increase in portal vein long-chain free fatty acids resulting in increased apolipoprotein (apo) B100 secretion by the liver (32,33). The long-chain fatty acids would divert apoB away from degradation in the endoplasmic reticulum and toward secretion. This would easily explain the increased small VLDL in insulin-resistant states with a decreased ratio of VLDL triglyceride to apoB (34,35) compared with the normal state.

Low HDL cholesterol has been associated with obesity and insulin resistance. This association has been suggested to be caused by increased catabolism of HDL particles (36,37) in hypertriglyceridemic and insulin-resistant states. HDL₂ seems to be specifically reduced in obesity (38), perhaps reflecting a decrease in the bigger buoyant subspecies of apoAI (without AII) HDL particles.

Although elevated LDL cholesterol is not usually present in obesity, an increase in intermediate-density lipoproteins and in small dense LDL is thought to manifest as typical LDL particles. In hypertriglyceridemic states, LDL cholesterol measurements do not accurately reflect the number of LDL particles because the cholesteryl ester and free cholesterol content is decreased per particle (39,40). Moreover, central obesity has been directly related to increased numbers of LDL particles that are small and dense (16,23,41,42).

Hypertriglyceridemia, low HDL₂ cholesterol, and small dense LDL particles cluster together in individuals and their relatives (43,44) and have been termed the atherogenic lipoprotein phenotype (8). The association of small dense LDL with CAD (44,45) may be mediated by the small dense LDL, by the other dyslipidemia, or by the remaining components of the central obesity–insulin resistance syndrome.

Central obesity with insulin resistance and increased free fatty acid levels is associated with increased hepatic lipase activity (16,38,46). Increased hepatic lipase activity in central obesity and in insulin-resistant states leads to removal of lipids from LDL and HDL, making them more dense and smaller. Thus, hepatic lipase activity is a major determinant of LDL size and density (47–50) and the amount of HDL₂ cholesterol (38,50–52).

Figure 1—Working model for relationship between intra-abdominal fat (IAF) and insulin resistance with the dyslipidemia seen in that setting. FFA, free fatty acid; TG, triglyceride.

The working hypothesis of our group and that of many other groups (53–56) is that central obesity causes insulin resistance and elevated free fatty acid levels, with the resultant increase in hepatic apoB secretion and increased hepatic lipase activity leading to hypertriglyceridemia, small dense LDL, and decreased HDL₂ cholesterol (Fig. 1). Whether increased free fatty acid levels cause insulin resistance (57) or vice versa is still unsettled.

MODIFIERS OF DYSLIPIDEMIA IN CENTRAL OBESITY

Untreated type 2 diabetes
The defect in insulin secretion in type 2 diabetes that occurs in the setting of central obesity and insulin resistance has effects on the dyslipidemia (58). Further hypertriglyceridemia can result from increased free fatty acids going to hepatic triglyceride or can result from decreased LPL-mediated triglyceride removal. VLDL particles are often bigger and more triglyceride-enriched and may lead to further small dense LDL via cholesteryl ester transfer protein (CETP). HDL cholesterol is often lower. After therapy for hyperglycemia, much of the remaining dyslipidemia in type 2 diabetes is a reflection of the underlying central obesity and insulin resistance.

Familial combined hyperlipidemia
Central obesity and insulin resistance are common components of familial combined hyperlipidemia (59–61). In the setting of central obesity, a gene(s) that elevates apoB has been proposed that is independent of insulin resistance and small dense LDL (62,63), which accentuates the dyslipidemia seen.

Promoter variant of hepatic lipase gene
Four common polymorphisms have been reported in the hepatic lipase promoter (64,65) that are in linkage dysequilibrium. The less common variant is associated with increased HDL cholesterol levels (64,65), predominantly due to increased HDL₂ cholesterol (50). This less common variant is also related to more buoyant LDL particles (50). This genetic variant would then modify the relation between central obesity and insulin resistance in the dyslipidemia present. In Caucasians, these promoter variants may account for 20–30% of the variance in hepatic lipase activity (50,64,65).

Figure 2—The role of CETP and hepatic lipase (HL) in determining the size and density of LDL and HDL is dependent on other factors that influence the size and triglyceride (TG)-to-apoB ratio in VLDL over a wide spectrum.

Triglyceride-enriched VLDL
Triglyceride-enriched VLDL exchanges triglyceride for cholesteryl ester in LDL in a process mediated by CETP (39). This process probably is exaggerated in conditions with very triglyceride-enriched VLDL, such as familial hypertriglyceridemia (34), estrogen replacement therapy (66), and high-carbohydrate diets (67). Each of these conditions can be associated with small dense LDL particles (68). This effect appears to be at one end of a spectrum of VLDL particle size, with the small VLDL of the central obesity–insulin resistance syndrome at the other. With large VLDL, the effect on LDL size and density is predominantly determined by CETP. With small VLDL (and insulin resistance), hepatic lipase is the major determinant of LDL size and density (Fig. 2). HDL cholesterol levels and composition would also reflect the balance between CETP and hepatic lipase.

CORONARY DISEASE AND CENTRAL OBESITY— The cause of increase in coronary disease that occurs with central obesity is likely to be multifactorial. The increases in small VLDL, IDL, and small dense LDL and the decrease in HDL₂ could each be important. In addition, the hyperglycemia of type 2 diabetes and the hypertension and coagulation defects seen with the central obesity syndrome also could contribute. On the other hand, the association of each of these interdependent risk factors for CAD could be mediated by one feature of the syndrome, e.g., small dense LDL (69). Further study is required to determine the role in CAD mortality of each of these components of the syndrome of central obesity.

Acknowledgments— These studies were supported by National Institutes of Health Grants DK-02456 and HL-30086. A portion of these studies were performed in the Clinical Research Center at the University of Washington (NIH 00037) and were supported by the Clinical Nutrition Research Unit (NIH DK-35816). J.D.B. has received an American Diabetes Association Mentor Award.

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From the Department of Medicine, University of Washington, Seattle, Washington.

Address correspondence and reprint requests to John D. Brunzell, MD, University of Washington, Department of Medicine, Box 356178, Seattle, WA 98195-6178. E-mail: brunzell@u.washington.edu.

Received for publication 6 July 1998 and accepted in revised form 25 November 1998.

Abbreviations: apo, apolipoprotein; CAD, coronary artery disease; CETP, cholesteryl ester transfer protein; LPL, lipoprotein lipase.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

This article is based on a presentation at a conference organized by the Indiana University Diabetes Research and Training Center. The conference and the publication of this article were made possible by an unrestricted educational grant from Eli Lilly and Company.

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