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Role of A Critical Visceral Adipose Tissue Threshold (CVATT) Part 3

Jan 18, 2005

Eric S. Freedland, MD, Boston University School of Medicine explores the value of Subcutaneous Adipose Tissue(SCAT) and other fats and how they might affect the body and hormone levels in part 3 of his series: Role Of A Critical Visceral Adipose Tissue Threshold (CVATT) In Metabolic Syndrome:

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 3 SCAT, VAT, and Total Fat Mass

Greater preadipocyte differentiation and protection
As discussed earlier, preadipocytes from SCAT depots have a greater capacity than VAT to differentiate into numerous, small, insulin-sensitive, adipocytes [70, 71]. These lipid-storing cells act as a buffer or sink for circulating FAs and TGs, thereby preventing their deposition in non-adipose tissues, e.g., skeletal muscle, pancreas, and liver, where they could contribute to lipotoxicity, apoptosis, and insulin resistance [73, 116].

Does SCAT replenish VAT?
In defending the role of VAT accumulation in individuals with metabolic syndrome, we must postulate a high rate of lipid turnover, with high rates of lipolysis at certain times matched by high rates of lipid deposition at other times. Otherwise, as Frayn points out, the hyperlipolytic VAT would ultimately disappear [117]. He also suggests that if SCAT were to become insulin resistant, and therefore resistant to fat storage, then fat might tend to be deposited in VAT depots. Another possibility is that the usually larger SCAT depot has a greater potential to contribute to insulin resistance through release of FFA into the systemic circulation. However, this would not adequately explain the subset of individuals who demonstrate metabolic profiles consistent with insulin resistance but are in fact lean, healthy-appearing with normal BMIs, excess VAT, little SCAT, and are referred to as “metabolically obese, normal weight (MONW) [27]. As described above, perhaps once VAT expands and SCAT depots reach their capacity for storing FAs, then do SCAT adipocytes become insulin resistant, release FFAs, and contribute to systemic insulin resistance and metabolic syndrome.

While some studies cast doubt on the portal theory and its implications for VAT’s direct delivery of FFA to the liver [118, 119], they leave open other mechanisms via which VAT could induce insulin resistance and other metabolic disturbances, e.g., by producing proinflammatory cytokines which could be directly delivered to the liver where they can potentially affect hepatic metabolism [117]. These will be discussed below.

Peripheral fat mass may protect against atherosclerosis and metabolic syndrome
If trunk fat is taken into account, accumulation of fat in the hips and legs is an independent predictor of lower cardiovascular and diabetes-related mortality, and it seems to protect against impaired glucose metabolism, especially in women [120-124]. In a study of 1,356 women ages 60-85, those with excessive peripheral fat had less atherosclerosis (determined by aortic calcification scores), and the quartile with both the highest amount of central fat and peripheral fat seemed to be partially protected by the high percentage of peripheral fat mass as reflected in a number of measured risk factors [121]. These findings corroborate similar findings by the same group who followed 316 postmenopausal women for 7.7 years and monitored progression of aortic calcifications [120]. In yet another study, Tanko et al demonstrated that peripheral fat mass (SCAT) in generally obese, post-menopausal women is associated with increased adiponectin and higher insulin sensitivity [125]. Together, these support protective roles for peripheral fat. In addition to fat trapping, these might include possible influences on adipokines, e.g., they might contribute to an increase in adiponectin, which could improve FA oxidation. One must interpret these results with caution because the measuring technique of dual-energy X-ray absorptiometry (DXA) does not allow separate quantification of intermuscular and subcutaneous fat in the arms and legs as well as SCAT in the trunk [121]. While VAT is a major predictor of insulin sensitivity in overweight and lean individuals [114, 126], others have found abdominal SCAT to contribute to insulin resistance independently of VAT [127, 128].

An example of metabolically innocent obesity
When there is an inability to store fat, due to lipodystrophy, the adipocytes’ storage capacity is exceeded and lipids accumulate and cause lipotoxicity in liver, muscle, and other organ tissues [7]. A counterpart of lipodystrophy may be illustrated by patients with multiple symmetric lipomatosis (MSL), a condition characterized by regional excess of subcutaneous adipose tissue. These patients have higher adiponectin levels, a high degree of insulin sensitivity and glucose tolerance, very low lipid levels in liver and muscle cells, and markedly little VAT [129]. In this case, SCAT may be protective and beneficial. This may be analogous to thiazolidinedione action, which also promotes SCAT deposition while improving insulin sensitivity and glucose tolerance [74, 75].

Estrogen promotes the accumulation of peripheral gluteo-femoral SCAT, which may be protective [130]. The abundant presence of peripheral fat mass in generally obese women is associated with increased plasma adiponectin, and the loss of estrogen with menopause is associated with an increase in central fat [131].This accounts for the progression in many overweight women after menopause from a predominantly pear-shape or “gynoid” habitus to the apple or “android” shape. Contrary to popular belief, menopause does not seem to independently cause a gain in total body weight; the increases in BMI that often accompany menopause are usually consistent with normal aging [132]. However, even without weight gain, body fat distribution changes; postmenopausal obese women tend to accumulate abdominal fat along with deterioration of risk factors, even if total body weight and BMI do not change during menopause transition.

After menopause, when ovarian function declines, adipocytes become the primary source of endogenous estrogens [133], and compared to “gynoid” or pear-shaped women, those with central obesity (apple- or “android-” shaped) have lower plasma SHBG and higher estradiol [125, 134]. This suggests regional differences in the enzymatic conversion of steroid hormones in VAT versus SCAT [125, 135-137]. In ovarian hormone-deficient women, SCAT adipocyte size, lipoprotein lipase (LPL) activity, and basal lipolysis were not found to be significantly greater compared to regularly cycling premenopausal women. However, in the ovarian hormone-deficient women, omental (VAT) adipocyte size was significantly higher, and the omental/SCAT LPL activity ratio and VAT lipolysis were also significantly higher [138]. For a given amount of total body fat, men have been found to have about twice the amount of VAT than what is found in premenopausal women but this may change after menopause when VAT storage becomes predominant [139, 140].

Along with an increase in VAT, a decline in estrogen is also associated with reduced lean body mass as well as other features of the metabolic syndrome including: dyslipidemia with elevation in Lp(a), triglycerides, and an increase in small, dense, LDL particles. Estrogen deficiency also may influence cardiac risk by its effects on the insulin action, the arterial wall, and fibrinolysis. Park et al showed that postmenopausal women lost less VAT compared with the premenopausal women during a weight reduction program (10.5 percent vs. 25.7 percent respectively) [141]. The reasons behind this are presently unclear.

As mentioned above, in menopause, adipocytes are primary sources of endogenous estrogens in women [125, 133], and estrogens are known inhibitors of IL-6 secretion [142]. It is worth noting that the relationship between BMI and serum IL-6 was observed only in postmenopausal women, and this relationship was lost among those women receiving hormone replacement [143]. Adipose tissue-derived estrogens in postmenopausal women would not be sufficient to reduce IL-6 in a similar way as endogenous estrogens do in premenopausal women[144]. Perhaps in premenopausal women, endogenous estrogen from the ovaries helps keep VAT volume relatively low and is thereby protective. Estrogen by itself seems to protect postmenopausal women receiving replacement therapy from VAT accumulation, and in women with type 2 diabetes, estrogen replacement may protect against the risk of cardiac events [145, 146].

Compared to men of similar age, premenopausal women appear to be significantly protected from CHD. However, by age 70 the incidence of CHD is equal in men and women, suggesting that estrogen deficiency causes a rapid acceleration in CHD risk [132]. Yet, in elderly, postmenopausal women, Tanko et al showed that those women with higher amounts of central versus peripheral obesity had significantly higher levels of estradiol and lower adiponectin. This suggests that prolonged and increased exposure of SCAT cells to estradiol may eliminate the protective effect of SCAT by affecting SCAT’s ability to release adiponectin thereby promoting the atherogenic effects of IL-6 [125]. Perhaps future research will help clarify whether central obesity has any implication for increased susceptibility to the adverse cardiovascular effects of hormone replacement therapy (HRT) in diabetic patients early after initiation of therapy [125].

Obesity, particularly visceral obesity, as well as insulin resistance and hyperinsulinemia are associated with breast cancer [147]. Insulin may increase estrogen action by increasing bioavailable estrogen due to a decrease in sex hormone-binding globulin, by influencing estrogen receptors, and by increasing aromatization of androgen to estrogen at the tissue level, a phenomenon which has been demonstrated in breast tissue. Estrogen upregulates the IGF-1 receptor and insulin-like growth factor binding protein-1 (IGFBP-1) and -2 and may directly activate the IGF-1 receptor, thereby increasing insulin signaling [148].

Around 1900, most women died soon after menopause. The average lifespan of persons in the United States has since lengthened by greater than 30 years [149], which means that women, and men, too, are now spending 30 or more years with hormonal and physiological states that society and medicine has not had to deal with previously. These, combined with significant dietary and lifestyle changes since 1900, must be considered as critical contributing factors to the world’s current epidemic of metabolic syndrome.

Next we look at how overnutrition, lipotoxicity, leptin, affect metabolic syndrome.

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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