Abstract

Defining Fat Depots

The various fat depots have unique characteristics. These range from the smaller, specific depots that track with visceral fat such as pericardial (19) and buccal (20) fat, to subdivisions of large depots like superficial and deep abdominal sc fat (21,22). Intra-abdominal fat includes omental and mesenteric (visceral) depots, both of which drain into the portal vein, along with perinephric fat, which drains into the systemic circulation. The lower body fat is commonly demarcated as all adipose tissue caudad to the inguinal ligament anteriorly and the ileac crest posteriorly. Subcutaneus lower body fat includes gluteal and leg depots, which may have differing characteristics (23), and adipose tissue in between the major muscle groups (so-called marbling) (24). Upper body sc fat includes superficial and deep truncal depots noted previously, upper extremity fat, and breast adipose tissue in women. One reasonably utilitarian approach is to characterize human body fat compartments as lower body fat, upper body sc fat, and intra-abdominal/visceral fat. An advantage of this approach is that the compartments can be measured readily using dual-energy x-ray absorptiometry and a single-slice computed tomography or magnetic resonance image of the abdomen (25,26). Those investigators with greater access to magnetic resonance imaging and considerable technical time to analyze the scans are able to define better the numerous specific fat depots (22).

Visceral Fat and Metabolic Complications–Cause and Effect?

Although the explanation for the strong association between visceral fat and metabolic abnormalities is not known, one hypothesis is that visceral fat produces and releases substances that cause metabolic abnormalities (27,28,29). More recently, an alternative hypothesis has been proposed. This concept is that visceral fat is another “ectopic fat depot” (30,31) not unlike pericardial fat (19), cheek fat (20), intramyocellular triglyceride (imTG) (32), and elevated hepatic triglyceride (33). In this paradigm, ectopic triglyceride accumulation is the result of energy imbalance wherein body fat stores exceed the functionally normal storage capacity of sc adipose tissue depots. The potential abnormal function(s) of sc fat includes a reduced ability to take up and store circulating triglyceride fatty acids along with excess free fatty acid (FFA) release under some conditions. This concept includes the abnormalities caused by greater infiltration of adipose tissue with inflammatory cells, excess release of potentially harmful cytokines, and reduced release of beneficial adipokines.

Normal Function of the Major Adipose Tissue Depots–Fatty Acid Metabolism

In vivo measures of systemic and regional adipose tissue FFA release have been performed in normal weight adult women and men under a variety of circumstances. Likewise, measures of dietary fatty acid storage and direct FFA storage in regional fat have been reported.

Under overnight postabsorptive conditions, upper body sc adipose tissue in both men and women is more lipolytically active than lower body adipose tissue as measured by FFA release per kg fat (34). In response to hyperinsulinemia (35) and meal ingestion (34,36), leg FFA release is much more readily suppressed than upper body sc fat. FFA release from the splanchnic bed, a surrogate measure of visceral adipose lipolysis, is relatively resistant to suppression by hyperinsulinemia and meal ingestion (34,35). The inability to measure FFA release directly into the portal vein in humans allows only indirect estimates of visceral adipose tissue lipolysis (37), and, thus, the rates of visceral adipose tissue lipolysis relative to visceral fat mass are not known.

Adipose tissue is also a major site of meal fatty acid storage. Normal weight men and women store roughly similar proportions of dietary fat in sc and visceral fat (38,39,40,41), but in men this is at the cost of greater triglyceridemia (40,41).

Paralleling the pattern of FFA release, the uptake of dietary fatty acids into upper body sc fat (milligram meal fat per gram of adipose tissue lipid) is more efficient than the uptake in lower body sc fat in normal weight men and women (38,39,40). Likewise, visceral fat stores more dietary fat (milligram meal fat per gram of adipose tissue lipid) than either upper body sc or lower body sc fat in both normal weight men (42) and women (38,43). This finding would argue that, at least in normal weight adults, visceral adipose tissue is more lipolytically active on a per unit weight basis than sc fat. However, the impact of visceral adipose tissue lipolysis on overnight postabsorptive hepatic FFA delivery appears to be very limited due to the typically small visceral fat mass in lean adults (37).

An unexpected recent finding is that systemic FFA can be restored back into sc and visceral fat without going through the very low-density lipoprotein (VLDL)-triglyceride pathway (44,45). Although the fraction of systemic FFA restored in whole body sc adipose tissue is relatively small (~3% for men and 9% for women), this process may play a role in the shuttling of FFA from one depot to another in such a manner as to modify fat distribution.

Subcutaneous and visceral fat combined store approximately 50% of dietary fat (38,40). Thus, for nonobese adults consuming a typical U.S. diet containing 100 g fat and maintaining stable body composition, adipose tissue must also net release 50 g triglyceride/d as FFA for total and regional fat mass to remain stable. Understanding this balance it is possible to estimate the net FFA release from regional fat depots by measuring meal fatty acid storage. Adipose tissue also takes up VLDL-triglyceride (46,47) and FFA directly (44,45), and, thus, total regional adipose FFA release exceeds net FFA release when assessed relative to dietary fat storage. These concepts become relevant when considering the role of different fat depots in delivering FFA to the portal and systemic circulation in obesity.

Abnormalities in Fatty Acid Metabolism in Upper Body Obesity

Adipose tissue release of FFA

Whole body FFA release is increased in upper body obesity under postabsorptive (50,51) and postprandial (36,52) conditions. Except in metabolically uncontrolled obesity and type 2 diabetes, fasting FFA concentrations/flux in upper body obese is only about 30% greater than in lean or lower body obese adults (50). This is not a large difference, given that the day-to-day variability of FFA concentrations/kinetics is approximately 30% under uncontrolled dietary conditions (53) and approximately 15% with conditions of careful dietary control (54). These relatively small differences in overnight postabsorptive whole body lipolysis may not be the best explanation for the link between upper body/visceral obesity, FFA, and the metabolic complications of obesity. However, there are conditions under which FFAs are vastly and routinely different in upper body obesity.

The most consistent finding with regards to adipose tissue lipolysis is that of much greater FFA release during hyperinsulinemia in upper body/visceral obesity compared with the nonobese or lower body obese state (36,50,52). The excess postprandial FFA release results in elevated postprandial FFA concentrations [~3- fold greater in upper body obese than lower body obese (36,52)]. By definition, this implies that adipocytes in upper body obesity are resistant to the antilipolytic effects of insulin. The explanation for this resistance is not clear. Some have argued that the enlarged abdominal or visceral adipocytes seen in upper body obesity are inherently resistant to insulin (55,56). Certainly, weight loss via diet and exercise, which reduce fat cell size, also improves insulin regulation of lipolysis (57), whereas surgical removal of abdominal sc fat via liposuction (no decrease in fat cell size) does not (58). On the other hand, surgical removal of omental fat during bariatric surgery was associated with significantly greater improvement in fasting plasma glucose and insulin concentrations along with a significantly greater decrease in body mass index than a control group that did not undergo resection of omentum (59). Unfortunately, we do not know whether regulation of adipose tissue lipolysis was affected by omentectomy or whether removal of visceral fat vs. greater relative weight loss accounted for the observed effects on insulin and glucose.

To provide a perspective on the relationship between plasma insulin concentrations vs. leg, splanchnic, and upper body sc adipose tissue FFA (palmitate) release, data from Meek (35) and Guo (36) et al. are plotted in Figs. 1–4​​​ using a logarithmic display format (60). In insulin-sensitive nonobese adults, the relative suppression of FFA release from the splanchnic bed as a result of higher plasma insulin concentrations (35) seems blunted compared with leg and upper body sc fat (Fig. 1​1).). Figures 2–4​​ depict the relationship between plasma insulin concentrations and palmitate release from upper body sc fat, leg fat, and the splanchnic bed in these same nonobese volunteers (35) compared with lower body obese and upper body obese women (36) studied before and during meal ingestion. Whereas the data points from nonobese and lower body obese (both more insulin sensitive) tend to display the same general relationship, the data points from upper body obese women (more insulin resistant) are displaced upwards, implying that each depot is to some degree insulin resistant. Because the total amount of FFA released from upper body sc fat is so much greater than that from the leg and splanchnic bed, however, insulin resistance in this depot appears to be quantitatively more important.

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Figure 1

Data from Meek et al. (35) obtained at baseline (n = 24) and during insulin clamp studies in nonobese adults are shown. The insulin doses were 0.25 (n = 6), 0.5 (n = 8), and 1.0 (n = 6) mU · kg⁻¹ · min⁻¹. The relationship between plasma insulin concentrations regional palmitate release are plotted on logarithmic axes. UBSQ, Upper body sc.

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Figure 2

Data from Meek et al. (35), who performed a series of insulin clamp studies in nonobese (non-ob) adults (see Fig. 1​1),), and Guo et al. (36), who studied regional FFA release at baseline and during meal ingestion, are plotted. The relationship between plasma insulin concentrations and upper body sc palmitate release are plotted on logarithmic axes. The line shows the best fit between values from nonobese and lower body obese (LBOb) volunteers (n = 8). UBOb, Upper body obese (n = 8).

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Figure 3

Data from Meek et al. (35), who performed a series of insulin clamp studies in nonobese (non-ob) adults (see Fig. 1​1),), and Guo et al. (36), who studied regional FFA release before and during meal ingestion, are plotted. The relationship between plasma insulin concentrations and leg palmitate release are plotted on logarithmic axes. The line shows the best fit between values from nonobese and lower body obese (LBOb) volunteers (n = 8). UBOb, Upper body obese (n = 8).

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Figure 4

Data from Meek et al. (35), who performed a series of insulin clamp studies in nonobese (non-ob) adults (see Fig. 1​1),), and Guo et al. (36), who studied regional FFA release before and during meal ingestion, are plotted. The relationship between plasma insulin concentrations and splanchnic palmitate release are plotted on logarithmic axes. The line shows the best fit between values from nonobese and lower body obese (LBOb) volunteers (n = 8). UBOb, Upper body obese (n = 8).

The implications of excess adipose tissue lipolysis in upper body obesity deserve attention. Most of the studies examining the adverse effects of experimentally elevating plasma FFA concentrations have used the paradigm of assessing their effect on insulin-stimulated glucose disposal (61), insulin-suppressed glucose (62), and hepatic triglyceride production (63), as well as insulin-stimulated tissue blood flow (64). Thus, it is reasonable to consider that high postprandial FFA concentrations are particularly relevant to the metabolic abnormalities seen in obesity. Given the association between visceral fat metabolic complications of obesity (16,65) and the finding of greater splanchnic FFA release during hyperinsulinemia (35), it is tempting to blame visceral adipose tissue lipolysis for elevated postprandial FFA concentrations in upper body obesity. However, in vivo studies have shown this not to be the case.

In lean men and women, leg adipose tissue lipolysis contributes approximately 15–20% of basal, systemic FFA release (34,35). In obese men and women, the average was 28% of FFA release (36,37). Because leg adipose tissue lipolysis is so sensitive to insulin (35) and meal (34,36) suppression, it does not seem to contribute to the elevated postprandial FFA in obesity. Upper body sc adipose tissue FFA release accounts for the majority (>60%) of systemic FFA under basal (37,66) and insulin-suppressed conditions (35,36,67). 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 sc fat (36), not visceral fat.

However, the net release of new FFA into the systemic circulation from the splanchnic bed does not fully reflect visceral adipose tissue lipolysis. The liver takes up a considerable fraction of FFA in the portal vein (68,69). In addition, some of the FFA entering the splanchnic bed via the arterial supply are taken up by nonhepatic tissues before they can enter the portal vein. Fasting FFA concentrations in the portal vein have not been found to be substantially greater than those typically seen in the arterial circulation (70). That said, the appearance of new FFA in the hepatic vein is probably a direct measure of the contribution of visceral adipose tissue lipolysis to systemic FFA availability and, thus, plasma FFA concentrations. We found that only 6–17% of systemic FFA come from the splanchnic bed under overnight postabsorptive conditions (34,35) but can increase to 40% during hyperinsulinemia (35). This might indicate either that visceral fat is very resistant to insulin’s antilipolytic effects when compared with sc fat [as noted in dogs (71)] or that the spillover of fatty acids from the hydrolysis of triglyceride-rich lipoproteins is a special issue in the splanchnic bed (72). In either case the liver is probably exposed to significantly greater FFA concentrations than the periphery during hyperinsulinemia, and this portal-systemic difference may well be exaggerated in upper body/visceral obesity.

Summary

An upper body/visceral fat distribution in obesity is strongly linked with the metabolic complications of obesity. Evidence from studies that manipulate FFA concentrations suggests that a number of these metabolic abnormalities are caused by elevated FFAs. Because the most consistent abnormality in FFA metabolism is failure to normally suppress FFA in response to insulin/meal ingestion, we suggest that postprandial elevations of FFAs are especially problematic in obesity. FFAs released from visceral fat make a minor contribution to systemic FFA concentrations, which are the obligate concentrations affecting muscle, pancreatic β-cells, and vascular endothelium. In persons with visceral obesity, omental and mesenteric fat may play a special role in delivering both excess FFA and IL-6 to the liver. We do not yet understand why upper body sc fat, the source of the majority of systemic FFAs, is dysregulated in upper body obesity. Weight loss via diet/exercise is able to improve the regulation of FFA metabolism (57), whereas simply removing sc fat does not (58).

Footnotes

References