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Keywords:

  • insulin resistance;
  • free fatty acids;
  • body composition

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results and Discussion
  5. Acknowledgement
  6. References

Objective: To review the evidence for and against the role of visceral adipose tissue as a major contributor to the metabolic complications of obesity through abnormal regulation of lipolysis.

Research Methods and Procedures: Data from investigators in the field who have studied visceral adiposity and metabolic health and/or regional and systemic free fatty acid (FFA) release were considered.

Results: Although visceral fat mass was positively correlated with adverse health consequences and excess FFA availability, visceral fat was not the source of excess systemic FFA availability. Upper body non-visceral fat contributes the majority of FFAs in lean, obese, diabetic, and non-diabetic humans. Increasing amounts of visceral fat probably result in greater hepatic FFA delivery.

Discussion: Systemic, as opposed to hepatic, insulin resistance is unlikely to be caused by high rates of visceral adipose tissue lipolysis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results and Discussion
  5. Acknowledgement
  6. References

Vague first reported in 1956 that obesity-related adverse health consequences occurred predominantly in those with a masculine, or upper body, distribution of fat (1). Epidemiological studies have clearly shown that the relationship between obesity (as measured by BMI) and components of the metabolic syndrome are even stronger for upper body obesity (as measured by waist circumference and waist-to-hip ratio) (2, 3, 4, 5, 6, 7, 8, 9, 10, 11). The use of imaging technology (computed tomography and magnetic resonance imaging) to localize upper body fat into intra-abdominal (primarily omental and mesenteric—collectively referred to as visceral fat) and subcutaneous depots has further refined the understanding of how fat distribution influences health. Most investigators have concluded that the amount of visceral fat is more strongly associated with these metabolic abnormalities (12, 13, 14, 15, 16) than is subcutaneous or total body fat, with some notable exceptions (17). Two lines of investigation led to the hypothesis that the fuel export function of visceral adipose tissue leads to the metabolic complications of obesity—in vitro measures of adipocyte lipolysis and realization of the adverse effects of excess free fatty acids (FFAs).1

Results and Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results and Discussion
  5. Acknowledgement
  6. References

Early studies of the relationship between adipocyte characteristics and obesity indicated that large fat cells are characteristic of upper body obesity and the complications of obesity (18, 19, 20). It has also been appreciated that large fat cells have higher rates of basal lipolysis in vitro (19, 21), perhaps especially when they are from visceral depots (22) and are in men (23). Other studies have shown that visceral fat cells have the same lipolytic activity as abdominal subcutaneous adipocytes when adjusted for size (24) and are less active if visceral fat cells are smaller (23, 24). The implications of these observations led to the suggestion that large visceral fat depots flooded the liver and the systemic circulation with FFAs (25, 26).

The importance of FFAs to adverse effects on glucose metabolism was initially emphasized by the studies of Sir Philip Randle (27). His studies of the abilities of increased extracellular FFA concentrations to impair glucose metabolism led to the term glucose—fatty acid cycle or Randle cycle. Thus, the potential importance of adipose tissue mass in general and visceral fat specifically was related to its lipolytic function. Randle hypothesized that FFA-induced insulin resistance involved increased mitochondrial ratios of [acetyl-CoA]/[CoA] and [NADH+]/[NAD] as a result of increased fatty acid oxidation. The mechanism was subsequently modified to pinpoint glucose transport as an early step in impaired insulin action in muscle. Elevation of FFA concentrations can induce peripheral (skeletal muscle) and hepatic insulin resistance (28, 29), increase very-low-density lipoprotein triglyceride production (30), alter vascular reactivity (31), and affect pancreatic β cell function (32). Lowering FFA concentrations can improve insulin action in adults with respect to glucose metabolism in type 2 diabetes (33). Subsequent studies have shown that the metabolic effect in muscle involves early insulin signaling pathways (34, 35) and is independent of FFA oxidation.

If elevation of FFA concentrations can impair insulin action and have other untoward metabolic effects, an understanding of the factors that regulate FFA concentrations is vital. Suppression of lipolysis, whether by insulin (36) or by pharmacological agents (37), results in reduced FFA concentrations, whereas stimulation of lipolysis (epinephrine, growth hormone) increases FFA concentrations. This is not uniformly the case, however. For example, with the onset of exercise, FFA concentrations fall because the uptake of FFA from the circulation increases to a greater degree than the rate of lipolysis (38). Another exception to the general rule that concentrations reflect lipolysis is the finding that women have 40% greater rates of lipolysis than men at the same plasma FFA concentrations (39), even when adjusted for resting energy expenditure (the best correlate of FFA flux). Perhaps not surprisingly, FFA release rates above or below the population norm for resting energy expenditure strongly relates to plasma FFA concentrations. Thus, within sex-specific biological relationships and subject to certain unique conditions, the integrated rate of adipose tissue lipolysis is the major determinant of plasma FFA concentrations, which in turn affect the ability of insulin to modulate glucose production and uptake. The regional differences in adipocyte lipolysis (studies in vitro) suggest, but do not prove, that regional variations in FFA release in vivo could have a major influence on plasma FFA concentrations, with visceral fat playing a disproportionate role.

Evidence to support this concept has come from two studies of adipose tissue using in vivo models. In a rat model of obesity, removal of the perinephric adipose depot resulted in substantial improvement of insulin-regulated glucose disposal (40). In a pilot study of human obesity, patients undergoing omentectomy coincident with a bariatric surgical procedure (vertical-banded gastroplasty) had a greater improvement in insulin action than patients undergoing the same procedure without omentectomy (41). On closer reflection and examination, neither of these examples can be taken as convincing evidence for the “visceral fat” hypothesis. The depot surgically removed in rats that improved insulin action was not visceral in that it does not drain into the portal vein. Subsequent studies in humans have shown that removal of large amounts of non-visceral fat does not improve insulin action (42). As for the study purporting to show that omental fat removal improves insulin action, the group undergoing omentectomy lost 9 kg more weight than the control group (41), a clinically significant, if not statistically significant, difference. Thus, the question remains open as to whether visceral fat is a cause or correlate of insulin resistance.

To the extent that abnormally high FFA release can cause some of the metabolic abnormalities associated with obesity, understanding whether there are regional differences in effective adipose tissue lipolysis will help resolve the issue as to whether visceral fat is the source of excess FFAs in upper body obesity. Our group has conducted a series of studies that have 1) documented heterogeneity of adipose tissue lipolysis in vivo; 2) determined the contribution of upper body non-visceral, leg, and visceral fat to systemic FFA availability, and 3) evaluated the contribution of visceral adipose tissue lipolysis to hepatic FFA delivery. These studies required the use of isotope dilution techniques to measure systemic and regional FFA uptake/release, hepatic vein, femoral vein, and femoral artery catheters for blood sample collection, regional body composition measurements using a combination of DXA and computed tomography imaging of the abdomen to quantify regional fat mass (43), and splanchnic and leg plasma flow measurements using indocyanine green. Systemic FFAs (as reflected by arterial FFA concentrations) will affect muscle, pancreatic β cells, and vascular effects. Portal FFA concentrations will affect hepatic glucose (44) and very-low-density lipoprotein triglyceride (30, 45) production and are determined both by systemic FFA delivery to the splanchnic bed and by visceral adipose tissue lipolysis (46, 47). While it is not feasible to measure portal FFA concentrations in humans—except under unique circumstances (45)—it is possible to estimate the proportion of hepatic FFA delivery that originates from visceral adipose tissue lipolysis (47).

We found that upper body non-visceral fat is more lipolytically active than leg fat (per kilogram of fat) in lean and obese women (48, 49) and lean and obese men (49, 50). In lean men and lean women, leg adipose tissue lipolysis contributes ∼15% to 20% of basal, systemic FFA release; in obese men and women, the average was 28% of FFA release. Leg adipose tissue is exquisitely sensitive to insulin (51) and meal (49, 52) suppression. Upper body non-visceral adipose tissue FFA release accounts for the majority (∼70%) of systemic FFAs under basal (48, 49, 50) and insulin-suppressed conditions (49, 51, 52, 53). Of note, the greater postprandial FFA concentrations in upper body obesity compared with lower body obesity could be entirely accounted for by excess FFA release from upper body non-splanchnic fat (52), not visceral fat.

The net release of new FFAs into the systemic circulation from the splanchnic bed does not fully reflect visceral adipose tissue lipolysis. The liver takes up a considerable fraction of FFAs in the portal vein. In addition, some of the FFAs entering the splanchnic bed through the arterial supply are taken up by non-hepatic tissues before they can enter the portal vein. Thus, FFA concentrations in the portal vein are not substantially greater than those typically seen in the arterial circulation (45). That said, the appearance of new FFAs in the hepatic vein is a direct measure of the contribution of visceral adipose tissue lipolysis to systemic FFA availability and, thus, plasma FFA concentrations. We found that only 6% to 17% of systemic FFAs come from the splanchnic bed under overnight postabsorptive conditions (50), although this can exceed 40% under hyperinsulinemic conditions (51). The latter observation suggests that visceral fat is more resistant to the antilipolytic effects of insulin than subcutaneous fat, which is consistent with results from dog studies (54).

It seemed that the issue of whether visceral obesity increases hepatic FFA delivery in overnight postabsorptive adults remained open to speculation without access to the portal vein. Fortunately, we were able to test whether the proportion of hepatic FFA delivery that originates from visceral lipolysis could be predicted using a model that uses only data collected from hepatic vein catheterization (47). We compared the actual proportion of hepatic FFA delivery in dogs from visceral adipose lipolysis as measured by a portal vein catheter to that predicted using a modeling approach (47). The good agreement between measured and predicted values allowed us to apply this model to data collected in a large number of lean and obese men and women (50). From these experiments, we found that the percentage of hepatic FFA delivery that comes from visceral adipose tissue lipolysis does increase with increasing visceral fat. In most non-obese adults, only 5% to 10% of hepatic FFA delivery is predicted to come from visceral lipolysis, whereas this increases to an average of 20% to 25% in visceral obesity (maximum values near 50% in some individuals). Of note, the contribution of visceral lipolysis to hepatic FFA delivery increased to a greater extent in women than men as a function of visceral fat (50).

Although increasing visceral fat is associated with a greater potential delivery of FFAs to the liver, it is worth recalling that even for adults with visceral obesity, >75% of hepatic FFA delivery is from the systemic circulation on average. If we recall that extrahepatic splanchnic tissues take up FFAs (∼20% of total splanchnic uptake), the concentration of FFAs in the portal vein in someone with very little visceral fat would be less that in the systemic circulation (Figure 1). If the uptake of FFAs in extrahepatic splanchnic tissues is the same in viscerally obese and lean persons, an individual with the extreme example (∼50% of hepatic FFA delivery from visceral fat) would have portal vein FFA concentrations double those of arterial concentrations (Figure 1).

image

Figure 1. The hypothetical arterial and portal vein FFA concentrations are depicted for a lean person and someone with large amounts of visceral fat. The assumptions are that: 1) the extra-hepatic splanchnic tissues are responsible for 20% of splanchnic FFA uptake in both and 2) visceral adipose tissue lipolysis accounts for 5% of hepatic FFA deliver in the lean person and 50% in the viscerally obese person.

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There remain some unanswered questions regarding other possible functions of visceral fat that could contribute to adverse metabolic function. If cytokine release (tumor necrosis factor-α, interleukin-6, resistin) is greater from visceral fat (and if they are not cleared by the liver), this could impact on peripheral function. The circulating concentrations of these cytokines are not strongly associated with insulin resistance, however. Although reduced adiponectin concentrations are reported in (and theorized to cause) insulin-resistant humans, this cannot be a function of visceral fat, because the suppressed release is from all depots, resulting in low concentrations.

In summary, visceral fat probably plays a role in the hepatic manifestations of visceral obesity, but to the extent that systemic FFA concentrations affect muscle, pancreatic β cells, and vascular function, it is the abnormal function of upper body non-splanchnic fat that should draw our attention.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Results and Discussion
  5. Acknowledgement
  6. References

The efforts of my collaborators, research fellows, my laboratory staff, the Mayo General Clinical Research Center staff, and the volunteers for the studies are greatly appreciated. This study was supported by NIH Grants DK40484, DK45343, DK50456, and RR-0585 and the Mayo Foundation.

Footnotes
  • 1

    Nonstandard abbreviation: FFA, free fatty acid.

References

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  2. Abstract
  3. Introduction
  4. Results and Discussion
  5. Acknowledgement
  6. References
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