Hepatology International

, Volume 7, Issue 2, pp 413–428

Should visceral fat, strictly linked to hepatic steatosis, be depleted to improve survival?


  • Carmine Finelli
    • Center of Obesity and Eating DisorderStella Maris Mediterraneo Foundation Chiaromonte
    • Department of Clinical and Experimental MedicineFederico II University Medical School of Naples
Review Article

DOI: 10.1007/s12072-012-9406-z

Cite this article as:
Finelli, C. & Tarantino, G. Hepatol Int (2013) 7: 413. doi:10.1007/s12072-012-9406-z


Numerous epidemiologic studies have implicated abdominal obesity as a major risk factor for insulin resistance, type 2 diabetes mellitus, cardiovascular disease, stroke, metabolic syndrome and its further expression, i.e., nonalcoholic fatty liver disease and death. Using novel models of visceral obesity, several studies have demonstrated that the relationship between visceral fat and longevity is causal, while the accrual of subcutaneous fat does not appear to play an important role in the etiology of disease risk. The need of reducing the visceral fat to improve survival, mainly taking into account the strict link between nonalcoholic fatty liver disease and the coronary artery disease is discussed.




The prevalence of overweight [body mass index (BMI) >25 kg/m2] and obesity (BMI > 30 kg/m2) has reached epidemic proportions in most of the developed world. Obesity increases the risk for several comorbidities including type 2 diabetes mellitus (T2DM) [1], stroke [2], cardiovascular disease (CVD) [3], and metabolic syndrome (MetS) [4], the further expression of which is hepatic steatosis (HS). The risks associated with obesity have been extended to cancer [5, 6], including prostate [7], breast [8], liver [9], kidney [10], colon [11], ovarian [12], and endometrial cancers [13].

Abdominal obesity and disease risk

The fundamental cause of obesity is a long-term imbalance in energy intake and expenditure (i.e., positive energy balance) leading to the increased body mass including the accumulation of subcutaneous and visceral fat. Although general obesity is an important risk factor for many diseases, several human studies have demonstrated that visceral fat accrual, which is the fat located in the viscera, is most strongly related to many health conditions, including CVD, insulin resistance, and T2DM [14]. The mechanism(s) linking visceral fat with the MetS is not entirely clear, but it has been suggested to involve its anatomical location, leading to a “portal” effect of greater free fatty acids (FFAs) and glycerol release [15]. Evidence has shown that adipose tissue is an active endocrine organ, capable of secreting many cytokines, often referred to as adipokines, that can promote inflammation and interfere with insulin action [16]. Furthermore, some studies have shown that subcutaneous and visceral fat are biologically distinct, with visceral fat demonstrating far greater proinflammatory characteristics than subcutaneous fat. In the remainder of this review, we will discuss the following: (1) the epidemiologic and surgical data in humans linking visceral fat and not subcutaneous fat to disease, (2) epidemiological and experimental data in humans linking visceral fat accretion to mortality risk and lifespan, and (3) treatment strategies aimed at reducing disease risk by depleting visceral fat stores.

Epidemiologic studies

The ability to prevent or delay the onset of disease is a critical determinant of lifespan. Some diseases are not treatable or preventable and have an inheritable component of risk. However, the leading causes of death and comorbidites in humans including CVD, stroke, and T2DM are age-related conditions that can be largely prevented or delayed by lifestyle interventions [17]. Epidemiologic studies have revealed that a common yet preventable risk factor for these diseases is the accumulation of visceral fat, which is a hallmark of aging in humans [18]. Using either waist circumference or waist–hip ratio (WHR) as a proxy of abdominal obesity, numerous studies have found that visceral fat is a stronger risk factor for insulin resistance, T2DM [19], CVD [20], stroke [21], and heart failure [22] than BMI or other fat depots.

However, the hazards of abdominal obesity are limited not only to metabolic disorders but also to cognitive decline [23], Alzheimer disease [24], and disability [25].

Liposuction of subcutaneous fat

Several studies have reported on the metabolic consequences of surgically removing large quantities of subcutaneous fat by liposuction. The general premise of these studies is that absolute fat mass is the most important contributor to obesity-related complications such that large-scale removal of abdominal subcutaneous fat should improve several metabolic parameters including insulin sensitivity. Results from these studies have been contradictory, with some showing beneficial effects of liposuction on insulin sensitivity [2629], but not others [3032], while one reported an improvement in the blood lipid profile, but not in insulin sensitivity [26]. It has been suggested that the conflicting nature of these studies is because of several uncontrolled confounders including the way insulin sensitivity was assessed, failure to match properly for baseline parameters, poor control of behavioral confounders after the procedure, and the removal of varying amounts of subcutaneous fat [33].

A study by Klein et al. [33] attempted to definitively address the potential of liposuction as a tool to treat obesity-related metabolic disorders by controlling for the aforementioned confounders. In a study consisting of 15 obese patients (8 nondiabetic controls and 7 T2DM patients) with similar BMI, several metabolic parameters were assessed before and 10–12 weeks after having about 10.5 kg of subcutaneous abdominal fat removed. Using the euglycemic–hyperinsulinemic clamp procedure, they found that liposuction did not significantly alter insulin action in muscle, liver, or adipose tissue; plasma levels of C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), adiponectin, glucose, insulin, and blood lipids as well as blood pressure. Therefore, surgically removing large quantities of subcutaneous abdominal fat does not appear to be sufficient to improve metabolic parameters and suggests that subcutaneous fat is not an important component of obesity-related metabolic disorders in humans.

Abdominal obesity and mortality risk

Several studies have reported that obesity, generally defined as a BMI > 30 kg/m2, increases the risk of disease-specific and all-cause mortality [3437] and reduces life expectancy [38]. Obesity has been linked not only to a reduced life expectancy but also to accelerated aging as demonstrated by obese females having telomeres that were 240 bp shorter than that of lean females of a similar age [39].

Because abdominal obesity, as assessed by waist circumference or the WHR in large population studies, has emerged as a stronger predictor of disease risk than BMI, studies have begun assessing the mortality risk posed by abdominal obesity [4042]. Wannamethe et al. [43] found that a particularly high waist circumference (>102 cm), WHR (top quartile), and a composite of waist circumference and sarcopenia were the strongest predictors of mortality in males. Another, a large cohort study in Europe reported that general (BMI) and abdominal adiposity (waist circumference; WHR) are both strong predictors of mortality risk but that the importance of abdominal obesity was most striking among persons with a low BMI [44].

Abdominal fat and global cardiometabolic risk

Excess weight, particularly abdominal obesity, causes or exacerbates C-reactive protein and metabolic risk factors, including hypertension, dyslipidemia, and T2DM [4547]. These risk factors synergistically increase the likelihood of morbidity and mortality of CVD [48, 49], which leads to rising healthcare costs [50].

Actions promoting health check-ups for obesity-related conditions and prevention strategies have been proposed [51]; however, the theoretical background has not been fully coordinated, and, most importantly, the actions to reduce abdominal adiposity have not been fully validated in terms of global cardiovascular risk management.

Some studies show that waist circumference is directly related to all-cause mortality when adjusted for BMI [48], and is also strongly associated with the mortality and morbidity of CVD [49]. The facts highlight the importance of visceral fat over subcutaneous fat deposits and promote the incorporation of waist circumference into the diagnosis of MetS [4547].

Obesity-management goals should encompass a reduction in total cardiovascular morbidity and mortality. Losing 5–10 % of body weight reduces the traditional cardiovascular risks [17, 51] (Fig. 1). Weight loss in abdominally obese patients is associated with selective mobilization of diabetogenic and atherogenic visceral fat, even 5–10 % weight loss is associated with preferential mobilization of visceral adipose tissue, leading to simultaneous improvement in all metabolic markers of coronary heart disease risk. Thus, simultaneous metabolic improvements associated with mobilization of visceral fat may contribute substantially to a reduced risk of acute coronary event in high-risk patients.
Fig. 1

Potential benefits of moderate (5–10 %) weight loss in abdominal fat and cardiometabolic risk

Increasing physical activity, in combination with a diet that emphasizes fresh fruits and vegetables, whole grains, and low-fat dairy products, can help patients reduce their weight and obesity comorbidity.

We do not know much about the long-term effect of weight loss on the development of T2DM and CVD outcomes in the form of death, myocardial infarction, and stroke. Currently ongoing are clinical trials that use health-promoting lifestyle interventions, new drugs, and even surgery, which are all aimed at weight loss, reduction in disease manifestations, and improved outcomes [52]. A trial to answer the most important question whether the improvements in cardiovascular risk factors by managed weight loss will be associated with reduction in long-term cardiovascular events is under investigation (The Look Action for Health in Diabetes trial) [52], and the expected data are essential for the future development of effective CVD-prevention strategies.

The concept of the MetS, which takes into account the central role played by visceral fat in the development of metabolic and CVDs, indicates how waist circumference measurement is useful for patient identification in the clinical setting. The MetS cannot be used to assess global CVD risk, but it is at best more modifiable CVD risk factor. Thus, global cardiometabolic risk should be considered individually. Increased visceral fat is associated with a shift in the normal balance of adipocytokine, resulting in a proinflammatory and proatherosclerotic state. Although evidence for therapeutic efficacy in the treatment of abdominal adiposity and clustering of cardiometabolic risks is limited, this is a promising challenge to reduce the highly contagious state around the world. As better understanding of the underlying molecular mechanisms develops, potential therapeutic targets will be identified.

Visceral fat and the obstructive sleep apnea syndrome risk

Obesity is the most important reversible risk factor for obstructive sleep apnea syndrome (OSAS) [53]. From an epidemiological point of view, the prevalence of OSAS showed a close correlation with adiposity, rising from a prevalence of 2–4 % in the general population [54] to a prevalence of at least 40 % in morbidly obese patients [55]. However, the prevalence and severity of OSAS in overweight and obese patients have been shown to be more dependent on the fat distribution than on the level of total fatness. Waist circumference was a better predictor of OSAS than BMI in overweight or moderately obese patients undergoing a sleep study for suspected sleep-disordered breathing [48]. Using a more precise method for the assessment of visceral fat accumulation, Vgontzas et al. [56] demonstrated that males obese patients with OSAS had a greater amount of computed tomography (CT)-determined visceral adipose tissue in the abdomen than a group of BMI-matched males without sleep-disordered breathing.

Neck, as a part of our body, is a potent anthropometric predictor of OSAS [5759]. However, given the relationship between waist circumference and neck circumference levels in obese subjects [48], the relative independent role of each of these two anthropometric parameters remains to be determined.

Decreased pharyngeal patency was considered the most important pathogenetic mechanism leading to OSAS in obese patients [53].

Reduction in pharyngeal size in obese patients with OSAS has been attributed to a mass-loading effect produced by fat deposited around the upper airways.

A reduction in pharyngeal size has been attributed to a reduction in lung volume. In visceral obesity, the accumulation of fat inside the abdomen pumps upward the diaphragm, causing a reduction in lung volumes [60]. The reduction of lung volume was enhanced by the supine position and during sleep [61].

Irrespective of the mechanism, it is also possible that intra-abdominal fat accumulation and fat deposition around the pharynx should coexist in obese patients, being two different faces of visceral obesity.

Body fat and steatohepatitis

It has become apparent that it is the “visceral” component of the measured abdominal fat that is most intimately associated with metabolic disease and adverse outcomes [62, 63]. Indirect evidence of the inflammatory output of visceral fat has been highlighted by the demonstration of increased levels of circulating cytokines and acute phase reactants in patients with visceral adiposity [64, 65]. Similarly, there is an evidence of a link between visceral fat and disease-related endpoints such as myocardial infarction, stroke, and overall mortality [62, 66]. What is yet to be conclusively demonstrated is direct histological evidence of increasing tissue inflammation and of a “chronic” wound healing response (as evidenced by the development of fibrosis), in association with increasing amounts of visceral fat.

The liver provides a unique opportunity to examine an end organ that has a direct communication with visceral fat and that is amenable to biopsy for the quantitation of fat, inflammation, and scarring. Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the MetS [67], is defined by the presence of macrovesicular fat in more than 5 % of hepatocytes, in the absence of significant alcohol use or other secondary causes of steatosis. Thus, these patients provide an ideal opportunity to examine the importance of visceral fat to progressive nonalcoholic steatohepatitis (NASH) and hence the inflammatory pathogenesis of the MetS.

The exact mechanisms by which visceral fat exerts its damaging metabolic consequences remain controversial, but a number of mechanisms have been proposed. The portal/fatty acid flux theory suggests that visceral fat, via its unique location and enhanced lipolytic activity, releases toxic FFAs, which are delivered in high concentrations directly to the liver. This leads to the accumulation and storage of hepatic fat and the development of hepatic insulin resistance [68, 69]. In addition, dysregulation and overflow of hepatic lipid are ultimately responsible for the formation of highly atherogenic small dense low-density lipoprotein particles and a reduction in circulating high-density lipoprotein [70]. At a molecular level, HS may itself beget inflammation through altered lipid partitioning within the hepatocyte, mitochondrial dysregulation, generation of reactive oxygen species, lipid peroxidation, and endoplasmic reticulum stress [70]. It has been suggested that this process (HS) alone is sufficient to set off the local and systemic inflammation that are responsible for the pathophysiology of the MetS (Fig. 2). Some results, however, suggest otherwise. It has been shown that the only independent predictor for both increasing inflammation and fibrosis in the steatotic liver is visceral fat [71]. These results were highly significant and independent of insulin resistance and the extent of HS. Of note, increasing levels of visceral fat were not associated with increasing levels of HS in that population of the afore mentioned study with pre-existing NAFLD and a high incidence of NASH. A number of studies have shown that, in unselected groups, visceral fat is a strong predictor of increasing steatosis [72, 73], suggesting that visceral fat is important in the genesis of fatty liver, but thereafter increases in steatosis may occur independently.
Fig. 2

The central role of visceral fat to disease. There is a close association between visceral fat and the metabolic syndrome (1), insulin resistance (2), hepatic steatosis (3), and tissue inflammation and fibrosis within the liver (4)

Much recent evidence has shown that macrophages accumulate in the adipose tissue of obese individuals [74] and that this process is exaggerated in visceral fat [75]. These macrophages are responsible for the production of proinflammatory cytokines and the modulation of adipocyte-derived cytokines. Harmful factors such as IL-6 and TNF-α have been shown to be expressed in greater amounts in visceral than in subcutaneous fat [76, 77], although with some criticism [16]. Visceral fat also has been shown to be a significant predictor for biomarkers of inflammation such as high-sensitivity CRP, fibrinogen, and plasminogen-activating inhibitor-1, independent of HS [78]. Adipocyte-derived factors such as adiponectin, leptin, resistin, and TNF-α are differentially expressed in visceral compared with subcutaneous fat and play important roles in the actions of these fat compartments. Adiponectin is the most highly abundant adipokine in human serum and has insulin-sensitizing and anti-inflammatory effects [79]. It is known to be reduced in obese states, particularly in visceral compared with subcutaneous fat [80]. The importance of adiponectin to inflammation and visceral fat has been demonstrated in studies of the peroxisome proliferator-activated receptor γ agonist pioglitazone, in which treatment resulted in increased levels of adiponectin, reductions in liver inflammation [81], and a shift of fat distribution from visceral to subcutaneous depots [82, 83].

Abdominal fat and hepatocellular carcinoma risk

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer death worldwide, accounting for >500,000 deaths annually, showing an increasing incidence throughout the world [84, 85]. HCC usually develops in patients with advanced liver fibrosis because of chronic liver diseases such as chronic hepatitis B, chronic hepatitis C, alcoholic liver disease [85, 86], and hemochromatosis [87]. In addition, NASH is considered to be another important liver disease preceding cirrhosis and HCC. NAFLD, increasing in prevalence in Western countries and in Japan because of the increasing prevalence of obesity [88], is shown to be a clinical condition that may progress to NASH and, subsequently, to HCC [89].

Recently, obesity has also been reported to be a risk factor of HCC development in patients with chronic liver diseases other than NASH [9092]. Emerging data have indicated that neuroendocrine systems that regulate weight and energy metabolism play a pivotal role in the development of HS [93]. Several mechanisms have been proposed by which accumulation and anatomic distribution of fat are related to the development of HS and fibrosis [94]. Eguchi et al. [94] reported that the severity of fatty liver was positively related to visceral fat accumulation and insulin resistance in both obese and nonobese NAFLD patients without viral hepatitis. This suggests that hepatic fat infiltration in NAFLD may be influenced by visceral fat accumulation independently of BMI.

HCC is characterized by extremely frequent intrahepatic recurrence even after successful curative treatments [95]. Both surgical hepatectomy and medical ablation are locoregional treatments in that the background liver diseases are left untreated. Liver transplantation forms an exception, after which recurrence is rare if the indication is appropriate. Two modes of intrahepatic recurrence have been distinguished: de novo carcinogenesis and intrahepatic metastasis [96]. The factors responsible for the development of primary HCC, such as age, sex, fibrosis stage, and the presence of viral hepatitis, will also affect de novo carcinogenesis [92], whereas the factors related to the primary HCC, such as the size and number of tumors, pathological grade, and the presence of vascular invasion, will affect the possibility of intrahepatic metastasis [86, 97].

In contrast to BMI, visceral fat accumulation is considered to be directly causative, through disturbing the adipocytokine balance of insulin resistance, which is a major cause of hepatic fat accumulation [98]. Excessive fat in the liver will lead to hepatocellular injury and possibly result in hepatocarcinogenesis through the direct cellular toxicity of excessive FFAs, oxidant stress and lipid peroxidation, or another mechanism [93]. Furthermore, visceral fat accumulation-induced insulin resistance causes hyperinsulinemia. Insulin has growth-promoting properties and increases free insulin-like growth factor levels, which play an important role in tumor growth and differentiation [99, 100]. Visceral fat accumulation may be involved in both tumor initiation and promotion or progression steps through these mechanisms.

Thus, it can be speculated that mechanisms involved in MetS play a greater role in the hepatocarcinogenesis among patients with high visceral fat accumulation.Visceral fat accumulation plays a significant role in de novo hepatocarcinogenesis among such patients, and probably reduction of visceral fat decreases HCC recurrence.

Abdominal fat and breast cancer risk

The relationship between general obesity and breast cancer risk has long been recognized [101], but there have been suggestions that central rather than general obesity may specifically predispose an individual to the development of breast cancer [102, 103]. Evaluation of the link between central obesity and breast cancer risk is important as it may give further insights into the etiology of breast cancer and establish whether waist is a useful index of disease risk within populations.

The link between central fat and breast cancer risk may be through the associated hyperinsulinemia and insulin resistance. Insulin is itself a mitogenic agent [104] and is also associated with downregulation of sex hormone binding globulin [105, 106] and insulin-like growth factor binding protein-1 and -2 [107], leading to increased levels of bioavailable mitogens estrogen [108], insulin-like growth factor-1 (IGF-1) [109], and testosterone [110].

Ideally any assessment of the effect of visceral and subcutaneous fat on breast cancer risk should rely on direct measurement of these compartments by techniques such as magnetic resonance imaging or CT.

However, because these techniques are expensive, studies have attempted instead to link waist or WHR to the risk of breast cancer. Waist circumference is a correlate of the amounts of visceral and subcutaneous fat (superficial and deep) [111], while WHR is an index of the relative accumulation of abdominal compared with gluteal fat [112]. Because waist measurements are also highly correlated with general obesity, whether the relationship between waist and breast cancer risk is independent of the effects of generalized obesity needs to be examined. The relationship between BMI and breast cancer risk differs between pre- and postmenopausal females. BMI has a strong positive association with postmenopausal breast cancer and an inverse correlation with premenopausal cancer risk [113].

The positive relationship between weight and risk among postmenopausal female is presumed to result from higher levels of estrogen derived from the aromatization of androstenedione within the larger adipose stores of fatter female [114]. The protective effect of excess weight in premenopausal females most likely reflects a residual protective effect of greater weight in the early premenopausal years, which is a predictor of longer anovular cycles and lower levels of progesterone and estrogen [115]. The relationship between BMI and the risk of postmenopausal breast cancer is attenuated among users of hormone replacement therapy (HRT) [113], because HRT obscures the relationship between weight and risk by elevating the levels of estrogen among lean and overweight females. Oral HRT has also been associated with improved insulin sensitivity and increased levels of sex hormone binding globulin [116], which is likely to confound any potential association between central obesity and breast cancer risk. The relationship between central obesity and breast cancer risk should therefore be explored in both pre- and postmenopausal females.

Abdominal fat and gastric cancer risk

Obesity was associated with gastric cardia cancer in some case–control studies in the world [117119], but its association with distal stomach cancer has not been well examined [120].

Obesity is manifested as a markedly high volume of adipose tissue. Recent studies have demonstrated that adipocytes produce a variety of secretory peptides, named adipokines [121, 122]. More recently some adipokines, such as leptin and adiponectin, have been shown to critically regulate the biological behavior of malignant cells [123131], raising the possibility that adipocytes may have positive roles in the development of malignant diseases through the secretion of adipokines in an endocrine or intracrine way. In addition, it has been suggested that the biochemical characteristics of visceral and subcutaneous adipose tissues are somewhat different [132, 133]. Taking these findings into account, a hypothesis has been raised that the distribution and the size of adipose tissue may have a specific association with cancer in human.

Several studies have shown that visceral fat areas from a single scan obtained at the level of the umbilicus (the approximate level of L4 and L5) closely correlate with the total volume of visceral fat.

However, recent studies have provided an evidence that adipose tissue can produce many cytokines (adipokines), such as leptin and adiponectin, which can potently affect the biological behavior of malignant cells [123131].

Abdominal fat and colon cancer risk

Studies of colon cancer risk in males have reported strong positive associations with obesity, particularly with central adiposity. Body weight and BMI are positively related to the risk of colon cancer in males, whereas in females, weak or no association exists [134, 135]. Although BMI has been shown to be associated with colon cancer, studies of rectal cancer risk have generally reported no association. The relationship between rectal cancer risk and central adiposity, overall fat mass, and overall fat-free mass is unknown [136]. Abdominal obesity and hyperinsulinemia or insulin resistance are of interest in connection with colon carcinogenesis. In addition, recent reports have shown that the risk of colorectal cancer is associated with abdominal obesity and insulin resistance [137]. Intra-abdominal adipose tissue mass can be assessed by measuring visceral fat (cm3) by CT scanning at the umbilical level [138, 139]. The area of visceral fat on the CT scan was shown to be related to the waist-to-hip circumference ratio [111].

Several mechanisms that implicate visceral adiposity in colorectal carcinogenesis have been hypothesized. One well-known hypothesis is that visceral adiposity may be associated with factors that promote the growth of colorectal adenomas, thereby increasing the risk of colorectal cancer.

Visceral adiposity is, in fact, a strong determinant of insulin resistance and subsequent hyperinsulinemia [140], while insulin is an important growth factor for colonic mucosal cells and colonic carcinoma cells in vitro [141] and may have the potential to mediate the association between visceral adiposity and colorectal cancer.

CT allows the accurate quantification of visceral fat and is presently the optimum technique with this regard [142]. However, there are several disadvantages associated with the use of this technique as an assessment tool of visceral adiposity in practical settings, including health hazards of exposure to ionizing radiation. On the other hand, although the WHR and waist circumference provide inexact measurements of visceral adiposity, they are not only safe but also cheap and relatively easy to perform [142]. These anthropometric measurements therefore remain useful for the general classification of large number of people by visceral adiposity.

In summary, there is evidence that visceral adiposity exerts an important influence on the pathogenesis of colorectal cancer. The mechanisms of this potential association between visceral adiposity and colorectal carcinogenesis warrant further investigation.

Visceral fat and prostate cancer risk

Cohort and case–control studies examining the relation between weight and prostate cancer have resulted in inconsistent findings [143152]. A reason for such conflicting results could be the failure to distinguish the contribution of central and peripheral obesity. BMI and other classical anthropometric measures are imperfect estimates of adiposity, particularly in males, mainly because of greater muscle mass. CT quantifies subcutaneous and internal abdominal (visceral) fat, allowing measurement of visceral fat and determination of its relation with disease risk. Some studies show an association between visceral adiposity, as assessed by CT, and prostate cancer risk. CT is more accurate and more reproducible than anthropometry for assessing body fat distribution [153]. A single CT scan of the abdomen is accurate for indicating overall abdominal adiposity [154] and is more reproducible than other CT techniques [153]. Also in this case, most studies on body fat distribution are done using CT at the level of the L4 vertebral body.

Age, ethnicity, and family history are established risk factors for prostate cancer [155]. Unfortunately, the results of major studies on prostate cancer and obesity or body fat distribution, as assessed by anthropometry, have been inconclusive [143152].

Several mechanisms can explain the association between visceral fat accumulation and increased risk of prostate cancer. Adipose tissue is a source of specific substances, including adiponectin, resistin, leptin, and adipsin, and secretes a variety of other cytokines, such as TNF-α and IL-6. There is ample evidence that visceral fat and subcutaneous fat cells differ metabolically. The metabolic products of visceral fat, namely FFAs, are delivered directly into the portal circulation to the liver, inducing a significant metabolic disturbance. It is well established that visceral fat accumulation is associated with insulin resistance, resulting in hyperinsulinemia [156]. Insulin can promote the growth of several different cell lines, including prostate tumors [157, 158], and high plasma insulin levels have been related to prostate cancer risk [159] and stage [160]. Insulin-resistant states are associated with increased levels of insulin that are associated with increased production of IGF-1 [161]. IGF-1 stimulates the development of both tumor and normal prostate cells [162].

Leptin, an adipocyte-specific hormone, may be associated with increased prostate cancer risk. Leptin is a cytokine generated and secreted by adipocytes that regulates many physiological processes such as satiety and body weight, energy homeostasis, and steroidogenesis [163]. Because adipocytes possess angiogenic activity [164], it has been suggested that leptin might stimulate endothelial cell proliferation and angiogenesis [165, 166], including tumor angiogenesis.

Some studies have shown an association between serum leptin levels and the risk of prostate cancer [167, 168]. Leptin expression is lower in omental than in subcutaneous adipose tissue, but it is known that leptin expression increases with age in omental adipose tissue, but not in subcutaneous tissue [169]; it is relevant that, in this study, participants were elderly male. Rönnemaa et al. [170] showed, in a study of 23 monozygotic twins discordant for obesity, using magnetic resonance imaging, that visceral fat has a greater impact on leptin levels than subcutaneous fat.

Weight loss, bariatric surgery, and cancer risk reduction

Despite extensive evidence showing a deleterious effect of overweight and obesity on cancer, relatively few data exist on the effects of weight gain or weight loss on altering the risk for cancer. The lack of data on weight loss is like a function of the small number of individuals able to achieve a sustained weight loss.

The International Agency for Research on Cancer evaluated data through 2000 and found limited evidence for an association between weight change and the risk for colorectal cancer [171]. However, subsequent studies have added evidence to support this adverse effect. Cohort studies examined changes in weight from early adulthood to later in life and found modestly higher relative risks (1.4–1.6). Case–control studies provided additional support. More recent evidence confirms that weight gain in adulthood appears to increase the risk for colon cancer. In a case–control study in Canada, male who gained ≥21 kg after the age of 20 years had a 60 % higher risk for colorectal cancer than male who had gained 1–5 kg [172]. The association was stronger when rectal tumors were excluded, suggesting that studies examining the association between weight gain and colorectal cancer may underestimate the association for colon cancer. No association between weight gain and colorectal cancer risk was observed among females, for whom higher estrogen levels might counteract the adverse effect of obesity through insulin pathways. Another study of males and females found that patients whose BMI had remained stable had a 25–35 % higher risk for colorectal cancer when compared with those whose BMI had increased from age 30 or 50 years to diagnosis [136]. Finally, a study of Austrian adults found evidence for a direct association between weight loss and a reduction in colon cancer risk among males [173].

Perhaps the best evidence that weight loss can reduce the risk for cancer comes from recent studies in bariatric surgery patients. Emerging evidence from two large cohort studies suggests that large weight loss from bariatric surgery reduces the risk for cancer death [174, 175]. The mean weight loss was in the range of 14–27 % 15 years after surgery in the Swedish patient population [175]. In the US patient sample, cancer death rates, excluding prevalent cancers, were 38 % lower [hazard ratio (HR) 0.62; 95 % confidence interval (CI) 0.61–0.74] in patients undergoing Roux-en-Y gastric bypass than in BMI-matched controls, with some indication that the reduction in the death rate was stronger in males than in females [174]. The cancer death rate reduction was larger when including prevalent cases of cancer at baseline (HR 0.40; 95 % CI 0.25–0.65). The limited sample sizes in both studies precluded examination of cancer-specific rates, though Sjöström et al. [175] noted that the results included both deaths from obesity-related cancers and cancers unrelated to obesity.

More recently, both studies demonstrated a lower cancer incidence in surgical patients. The Swedish study demonstrated a lower risk for cancer in females undergoing bariatric surgery than in matched obese controls (HR 0.58; 95 % CI 0.44–0.77), though no such effect was observed in males (HR 0.97; 95 % CI 0.62–1.52) [176]. The amount of weight loss was not associated with cancer risk. Similarly, a US-based study found a significant cancer risk reduction in bariatric surgery patients (HR 0.76; 95 % CI 0.65–0.89). This study found that the risk reduction was largely concentrated in obesity-related cancers (i.e., esophageal adenocarcinoma, colorectal cancer, pancreatic cancer, postmenopausal breast cancer, corpus and uterus cancers, kidney cancer, non-Hodgkin lymphoma, leukemia, multiple myeloma, liver cancer, and gallbladder cancer). Subsequent studies have reported similar cancer risk reductions [177, 178].

Ample observational data support a detrimental effect of obesity on the risk for several cancers, including breast and colon cancer, two of the most common cancers in North America and Europe. Examination of possible mechanisms provides further evidence that the observed associations have biologic rationale. Finally, growing research indicates that a change in weight is associated with subsequent changes in the risk for several cancers. Weight loss after menopause significantly reduces the risk for breast cancer [179]. Taken together, this indicates an important role for obesity and weight change in cancer risk.

Mortality is the ultimate hard end-point of any intervention whereas quality-adjusted life years are more important for patients regardless of age. Several large studies have demonstrated lower gross mortality in bariatric surgery patients despite their operative mortality compared to regular care or general population actuarial data [180184]. In a 2007 retrospective cohort study in patients with open gastric bypass surgery at a median age of 40 years compared with severely obese controls there was a 40 % lower rate of all-cause mortality in the surgical group [180]. In a Canadian observational cohort study using a national registry, Christou et al. [184] found an 89 % relative risk reduction in the operative group after 5 years, compared with those managed medically. An important limitation of studies such as these is that they exclude patients with severe comorbidities because of perceived operative risk. There is, therefore, an undersampling of the sickest patients although they might actually derive the greatest short- and long-term benefits from bariatric surgery, especially using laparoscopic approaches in dedicated centers of excellence [174].

The controversy of body fat in caloric restriction-associated survival

Studies dating back to the early 1900s by Tannenbaum [185, 186] were the first to demonstrate that a reduction in food intake was capable of increasing lifespan and inhibiting tumor formation in rats [187]. Nearly a century later, calorie restriction (CR) remains the only known behavioral intervention capable of delaying the onset of many age-related diseases and extending maximal survival [188, 189]. The fact that limiting calorie intake has such profound effects on mammalian aging and disease is intriguing, because it suggests that the rate of biological aging is intimately related to energy metabolism. In the laboratory, CR is generally implemented by limiting food intake 20–40 % of ad libitum-fed controls [189]. Thus, the beneficial effects of CR have historically been attributed to a reduction in food intake [18, 190, 191]. However, this simplistic view has been called into question because CR is characterized not only by less food intake but also by concurrent changes in energy balance, body mass, and body composition [192, 193]. Because adipose tissue has been historically viewed as an inert storage depot for triglycerides, this robust phenotypic change had been widely discounted as merely a by-product of reducing food intake [190, 194, 195]. It was not until 1960 that a reduction in fat stores was proposed as an important mediator of CR [196].

More studies are needed to understand the molecular mechanisms underlying the beneficial effects of CR on survival.

Evidence against a role for body fat in determining lifespan

In 1984, one historic study by Harrison et al. [195] found that calorie-restricted ob/ob mice lived longer than ad libitum-fed wild types, despite having nearly twice as much body fat. Indeed, this study made a compelling case against a role for body fat in the determination of lifespan. There has also been controversy regarding the role of body fat in both spontaneous and transgenic long-lived mutants. For instance, several models of growth hormone deficiency or resistance including the Ames dwarf, Snell dwarf, and the GHR−/− mouse have reduced body size and live substantially longer than controls. However, these mice all have a high percentage of body fat, although to the best of our knowledge, body fat distribution in these models has not been reported.

A paradigm shift

Since the discovery of leptin in 1994 [197], the view of adipose tissue as an inert storage depot began to change. Indeed, evidence began to mount that obesity and specifically visceral fat are associated with a low-grade inflammation because of the increased secretion of numerous proinflammatory cytokines from adipocytes and their associated macrophages [198, 199]. Many of these cytokines also referred to as “adipokines,” including leptin, TNF-α, IL-6, heparin-binding epidermal growth factor, and vascular endothelial growth factor among others, may play an important role in many disease pathologies by promoting angiogenesis, inflammation, cell proliferation, and insulin resistance [199, 200]. Considering this new perspective of fat, coupled with studies linking age-related changes in body composition with insulin resistance, we hypothesized that the ability of CR to improve insulin action is by reducing visceral fat.

Treatment studies

Some groups have demonstrated various treatment strategies for visceral fat and/or its complications. In an initial study [201], leptin was subcutaneously administered twice daily for 1 month to rats, because this fat-derived peptide had been shown to play an important role in energy homeostasis.

The enzyme 11β hydroxysteroid dehydrogenase type 1 (11β HSD-1) converts inactive cortisone into active cortisol in cells, and excess glucocorticoids promote visceral fat deposition. When this enzyme was overexpressed in adipose tissue in mice, animals developed visceral obesity and diabetes [202]. Therefore, it seemed intuitive that pharmacologic inhibition of 11β HSD-1 might serve as a therapeutic target for the MetS [203]. When a selective and potent 11β HSD-1 inhibitor was given to mice, a reduction in body mass, retroperitoneal fat pad weight, as well as serum insulin, glucose, and lipids was observed [204]. Similarly, administration of this inhibitor resulted in improved glucose tolerance in a mouse model of T2DM and attenuated vascular plaque formation in ApoE−/− mice [204].

Prevention of systemic inflammation

Mounting evidence supports a role for adipose tissue-derived proinflammatory cytokines in the pathogenesis of diabetes and atherosclerotic diseases. Therefore, Ohmon et al. [205] administered pioglitazone, which has been shown to reduce monocyte chemoattractant protein-1 levels and fat inflammation, to ApoE−/− mice that received a visceral fat transplant or to sham-operated controls.

Pioglitazone treatment lowered monocyte chemoattractant protein-1 levels and macrophage content in the visceral fat transplant and reduced atherosclerosis development in visceral fat-transplant mice, but not in sham-operated mice. Likewise, in obese mice, short-term treatment with a pharmacological antagonist of chemokine (C–C motif) receptor 2 lowered macrophage content in adipose tissue and systemic inflammation, resulting in improved insulin action [206]. Therefore, drugs that can interfere with the infiltration of macrophages into fat, specifically visceral fat, may provide an effective strategy for the prevention of cardiovascular complications and MetS because of abdominal obesity.

Future directions

Numerous epidemiologic studies have implicated abdominal obesity as a major risk factor for insulin resistance, T2DM, CVD, stroke, MetS, and death. Using novel models of abdominal obesity, several studies have shown that the relationship between visceral fat and survival is causal, while the accumulation of subcutaneous fat does not appear to play an important role in the etiology of disease risk [207]. Treatment strategies including pharmacologic agents (leptin, β3-agonists) can improve glucose tolerance by effectively reducing visceral fat [202, 203]. New and irrefutable evidence also supports a role for inhibitors of macrophage infiltration into fat [thiazolidinediones, chemokine (C–C motif) receptor 2 antagonists], and hence systemic inflammation, for the treatment of insulin resistance and vascular disease [206]. Therefore, two lines of investigation worth pursuing include (1) understanding the secretory biology of visceral fat to identify the important mediators of the MetS and (2) the development of drugs designed to modulate body fat distribution.

Specific recommended intake levels vary based on a number of factors, including current weight, activity levels, and weight loss goals. There are many other behavioral factors that influence weight loss and may be more effectively intervened upon over an extended intervention period to achieve sustained weight loss. We outline several of these in Table 1. Rather than focusing on specific calorie calculations, we recommend behavioral targets that should lead to an energy deficit and increase and maintain patient motivation [207].
Table 1

Physical activity, diet, and behavioral goals for sustained weight loss

Physical activity/Sedentary behavior goals

 Brisk walking (or similar effort) for at least 20 min increasing up to 60 min, 6 days per week or walking a total of 10,000 steps per day (building up to 10,000 if needed)

 Limit television watching to less than 2 h per day

 Do strength training exercises at least 2 days per week

Diet goals

 Replace sugary drinks with unsweetened choices (water, diet tea)

 Eat breakfast every day

 Eat a diet rich in fruits and vegetables and whole grain foods, such as brown rice and whole wheat bread

 Drink alcohol in moderation, if at all (no more than 1 drink per day for females, 2 drinks per day for males)

Behavioral goals

 Log weight every day (at the same time every day)

 Exercise at the same time every day (such as before work/school, during lunch)

 Keep portion sizes small and avoid seconds

 Avoid fast food restaurants. Choose healthier options if you need to, such as a salad with fat-free dressing or a fruit cup

There are many unanswered questions on the association of obesity and visceral fat with health risks. Research priorities with regard to these associations are numerous. Most important is the fact that many of the above cited studies show an association or correlation between obesity, visceral fat, and morbidity, but correlation does not necessarily indicate causality [208].

Clear confounders are physical activity, composition of the diet, caloric intake, and smoking. The role of each of these confounders on comorbid conditions needs to be investigated.

More investigation is also needed on the following: (1) the relation of visceral fat to comorbidities, with better characterization of the visceral fat so as to be able to sort out the contribution of central versus subcutaneous fat tissue to each comorbidity; (2) the genetics of the relationship among obesity, visceral fat, and each of the comorbidities; (3) the impact of gender, race, intensity, and duration of obesity and visceral fat on each of the comorbidities; and (4) the interaction between obesity and visceral fat and other potential associated factors responsible for particular comorbidities.

It is necessary to determine visceral fat reduction to induce favorable metabolic changes in humans, and early intervention has the greatest potential to decrease visceral fat and reduce the risk of obesity-related metabolic problems [209], and last but not the least of the drug-induced liver injury [210].

In summary, these studies highlight the consistent relationship of visceral fat with disease and mortality risk in humans, the distinct metabolic capacity of visceral fat, the importance of accounting for body fat distribution in disease risk, and visceral fat depletion as a potential treatment strategy to prevent or delay age-related diseases and to improve survival.

Copyright information

© Asian Pacific Association for the Study of the Liver 2012