Visceral adiposity as a target for the management of the metabolic syndrome

Abstract

Atherosclerosis, the underlying cause of atherosclerotic cardiovascular disease (ACVD), develops due not only to a single cardiovascular risk factor but to a variety of complex factors. The concept of the multiple cardiometabolic risk factor clustering syndrome has been proposed as a highly atherogenic state, independent of hypercholesterolemia and smoking. Body fat distribution, especially visceral fat accumulation, is a major correlate of a cluster of diabetogenic, atherogenic, prothrombotic, and proinflammatory metabolic abnormalities referred to as the metabolic syndrome, with dysfunctional adipocytes and dysregulated production of adipocytokines (hypoadiponectinemia). Medical research has focused on visceral adiposity as an important component of the syndrome in Japanese subjects with a mild degree of adiposity compared with Western subjects. For the prevention of ACVD at least in Japan, it might be practical to stratify subjects with multiple risk factors for atherosclerotic cardiovascular disease based on visceral fat accumulation. Visceral fat reduction through health promotion programs using risk factor-oriented approaches may be effective in reducing ACVD events, as well as producing improvement in risks and hypoadiponectinemia. This review article discusses visceral adiposity as a key player in the syndrome. Visceral fat reduction with life-style modification is a potentially useful strategy in the prevention of ACVD in patients with the metabolic syndrome.

Key words::

• Adiponectin
• adipotoxicity
• atherosclerosis
• visceral fat

Abbreviations
AACE	=	American Association of Clinical Endocrinologists
ACVD	=	atherosclerotic cardiovascular diseases
AHA	=	American Heart Association
BIA	=	bioelectrical impedance analysis
CT	=	computed tomography
EGIR	=	European Group for the Study of Insulin Resistance
FFA	=	free fatty acids
IAS	=	International Atherosclerosis Society
IASO	=	International Association for the Study of Obesity
IDF	=	International Diabetes Federation
NCEP-	=	National Cholesterol Education Program—Third
ATP III	=	Adult Treatment Panel
NHLBI	=	National Heart, Lung, and Blood Institute
VFA	=	visceral fat area
WHF	=	World Heart Federation
WHO	=	World Health Organization

Key messages

• For practical prevention of atherosclerotic cardiovascular events, it might be useful to stratify subjects with multiple risk factors based on visceral fat accumulation.

• Adoption of the concept of visceral adiposity could facilitate the prevention of future ACVD events in subjects with the metabolic syndrome.

Introduction

Epidemiological, metabolic, and experimental studies conducted over more than half a century have permitted the identification of the major risk factors for cardiovascular disease (1–4). The metabolic syndrome is conceptualized as a complex of interrelated cardiovascular risk factors, beyond the classic risk factors such as hypercholesterolemia and smoking (5–8). These factors include dysglycemia, elevated blood pressure, elevated triglyceride levels, low high-density lipoprotein cholesterol levels, and obesity (9–12). Studies of Japanese-Americans in Hawaii and Seattle also suggest that the Japanese as a race cannot handle glucose metabolism as well as Caucasians do when over-nourished and are liable to develop intolerance and complications even with a mild excess of adiposity (13–17). Especially, obese East and South Asians including Japanese have a mild degree of adiposity, compared with European and American subjects (18–24). Different from the amount of total body fat, body fat distribution, especially accumulation of visceral adipose tissue, has been found to be a major correlate of a cluster of diabetogenic, atherogenic, prothrombotic, and proinflammatory metabolic abnormalities referred to as the metabolic syndrome (25–27). Diagnosis of the metabolic syndrome should allow the physician to recommend visceral fat reduction with life-style modification to reduce multiple risks and prevent atherosclerotic cardiovascular diseases (ACVD). This review discusses visceral adiposity as a target for the management of the metabolic syndrome from a Japanese perspective.

Concept of the visceral fat syndrome

Atherosclerosis, the underlying etiology of various cardiovascular diseases, occurs and develops not because of a single cardiometabolic factor (1–4) but several complex cardiometabolic risk factors (5–8). Among these is hypercholesterolemia, which is well known, particularly elevated serum levels of low-density lipoprotein, to play the most important role in the development of atherosclerosis (1,2). Management of hypercholesterolemia became possible after the development of effective cholesterol-lowering drugs such as statins (28–32). However, it is also true that cardiovascular diseases occur in subjects without hypercholesterolemia (33,34). Although diabetes mellitus, hypertension, and lipid disorders such as hypertriglyceridemia or low levels of high-density lipoprotein cholesterol are recognized risk factors for atherosclerosis, they are considered to be weaker contributing factors than hypercholesterolemia. In the past 20 years, clinical and epidemiological studies have demonstrated that the coexistence of these risk factors is a strong risk factor in itself, and multiple risk factor clustering syndrome has become as important as hypercholesterolemia as an underlying cause of ACVD (35–37). The incidence of obesity has increased worldwide due to the life-style of overeating and physical inactivity.

In 1956, Vague (38) was the first to discover the link between adipose tissue distribution and complications in obese subjects. Subsequent clinical research demonstrated that body fat distribution, abdominal obesity, rather than total amount of fat is linked to obesity-related disorders (25,35–38). In 1983, Tokunaga et al. (39) introduced a new method for fat analysis using computed tomography (CT) scanning, which allowed the separate analysis of subcutaneous fat and intra-abdominal visceral fat (representing fat accumulation predominantly in the mesenteric and omental regions). In obese subjects, the mean number of ACVD-related risk factors increases with CT-measured increase in visceral fat area (VFA) but not with increase in subcutaneous fat area (Figure 1) (40). Furthermore, the mean number of risk factors did not correlate with the abdominal subcutaneous fat area in obese people (Figure 1) (40), suggesting a possible protective effect for subcutaneous fat (41–43). Thus, accumulation of intra-abdominal visceral fat, which is a unique adipose tissue both anatomically and metabolically, locates upstream of obesity-related metabolic disorders, including insulin resistance, glucose intolerance, dyslipidemia, and elevated blood pressure, leading to atherosclerosis based on clustering of multiple risk factors (Figure 1) (25,26,36,44–47). This is conceptualized as ‘visceral fat syndrome’ (48,49) or the ‘metabolic syndrome’. On the other hand, reduction of intra-abdominal fat improved metabolic disorders (50,51).

Figure 1. Visceral obesity and subcutaneous obesity. Top: Correlation of visceral fat area and subcutaneous fat area with obesity-related cardiovascular risk factors in obese subjects (body mass index ≥25 kg/m²). Bottom: Schematic diagrams of the complications associated with visceral obesity (left) and subcutaneous obesity (right). Reproduced with permission from Annals of Medicine (40). (HT = hypertension; FFA = free fatty acids; DL = dyslipidemia; DM = diabetes mellitus; ACVD = atherosclerotic cardiovascular disease).

Global and Japanese criteria for the metabolic syndrome

The concept of the metabolic syndrome, which closely corresponds to the ‘multiple risk factors clustering syndrome’ (35–37), has been noted worldwide (5,6,52). Several cohort (53–57) and meta-analysis (58–60) studies have demonstrated that the presence of the metabolic syndrome is associated with increased frequency of ACVD events as well as cardiovascular morbidity and mortality. In this regard, various expert groups have attempted to develop a clear definition for the metabolic syndrome. The first accepted one was proposed by the World Health Organization (WHO), based on type 2 diabetes and insulin resistance (61). Next, other definitions were proposed by various organizations, such as the European Group for the Study of Insulin Resistance (EGIR) (62), the National Cholesterol Education Program—Third Adult Treatment Panel (NCEP-ATP III) (63), the American Association of Clinical Endocrinologists (AACE) (64), the International Diabetes Federation (IDF) (65), and a committee comprising several Japanese medical societies (66,67). In 2009, the IDF Task Force on Epidemiology and Prevention, of the National Heart, Lung, and Blood Institute (NHLBI), American Heart Association (AHA), World Heart Federation (WHF), International Atherosclerosis Society (IAS), and International Association for the Study of Obesity (IASO), prepared a worldwide consensus statement for the criteria of the metabolic syndrome, which did not include abdominal obesity (68). In contrast, central adiposity is considered by the current Japanese definition of the metabolic syndrome a prerequisite for diagnosis, along with any two of the following abnormalities: 1) high blood pressure, 2) dyslipidemia, or/and 3) elevated fasting glucose level. One major difference between the global and Japanese criteria for the definition of the metabolic syndrome is that the Japanese adopted visceral fat accumulation as an important component of the definition (67) because of the ethnic and racial difference in the pattern of adiposity (18–24).

Pathophysiology of visceral obesity— the visceral fat centric hypothesis

Adipose tissue provides free fatty acids (FFA) and glycerol through lipolysis (69). Subcutaneous fat serves as a long-term depot for excess energy as well as maintenance of insulin sensitivity. In fact, insulin sensitivity is not different between individuals with small and large amounts of subcutaneous fat (70–73). In contrast, the hypertrophied adipocytes in intra-abdominal visceral fat exhibit hyperlipolytic activity that is resistant to the antilipolytic effect of insulin (74,75). The resulting hyper-free-fatty-acidemia and hyperglycerolemia in the portal vein (76) increase the production of triacylglycerol-rich lipoproteins (77–79) and glucose in the liver (80–81), leading to insulin resistance in the liver and muscle. Visceral fat tissue is saturated with triglycerides but has limited capacity for storage of energy excess; the triacylglycerol surplus is thus deposited at undesirable sites such as the liver, skeletal muscle, and pancreas, i.e. ectopic fat deposition, as a consequence of hyperinsulinemia/insulin resistance and hyper-free-fatty-acidemia in the portal vein (5,26,82–87) (Figure 1).

Adipose tissue is not only specialized in the passive storage of excess energy in the form of triglycerides, but it is also a remarkable endocrine organ producing a variety of bioactive substances (88). The latter are conceptualized as ‘adipocytokines’ (89). Our group discovered adiponectin as an adipocytokine in the human adipose cDNA library (90), and subsequent experiments confirmed that it has anti-atherosclerotic properties (91). At the same time, adiponectin was identified independently by three other groups using different approaches and was termed adipocyte complement-related protein of 30 kDa (ACRP30) (92), adipoQ (93), and gelatin-binding protein of 28 kDa (GBP28) (94). The production and secretion of adipocytokines are dynamically regulated mainly by nutritional status. Life-style factors, such as overeating and physical inactivity, induce visceral fat accumulation, which results in adipocyte dysfunction and dysregulated production of adipocytokines (over-production of offensive adipocytokines such as plasminogen activator inhibitor-1, and under-production of defensive adipocytokines such as adiponectin (95)), leading to a state of adipotoxicity. Taken together, abdominal obesity, including dysfunctional visceral fat adipocytes, dysregulated production of adipocytokines, such as hypoadiponectinemia, and ectopic fat deposition (Figure 1) might be the major mechanism of life-style-related diseases accompanied by organ failure and fibrosis (hence the term ‘visceral fat centric hypothesis’, Figure 2) (91).

Figure 2. Differences in the pathophysiology of atherosclerotic cardiovascular disease (ACVD) in subjects without (left) and with (right) visceral fat obesity. (HDL-C = high density lipoprotein-cholesterol; PAI-1 = plasminogen activator inhibitor-1; HT = hypertension; DM = diabetes mellitus; DL = dyslipidemia).

Visceral fat reduction as preventative measure against future ACVD events

The control of cardiovascular risk factors is an important strategy to prevent ACVD in the general population. Although measurement of the amount of visceral fat by CT is accurate, this technique is not readily available in clinics, has several problems related to cost-effectiveness and/or radiation exposure, and is not suitable for screening large groups of individuals. Thus, there is a need for a simple and non-invasive method to assess visceral fat accumulation. The bioelectrical impedance analysis (BIA) method, which is based on the difference in electric resistance between fat and components of other organs (96–98), should meet this need. Currently, the visceral fat belt, a new simple device for non-invasive estimation of VFA based on the abdominal BIA method (99), is being co-developed by two companies and our laboratory (we declare no conflict of interest and lack of intellectual property rights). Preliminary studies showed that the VFA measured using this belt correlated significantly with that measured by CT scan (99). Considered collectively, the abdominal BIA method is potentially useful in routine clinical practice for evaluation of visceral fat accumulation associated with the metabolic syndrome.

A health promotion program using this visceral fat belt as a risk factor-oriented approach, not obesity-oriented approach (called ‘Hoken-shido’ in Japanese), was performed by medical personnel, especially health nurses, in the general population (100–106). Visceral fat reduction with life-style modification through this program lessened ACVD events in subjects with abdominal obesity (105), in parallel with reductions in the number of obesity-related cardiovascular risk factors (100) and increases in serum adiponectin levels (102).

Stratification based on visceral fat accumulation to prevent ACVD events

For individuals with hypertension, dyslipidemia, and/or hyperglycemia, it is important to divide them into those with or without fat accumulation for proper management especially prevention of ACVD (Figure 3). For subjects free of visceral fat accumulation, programs designed to reduce body weight will be futile compared with specific approaches for each risk factor. In this regard, thin subjects with essential hypertension and salt sensitivity (23,107–110), thin subjects with type 2 diabetes and low insulin secretion capacity (23,111–114), and subjects with familial dyslipidemia (115–117) are commonly encountered in East and South Asian countries. On the other hand, loss of body weight and exercise are effective in the visceral fat accumulation group (Figure 3). For clinically meaningful prevention of future ACVD, it may be important to stratify subjects with multiple risk factors into those with or without visceral fat accumulation, especially for East and South Asians. Various life-style interventions to reduce visceral obesity, such as calorie restriction and exercise, could be implemented to prevent ACVD events. One such program, called ‘Adipo-Do-It’ has already been implemented (95).

Figure 3. Visceral fat accumulation and hypoadiponectinemia are related to a variety of diseases (visceral fat centric theory).

Summary

Adoption of the concept of visceral adiposity could facilitate the prevention of future ACVD events in subjects with the metabolic syndrome.

Declaration of interest: This research was supported in part by a Grant-in-Aid for Scientific Research No. (C) 21591177 (to K Kishida) and a Grant-in-Aid for Scientific Research on Innovative Areas No. 22126008 (to T Funahashi and K Kishida). The authors declare no other conflicts of interest.