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Role of A Critical Visceral Adipose Tissue Threshold (CVATT) Part 5

Mar 1, 2005

We all have a patient that is a relatively “thin” individual (with a normal BMI) and has an excess of VAT, and may be metabolically obese, normal weight (MONW) [27]. Then there are those with a large “pot bellies” who may have a great capacity to store fat as SCAT with relatively little VAT. Eric S. Freedland, MD, Boston University School of Medicine, helps us understand The Role Of A Critical Visceral Adipose Tissue Threshold (CVATT) In MONW, MNO Patients, and why this occurs.

Role of A Critical Visceral Adipose Tissue Threshold (CVATT) In Metabolic Syndrome:
Implications for Controlling Dietary Carbohydrates

Eric S. Freedland, MD
Boston University School of Medicine


Part 5 Critical Visceral Adipose Tissue Threshold (CVATT)—Individual Variations among MONW, MNO patients

The CVATT has tremendous individual variation; thus a relatively “thin” individual (with a normal BMI) and an excess of VAT for him, may be metabolically obese, normal weight (MONW) [27]. Meanwhile, another individual with a large “pot belly” may have a great capacity to store fat as SCAT with relatively little VAT or he may have a high threshold for VAT. This may explain the finding that some individuals weighing even up to 200 kg do not show any signs of type 2 diabetes or dyslipidemia. Meanwhile in others, diabetes or dyslipidemia either develop or deteriorate with an increase in body weight of only one kg [174]—perhaps just enough to exceed the CVATT.

A number of studies have looked at a possible CVATT [175-181]. Using CT scans to measure VAT volume, Williams et al found that a value of above 110 cm2 was associated with an increased risk of CHD in pre-and postmenopausal women [176]. Similarly, Despres and Lamarche observed a VAT cutoff of 100 cm2 was associated with increased CHD risk in young adult men and premenopausal women (mostly of French Canadian descent) [178], and a cutoff range of 100-110 cm2 has also been observed by others [175, 180]. Other studies have suggested thresholds of > 130 cm2 for metabolic deterioration [182, 183]. De Nino et al found that insulin resistance did not appear until women were older than 60 years and had accumulated levels of VAT that approximated the levels seen in men, suggesting a possible threshold effect of VAT on insulin resistance [184]. As discussed below with MONW, genetic and ethnic factors play a role. For example, in nonobese and obese Japanese males and females, fat areas at the umbilicus (as determined by CT) had threshold values for metabolic syndrome with only > 100 cm2 for men and > 90 cm2 for women [185].

Brochu et al were unable to demonstrate that obese postmenopausal women who reduced their weight and attained a level of VAT below 110 cm2 would show greater improvement in their metabolic profile compared to those who also lost weight but remained above the 110 cm2 VAT threshold [177]. However, there were only 25 total subjects and the women had relatively normal metabolic profiles at baseline. Perhaps due to the relatively small number of subjects, only five lost less than 20 percent of their baseline VAT value. Thus it is unclear whether even smaller losses of VAT than those observed improved metabolic outcomes. The researchers did find larger losses of VAT and a greater improvement in insulin sensitivity in those who attained a VAT level < 110 cm2 [177]. It should also be noted that in postmenopausal women, peripheral SCAT may be protective, even in the face of large amounts of VAT, and this needs to be accounted for [120, 121, 125]. While studying obese Japanese women, Tanaka et al recently validated the 100 cm2 CVATT but their longitudinal data from both pre- and posttreatment suggest that these women should reduce their VAT area to

Metabolically obese normal weight (MONW)
VAT accumulation contributes to metabolic risk factors in nonobese individuals [186, 187]. Ruderman et al have shown that normal weight individuals may also have insulin resistance and the disorders of the metabolic syndrome [27]. They designated such individuals as “metabolically obese normal weight—MONW [188, 189].” MONW subjects (BMI < 25 kg/m2) have been characterized by an excess of VAT area (> 100 cm2 by abdominal CT), insulin resistance, and hyperinsulinemia [25-27]. As pointed out earlier, the development of insulin resistance may limit further weight gain [34, 38-41, 190]. A rapid and early development of insulin resistance prior to significant weight gain would explain that a significant number of the normal-weight population have insulin resistance [27]. The prevalence of MONW could be as high as 13-18 percent [27, 191, 192].

MONW and low birthweight
Both low birthweight (LBW) [193] and lowest weight at one year of age have been linked to VAT accumulation [194], insulin resistance, and cardiovascular risk factors in middle-aged and elderly individuals, many of whom could be classified as MONW with metabolic syndrome. By middle age, many LBW subjects have BMIs less than 24-26 kg/m2 and would be classified as MONW. While some data suggest that LBW babies have central adiposity in middle age, definitive measurements of VAT in these individuals are still lacking [27].

Ethnicity and MONW
One should consider ethnic differences when attempting to identify MONW subjects. Lean appearing individuals, especially in certain ethnic groups such as the Japanese, may have significant amounts of VAT that surpass their CVATT but appear with what, for the general population, would be considered a normal BMI and waist circumference [195]. For example, nonobese Japanese (BMI<25) with increased VAT areas (100-110 cm2) fulfill the criteria for MONW [26, 180]. In another study, relatively lean Japanese patients with newly diagnosed type 2 diabetes had increased VAT. Through diet and without medication for three months, the amount of VAT in these patients became comparable to that in normal-weight control subjects. Therefore, a three-month dietary treatment regimen with small to moderate weight loss was very effective in decreasing excess VAT in this population [196]. This illustrates the importance of early recognition of an individual’s approaching or exceeding his CVATT. Park et al were among the first to demonstrate that healthy, non-obese Asian American women may have higher amounts of VAT, and that normative values or standards for VAT derived from Caucasians may not be applicable to Asians [195]. On the other side of the spectrum, a 10-year prospective study studied increased BMI in Micronesian Nauruans (an ethnic group from the central Pacific Ocean with rapidly increase in prevalence of obesity) and Melanesian- and Indian-Fijians. Overall, there was little evidence to suggest that obesity was a risk factor for total or cardiovascular mortality in these populations [197].

Metabolically normal obese (MNO)
McGarry found that one of his most obese patients in a series (BMI 32.8 kg/m2) was one of the most insulin-sensitive but had one of the lowest values for intramyocellular lipid (IMCL). Conversely, another subject, with a BMI of only 18.9 kg/m2, proved to be highly insulin-resistant but had a large amount of IMCL. This supports that insulin sensitivity appears to correlate more with where the fat is located rather than the total amount in the body [42]. This has implications for the phenomena of the metabolically obese normal weight (MONW) and the metabolically normal obese (MNO) individuals.
Like some of the Micronesian Nauruans and Indian-Fijians above, there are individuals who are obese and who nevertheless are metabolically normal—“metabolically normal obese; MNO.” Unlike their MONW counterparts, MNO individuals have very little VAT accumulation. They often share an onset of obesity early in childhood, and have normal VAT, lower TGs, and increased HDL. The actively competitive Japanese wrestlers maintain their gross obesity by consuming a 5,000 to 6,000 calorie diet. They are MNO, and their VAT is normal in amount, i.e., they have excessive amounts of SCAT [91]. On retirement, when they discontinue their rigorous training regimen, they markedly develop increased insulin resistance and metabolic syndrome. It is likely that their VAT increases concomitantly [27, 28] and exceeds their CVATT. Data from the European Group for the Study of Insulin Resistance (1146 hyperinslinemic/euglycemic clamp studies from 20 clinical centers in Europe) showed that in “simple” obesity, insulin resistance is not as prevalent as previously thought [198]. MNO could account for as much as 20 percent of the obese population [192]. In another study using HOMA to determine insulin resistance, Bonora et al showed that 11 percent of the entire group of overweight individuals fit the criteria of MNO [199]. Brochu et al extensively studied 43 sedentary, obese, postmenopausal women and found that 17 were MNO, while 26 had reduced insulin sensitivity (estimated by clamp) [200]. The two groups were similar in total body fat mass, SCAT amount, as well as waist circumference, and total daily energy expenditure. However, lean body mass was significantly greater in the metabolically abnormal subjects. Unlike SCAT, VAT measured by CT was inversely related to the insulin sensitivity and to a classification of MNO. In fact, despite similar levels of total body fatness, MNO individuals showed 49 percent less VAT as measured by CT. However, the level of VAT was still significant. Furthermore, using doubly labeled water and indirect calorimetry, Brochu et al were unable to demonstrate a meaningful difference between resting metabolic rate and daily physical energy expenditure between MNO and obese individuals at risk [200].

MNO and childhood obesity
Several investigators have found that there has been a positive association between insulin sensitivity and duration of obesity, i.e., those who are obese since childhood are more likely to remain insulin sensitive. In one study 48 percent of the MNO women presented with a history of an earlier age-related onset of obesity (between 13 and 19 years of age) and less VAT compared with 29 percent of the metabolically abnormal obese [200].

Insulin sensitivity seems to be dependent upon adipose cell size; as adipocytes within tissue grow larger, they become more insulin resistant [201]. Normal-sized, more insulin-sensitive adipocytes have been Perhaps today we are beginning to see that with the marked increase in overfeeding and extent of obesity at younger ages, hypertrophy of fat cells may occur earlier and hence metabolic syndrome is now occurring with greater frequency in children.

Puberty and VAT
During puberty, a certain degree of insulin resistance is normal, and children who are more insulin resistant have decreased SCAT gain [203]. Early in the development of juvenile obesity, increased VAT, hyperinsulinemia, and insulin resistance are closely linked [204]. Adrenal androgens are elevated in obese children and have been associated with early pubertal development in these children.[205, 206] Sex differences in VAT begin to emerge during puberty, with boys having more VAT than girls. Some studies suggest that the rate of VAT accumulation can be slowed in children by using exercise interventions [207, 208].

Fit and fat
VAT is strongly associated with fitness even within individuals of the same weight. This is illustrated by the earlier mentioned example of the active Sumo wrestler in his prime who has relatively little VAT [91]. Regular exercise can selectively reduce VAT with minimal change in weight [209-211]. This could especially add to the frustration level of the middle-aged or post-menopausal woman who regularly exercises moderately without inducing measurable reduction in body weight or fatness. She may still benefit from reducing her VAT or attenuating the gain of VAT “normally” experienced by sedentary women as they age. It should be emphasized that the lower VAT level associated with increased fitness is modest but nonetheless clinically important. Reduced morbidity is likely explained by factors in addition to a reduced VAT, and VAT likely explains morbidity independent of fitness [212]. Sumo wrestlers tend to have most of their central adiposity stored subcutaneously (as SCAT), and, perhaps a shift toward more VAT accompanies their contracting metabolic syndrome upon their retirement—with premature death to follow [27, 91]. This may also explain the body of work showing that overweight or “fat” individuals who are fit (according to cardiorespiratory testing on a treadmill) are at less risk for a cardiac event or developing type 2 diabetes than a “leaner” individual who is unfit [213, 214]. Thus, the former could be considered “fit and fat.” High levels of cardiorespiratory fitness (CRF) reduce C-reactive protein (CRP) and the rate of cardiovascular morbidity and mortality, independent of obesity [215]. CRF is also associated with lower abdominal fat independent of BMI. For a given BMI or waist circumference (WC), individuals with moderate CRF also had lower levels of total fat mass and abdominal SCAT and VAT than individuals with low CRF for a given BMI or WC value [212, 216]. Low CRF is an independent risk factor for mortality in healthy-appearing and diseased populations, and is associated with elevated CRP and reduced fasting glucose control in women with type 2 diabetes [217]. It is likely that compared to the fit and fat, the unfit and lean-appearing individual may have greater amounts of “hidden” VAT.

Effects of exercise
In obese patients, increasing physical activity can enhance fat oxidation, reduce IMCL, and improve insulin sensitivity [218]. Exercise training may reduce waist size independent of changes in BMI, and exercise without weight loss is effective in reducing VAT and preventing further increases in obesity [212, 219].

Ross et al showed that either modality, caloric restriction alone or daily exercise without calorie restriction, is an effective strategy for reducing obesity in moderately obese men.
Their findings also suggest that exercise without weight loss is a useful method for reducing VAT and preventing further increases in obesity [219]. Irwin et al studied 168 overweight, postmenopausal, previously sedentary women in a randomly controlled trial of exercise versus no exercise. While the body weight lost at 12 months among the exercisers was modest, the amount of intra-abdominal fat lost was considerable (8.5 g/ cm2) and was dose-dependent. The women who exercised for approximately 200 min/wk lost 4.2 percent of total body fat and 6.9 percent of VAT without reducing their energy intake [211]. Exercise may counteract the abnormal metabolic profiles associated with abdominal obesity by reducing VAT along with other independent mechanisms. It promotes adaptive responses including those causing muscles to increase their use of lipid stores rather than relying primarily on carbohydrate reserves. Even a single bout of exercise can reduce triglyceride levels, increase HDL levels, reduce resting blood pressure, increase glucose tolerance, and reduce insulin resistance [220].

While evidence supports that CRF may be associated with a lower VAT, this is certainly not proven. However, study results suggest that individuals with moderate to high CRF levels have lower WC than men with low CRF independent of BMI [212, 221]. Data support that the substantial reductions in health risk often associated with modest weight loss

Eric S. Freedland, MD graduated from University of Rochester School of Medicine in 1982, trained in internal medicine at Mt. Auburn Hospital in Cambridge, MA, and emergency medicine at Harbor-UCLA Medical Center in Torrance, CA, and has held faculty positions at Harvard Medical School (1990-1991) and Boston University School of Medicine (1992-2004). Dr. Freedland has developed a nutrition-centered model of disease with a special emphasis on diabetes. A staunch advocate for prescribing lifestyle changes before drugs, Dr. Freedland has written and lectured extensively on this subject

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