Lipolysis is the breakdown of fat in fat cells, for use as fuel, and ongoing lipolysis can prevent the buildup of excess fat in those cells, Liew said. Their search for answers led them to a cellular structure called the endoplasmic reticulum, or ER, which is responsible for producing all the proteins in the cell.

Nutrients from a meal enter the ER, but an excess due to overeating can significantly stress it. In obesity, a stressed ER in visceral fat cells leads to production of inflammatory molecules called cytokines — but exactly how was unclear.

Liew and coworkers found that in the absence of TRIP-Br2, ER stress could no longer trigger cytokine production and inflammation in obesity. They also found that the up-regulation of TRIP-Br2 in visceral fat depends on an intermediary factor called GATA 3 that turns on TRIP-Br2.

Co-authors on the study are Guifen Qiang, Hyerim Whang Kong and Maximilian McCann of UIC; Difeng Fand and Jinfang Zhu of the National Institute of Allergy and Infectious Disease; Xiuying Yang and Guanhua Du of the Chinese Academy of Medical Sciences and Peking Union Medical College; and Matthias Bluher of the University of Leipzig.

This research was supported in part by the Research Open Access Publishing Fund of UIC; grants K99 DK and R00 DK from the National Institutes of Health; a Novo Nordisk Great Lakes Science Forum Award; a RayBiotech Innovative Research Grant Award; a Center for Society for Clinical and Translational Research Early Career Development Award; UIC startup funds; and grant SFB , B01 from the Deutsche Forschungsgemeinschaft.

Contact Sharon Parmet sparmet uic. Faculty , Research. fat , inflammation , metabolic disease , obesity.

According to Pouliot et al. The threshold value is similar in men and women in that for a given waist circumference, men and women had comparable levels of abdominal visceral adipose tissue. Thus, waist circumference, a convenient and simple measurement unrelated to height 46 and correlated with BMI and WHR 47 , determines the extension of abdominal obesity, which appears closely linked to abdominal visceral adipose tissue deposition.

Furthermore, while changes in waist girth reflect changes in risk factors for cardiovascular disease 48 and other forms of chronic disease, the risks vary in different populations; therefore, globally applicable cut-off points cannot be developed.

For example, abdominal fatness has been shown to be less strongly associated with risk factors for cardiovascular disease and type 2 diabetes in black women than in white women Risk factors such as total and HDL cholesterol were correlated with subcutaneous and abdominal fat areas by CT as well as their sum in healthy nonobese Asian Indians.

On the other hand, while there was an association of visceral adiposity with insulin secretion during an oral glucose test in men, such was not found in women In addition, it has been reported that visceral obesity is strongly related to coronary heart disease risk factors in nonobese Japanese-American men Also, people of South Asian Indian, Pakistani, and Bangladeshi descent living in urban societies have a higher incidence of obesity complications than other ethnic groups These complications are seen to be associated with abdominal fat distribution, which is markedly higher for a given level of BMI than in Europeans.

Finally, although women have an almost equivalent absolute risk of coronary heart disease CHD to men at the same WHR 53 , 54 , they show increases in relative risk of CHD at lower waist circumferences than men.

Thus, there is a need to develop sex-specific waist circumference cut-off points appropriate for different populations. The studies by Ferland et al.

Therefore, the waist circumference, and the abdominal sagittal diameter as will be discussed below , are the anthropometric indexes preferred over the WHR to estimate the amount of abdominal visceral fat and related cardiovascular risk profile.

Using the equations for prediction, multiscan CT was used to determined visceral adipose tissue volume from the waist circumference in a sample of 17 males and 10 females with different degrees of obesity Again, it was concluded that the WHR is a suboptimal predictor of visceral adipose tissue volume.

Abdominal sagittal diameter. The sagittal diameter is measured with a ruler as the vertical distance from the horizontal spirit level to the examination table after a normal expiration Kvist et al. The correlation of the sagittal diameter with visceral fat volume was 0.

The correlations between the waist circumference and visceral fat were, respectively, 0. These correlations are considerably higher than those observed between anthropometric variables and the visceral fat area measured at the level of the umbilicus in obese men and women Ferland et al.

Desprès et al. Busetto et al. It is very likely, therefore, that the range of fatness in subjects studied greatly influences the magnitude of the correlations and perhaps also the comparison between the sagittal diameter and the waist circumference with regard to their utility in predicting intraabdominal fat.

In addition, the distinction between studies that used only visceral fat area and those that calculated visceral fat volume from multiple scans may be important to make Ross et al. A study from the Canadian group 38 conducted in a large group of males and females evaluated systematically the three anthropometric indexes and their association with abdominal visceral adipose and subcutaneous areas measured by CT between the fourth and fifth lumbar vertebrae and metabolic profile.

As seen in Table 1 , there was a strong association between waist girth and body fat mass, the slope of the regression line being steeper in women data not shown. With relation to the abdominal visceral fat area, for a given waist circumference, men and women had similar levels and the slopes of the regression lines were not different between genders.

Essentially similar results were observed with the abdominal sagittal diameter. However, in contrast with waist circumference, the slopes of regression of abdominal sagittal diameter to abdominal visceral fat area were significantly different between genders and were steeper in men data not shown.

Finally, it can be seen that the WHR was less strongly correlated with total body fat mass and abdominal visceral and subcutaneous areas than the other indexes. This study demonstrated that most of the variance in waist girth and abdominal sagittal diameter can be explained by variations in body fat mass and in abdominal visceral and subcutaneous adipose tissue areas 0.

With relation to the metabolic variables related to cardiovascular risk plasma triglycerides and high-density lipoprotein cholesterol levels, fasting and postglucose glucose and insulin levels , in women, the waist circumference and the abdominal sagittal diameter were more closely related to the metabolic variables than the WHR, whereas such differences were not apparent in men.

They concluded that waist circumference values above approximately cm, abdominal sagittal diameter values greater than 25 cm, and WHR values greater than 0. Correlations r values between the anthropometric indexes and body fat mass, abdominal visceral, and abdominal subcutaneous fat areas in 81 men and 70 women.

Correlations between sagittal diameter and waist circumference are usually quite high [ e. Although the sagittal supine diameter can be studied with relatively good precision 61 , it is clear that this measurement requires appropriate equipment and skilled personnel.

Since most people are measuring the WHR as an indicator of visceral fat, the focus should be switched to the waist girth alone without affecting the ranking of individuals with respect to visceral fat when based on the waist circumference compared with the sagittal diameter Computed tomography CT.

CT can be considered the gold standard not only for adipose tissue evaluation but also for multicompartment body measurement 61 , The reported error for the determination of total adipose tissue volume after performing 28 scans is 0. The subcompartments of adipose tissue volume, visceral and subcutaneous adipose tissue, can be accurately measured with errors of 1.

In eight nonobese Swedish males evaluated by the multiscan CT technique, the volume of visceral abdominal adipose tissue in the intraperitoneal and retroperitoneal compartments was found to be 1.

Using a multislice magnetic resonance protocol, Abate et al. In effect, in 13 lean males, Abate et al. If only one scan is used to measure the visceral adipose tissue area, a strictly defined longitudinal level is very important since the average visceral adipose tissue area shifts if there is a change in position, even of a few centimeters.

This, according to Sjöström et al. Instead, the longitudinal level must be defined in a strict relation to the skeleton, usually between the L4 and L5 vertebrae. The subjects are examined in a supine position with their arms stretched above their heads.

The choice to perform the scan at the level of the umbilicus was initially proposed by Borkan et al. Subsequently, Tokunaga et al. In addition to the recommendations of the Japanese investigators, studies from Korea 20 and from our clinic use the scan at the umbilicus.

Visceral fat is defined as intraabdominal fat bound by parietal peritoneum or transversalis fascia, excluding the vertebral column and the paraspinal muscles; subcutaneous fat is fat superficial to the abdominal and back muscles. Subcutaneous fat area is calculated by subtracting the intraabdominal fat area from the total fat area.

In addition, visceral fat increases with age Figure 1 shows cross-sectional abdominal areas obtained by CT at the level of the umbilicus in two women matched for the same BMI, who differed markedly in the accumulation of fat in the abdominal cavity but less so in the subcutaneous abdominal fat.

Computed tomography showing cross-sectional abdominal areas at umbilicus level in two patients demonstrating variation in fat distribution. A, Visceral type yr-old female, B, Subcutaneous type yr-old female, In obese subjects the level of the umbilicus can change from one patient to another, thus changing the visceral adipose tissue area; therefore, it is advisable that the scan area be defined in strict relation to the skeleton.

Chowdhury et al. However, the values for abdominal cut-off points were related to increased cardiovascular risk Table 2. Using the scan at the umbilicus as described by several investigators gave results similar to, although somewhat lower than, those reported using the L4-L5 level.

Abdominal visceral adipose tissue area cut-off points related to increased cardiovascular risk. Regarding the relationship between the modifications in subcutaneous and visceral adipose tissue, with changes in body weight, it was shown that after severe weight loss, subcutaneous fat at the abdominal level is lost in greater proportion than visceral fat, but the mechanism of these differential changes in both compartments of abdominal fat is unknown, suggesting that visceral fat does not reflect nutritional status to the extent that sc fat does In the same way, published data suggest that, at least in relative terms, visceral fat increases less than subcutaneous fat with increased body weight However, because the amount of subcutaneous abdominal fat is calculated indirectly, it is likely that significant measurement error could be introduced Regarding the reproducibility of CT measurement of visceral adipose tissue area, Thaete et al.

The duplication occurred after the initial scan; the subjects were repositioned before repeat scanning. As indicated in the Introduction , individuals with a high accumulation of visceral abdominal fat, as shown by CT scans, had an increased risk for development of type 2 diabetes, dyslipidemia, and coronary heart disease.

Table 2 shows the thresholds above which metabolic complications would be more likely to be observed in visceral adipose tissue areas. Desprès and Lamarche 73 , Hunter et al. They found that a value above cm 2 was associated with an increased risk of coronary heart disease in pre and postmenopausal women 75 ; the same group 74 found that males with abdominal visceral fat cross-section areas measuring more than cm 2 were clearly at an increased risk for coronary disease.

On the other hand, Desprès and Lamarche 73 found that in both men and women a value of cm 2 was associated with significant alterations in cardiovascular disease risk profile and that a further deterioration of the metabolic profile was observed when values greater than cm 2 of visceral adipose tissue were reached.

From the same center, Lemieux et al. It was concluded that waist circumference was a more convenient anthropometric correlate to visceral adipose tissue because its threshold values did not appear to be influenced by sex or by the degree of obesity.

Anderson et al. The most extensive studies using a single CT scan at umbilical level was done by Matsuzawa and colleagues 17 , However, they did not present the raw data on visceral and subcutaneous areas but only their ratios, thus precluding their inclusion in Table 2.

In another study, performed in Japan by Saito et al. Lottenberg et al. Magnetic resonance imaging MRI. MRI provided results similar to CT without exposure to ionizing radiation, the main problem with CT multislice measurements.

It demonstrated good reproducibility for total and visceral adipose tissue volumes 63 , which were slightly lower than previously reported using CT 55 , although the percent contribution of visceral to total adipose tissue volume was similar 18 vs. Subcutaneous adipose tissue and visceral fat areas at the L4-L5 level determined in 27 healthy men by MRI were These areas were highly predictive of the corresponding volume measurements computed from the scan MRI, confirming the CT studies of Kvist et al.

Two studies have compared estimates of subcutaneous and visceral adipose tissue by CT and MRI. Comparison between MRI and CT in seven subjects showed a high degree of agreement in measurement of total subcutaneous adipose tissue area but not visceral adipose tissue area As already mentioned, MRI has been validated in three cadavers, confirming its accuracy Ultrasound US.

US subcutaneous and intraabdominal thicknesses, the latter corresponding to the distance between abdominal muscle and aorta, were measured 5 cm from the umbilicus on the xipho-umbilical line with a 7. The intraindividual reproducibility of US measurements was very high both for intraabdominal and subcutaneous thickness as well as for interoperators 83 , Several studies demonstrated a highly significant correlation between the intraabdominal adipose tissue determined by CT and by US.

A decade ago, Armellini et al. In a more recent study, Tornaghi et al. In a study of men C. Leite, D. Matsuda, B. Wajchenberg, G. Cerri, and A. Halpern, unpublished data , in which In obese women, after a 6-kg weight loss, a significant decrease was found in intraabdominal fat but not in subcutaneous adipose tissue, as determined by both CT and US There was also a significant correlation between changes in intraabdominal adipose tissue using both techniques, indicating that US can be used in the evaluation of body fat distribution modifications during weight loss.

This is another confirmation of the reliability of the US intraabdominal determinations. The amount of visceral fat increases with age in both genders, and this increase is present in normal weight BMI, In a study of subjects 62 males and 68 females with a wide range of age and weight , Enzi et al.

This fat topography was retained in young and middle-aged females up to about 60 yr of age, at which point there was a change to an android type of fat distribution. This age-related redistribution of fat is due to an absolute as well as relative increment in visceral fat depots, particularly in obese women, which could be related to an increase in androgenic activity in postmenopausal subjects.

On the other hand, they showed that males at any age tend to accumulate fat at the visceral depot, increasing with age and BMI increase. In the male, a close linear correlation between age and visceral fat volume was shown, suggesting that visceral fat increased continuously with age Although this correlation was also present in women, the slope was very gentle in the premenopausal condition.

It became steeper in postmenopausal subjects, almost the same as in males Further, Enzi et al. From the published data 68 , 90 , it can be concluded that both subcutaneous and visceral abdominal fat increase with increasing weight in both sexes but while abdominal subcutaneous adipose tissue decreases after the age of 50 yr in obese men, it increases in women up to the age of 60—70 yr, at which point it starts to decline Fowler et al.

Finally, as previously indicated, visceral fat is more sensitive to weight reduction than subcutaneous adipose tissue because omental and mesenteric adipocytes, the major components of visceral abdominal fat, have been shown to be more metabolically active and sensitive to lipolysis Lemieux et al.

In addition, the adjustment for differences in visceral fat between men and women eliminated most of the sex differences in cardiovascular risk factors. There is evidence supporting the notion that abdominal visceral fat accumulation is an important correlate of the features of the insulin-resistant syndrome 23 , 24 , 29 but this should not be interpreted as supporting the notion of a cause and effect relationship between these variables This subject will be discussed later on.

The correlations of abdominal visceral fat mass evaluated by CT or MRI scans with total body fat range from 0. They tend to be lower in the lean and normal weight subjects than in the obese As indicated by Bouchard et al. When they examined the relationship of total body fat mass to visceral adipose tissue accumulation in men and in premenopausal women, Lemieux et al.

Furthermore, the relationship of visceral adipose tissue to metabolic complications was found to be independent of concomitant variation in total body fat, and it was concluded that the assessment of cardiovascular risk in obese patients solely from the measurement of body weight or of total body fatness may be completely misleading 19 , 22 , 36 , Indeed, it appears that only the subgroup of obese individuals characterized by a high accumulation of visceral adipose fat show the complications predictive of type 2 diabetes and cardiovascular disease On the other hand, after adjustment for total body fat, Abate et al.

Intraabdominal visceral fat is associated with an increase in energy intake but this is not an absolute requirement. Positive energy balance is a strong determinant of truncal-abdominal fat as shown by Bouchard and colleagues 96 in overfeeding experiments in identical twins.

The correlations between gains in body weight or total fat mass with those in subcutaneous fat on the trunk reached about 0. In contrast, these correlations attained only 0.

Thus, positive energy balance does not appear to be a strong determinant of abdominal visceral fat as is the case with other body fat phenotypes 7. In effect, as discussed in the CT section of imaging techniques for evaluation of intraabdominal visceral fat, some investigators 70 , 71 have shown that either when the subjects lose or increase their weight, particularly females, visceral fat is lost or gained, respectively, less than subcutaneous fat at the abdominal level.

However, at variance from these data, Zamboni et al. Similarly, as already mentioned, Smith and Zachwieja 32 noted that all forms of weight loss affect visceral fat more than subcutaneous fat percentage wise , and there was a gender difference, with men appearing to lose more visceral fat than women for any given weight loss.

LPL activity, being related to the liberation of the lipolytic products [from chylomicra and very-low-density lipoproteins VLDL ] to the adipocytes for deposit as triglycerides, is a key regulator of fat accumulation in various adipose areas, since human adipose tissue derives most of its lipid for storage from circulating triglycerides.

However, adipocytes can synthesize lipid de novo if the need arises, as in patients with LPL deficiency According to Sniderman et al. The increase of visceral fat masses with increasing total body fat was explained by an increase of fat cell size only up to a certain adipocyte weight.

However, with further enlargement of intraabdominal fat masses with severe obesity, the number of adipocytes seems to be elevated , In women, but not in men, omental adipose tissue has smaller adipocytes and lower LPL activity than subcutaneous fat depots since variations in LPL activity parallel differences in fat cell size 7.

When adipocytes enlarge in relation to a gain in body weight, the activity of LPL increases in parallel, possibly as a consequence of obesity-related hyperinsulinism. The higher basal activity of adipose tissue LPL in obesity is accompanied by a lower increment after acute hyperinsulinemia Lipid accumulation is favored in the femoral region of premenopausal women in comparison with men In the latter, LPL activity as well as the LPL mRNA levels were greater in the abdominal than in gluteal fat cells, while the opposite was observed in women, suggesting that regional variation of gene expression and posttranslational modification of LPL could potentially account for the differences between genders in fat distribution With progressive obesity, adipose tissue LPL is increased in the depots of fat in parallel with serum insulin.

However, when obese subjects lost weight and became less hyperinsulinemic, adipose LPL increased further and the patients who were most obese showed the largest increase in LPL, suggesting that very obese patients are most likely to have abnormal LPL regulation, independent of the influence of insulin.

In response to feeding, the increase in LPL is, as indicated, due to posttranslational changes in the LPL enzyme. However, the increased LPL after weight loss involved an increase in LPL mRNA levels, followed by parallel increases in LPL protein and activity Because the response to weight loss occurred via a different cellular mechanism, it is probably controlled by factors different from the day-to-day regulatory forces.

In addition, because the very obese patients demonstrated a larger increase in LPL with weight loss than the less obese patients, these data suggest a genetic regulation of LPL that is most operative in the very obese The role of sex steroids, glucocorticoids, and catecholamines in the regulation of adipose tissue LPL activity in various fat depots will be discussed in the section on hormonal regulation of abdominal visceral fat.

Lipid mobilization and the release of FFA and glycerol are modulated by the sympathetic nervous system. Catecholamines are the most potent regulators of lipolysis in human adipocytes through stimulatory β l - and β 2 -adrenoreceptors or inhibitoryα 2-adrenoreceptors A gene that codes for a third stimulatory β -adrenoreceptor, β 3 -adrenoreceptor, is functionally active principally in omental adipocytes but also present in mammary fat and subcutaneous fat in vivo In both genders and independently of the degree of obesity, femoral and gluteal fat cells exhibit a lower lipolytic response to catecholamines than subcutaneous abdominal adipocytes, the latter showing both increased β l - and β 2 -adrenoreceptor density and sensitivity and reduced α2-adrenoreceptor affinity and number Refs.

The increased sensitivity to catecholamine-induced lipolysis in omental fat in nonobese individuals is paralleled by an increase in the amount of β l - and β 2 -receptors, with normal receptor affinity and normal lipolytic action of agonists acting at postadrenoreceptor steps in the lipolytic cascade , ; this is associated with enhanced β 3 -adrenoreceptor sensitivity, which usually reflect changes in receptor number in comparison with subcutaneous adipocytes , Comparison of lipolysis, antilipolysis, and lipogenesis in omental and subcutaneous fat in nonobese and obese individuals.

Adipocytes from obese subjects generally show increased lipolytic responses to catecholamines, irrespective of the region from which they are obtained, and enhanced lipolysis in abdominal compared with gluteo-femoral fat 21 , The antilipolytic effect is also reduced in vitro in obesity, both in omental and subcutaneous adipocytes The typical features of visceral fat, e.

An increased β 3 -adrenoreceptor sensitivity to catecholamine stimulation may lead to an increased delivery of FFA into the portal venous system, with several possible effects on liver metabolism. These include glucose production, VLDL secretion, and interference with hepatic clearance of insulin , resulting in dyslipoproteinemia, glucose intolerance, and hyperisulinemia.

Lönnqvist et al. They observed that males had a higher fat cell volume with no sex differences in the lipolytic sensitivity to β l - and β 2 -adrenoreceptor-specific agonists or in the antilipolytic effect of insulin. However, the lipolytic β 3 -adrenoreceptor sensitivity was 12 times higher in men, and the antilipolytic α2-adrenoreceptor sensitivity was 17 times lower in men.

It was concluded that in obesity, the catecholamine-induced rate of FFA mobilization from visceral fat to the portal venous system is higher in men than women.

This phenomenon is partly due to a larger fat cell volume, a decrease in the function ofα 2-adrenoceptors, and an increase in the function of β 3 -adrenoreceptors. These factors may contribute to gender-specific differences observed in the metabolic disturbances accompanied by obesity, i.

Glucocorticoid receptors. Glucocorticoid receptors, one of the most important receptors for human adipose tissue function, are involved in metabolic regulation and distribution of body fat under normal as well as pathophysiological conditions.

Glucocorticoid receptors in adipose tissue show a regional variation in density with elevated concentrations in visceral adipose tissue In spite of the lower receptor density, the elevated cortisol secretion results in clearly increased net effects of cortisol.

Androgen and estrogen receptors. Adipocytes have specific receptors for androgens, with a higher density in visceral fat cells than in adipocytes isolated from subcutaneous fat.

Unlike most hormones, testosterone induces an increase in the number of androgen receptors after exposure to fat cells , thereby affecting lipid mobilization. This is more apparent in visceral fat omental, mesenteric, and retroperitoneal because of higher density of adipocytes and androgen receptors, in addition to other factors However, at variance with the effects of testosterone, dihydrotestosterone treatment does not influence lipid mobilization In females, there is an association between visceral fat accumulation and hyperandrogenicity, despite the documented effects of testosterone on lipid mobilization and the expected decrease in visceral fat depots.

The observation that visceral fat accumulation occurs only in female-to-male transsexuals after oophorectomy suggests that the remaining estrogen production before oophorectomy was protective The androgen receptor in female adipose tissue seems to have the same characteristics as that found in male adipose tissue.

However, estrogen treatment down-regulates the density of this receptor, which might be a mechanism whereby estrogen protects adipose tissue from androgen effects. Estrogen by itself seems to protect postmenopausal women receiving replacement therapy from visceral fat accumulation Estrogen receptors are expressed in human adipose tissue and show a regional variation of density, but whether the quantity of these receptors is of physiological importance has not been clearly established With regard to progesterone, adipose cells seem to lack binding sites and mRNA for progesterone receptors, indicating that progesterone acts through glucocorticoid receptors GH receptors.

While it is well established that GH has specific and receptor-mediated effects in adipose tissue of experimental animals, the importance of GH receptors in human adipose tissue is not fully elucidated at present although the available data indicate a functional role.

However, GH is clearly involved in the regulation of visceral fat mass in humans. Acromegaly, a state of GH excess, is associated with decreased visceral fat while in GH deficiency there is an increase in visceral fat and in adults with GH deficiency, recombinant human GH replacement therapy results in adipose tissue redistribution from visceral to subcutaneous locations; however, the regulation of adipose tissue metabolism requires synergism with steroid hormones A direct demonstration of a regulation of the GH receptor in human fat cells has not yet been performed Thyroid hormone receptors.

Thyroid hormones have multiple catabolic effects on fat cells as a result of interactions with the adrenergic receptor signal transduction system, and most of these interactions are also present in human fat cells There are data regarding the characterization of the nuclear T 3 receptor in human fat cells Although receptor regulation has not yet been demonstrated, there is little doubt that the thyroid hormone receptors are important for the function of human adipose tissue Further, no data are available on the correlation between visceral fat mass and thyroid hormone levels.

Adenosine receptors. Adenosine behaves as a potent antilipolytic and vasodilator agent and can be considered as an autocrine regulator of both lipolysis and insulin sensitivity in human adipose tissue.

Site differences in ambient adenosine concentration, perhaps controlled by blood flow, may also modulate adipose tissue metabolism 7. Adenosine content is higher in omental than in abdominal subcutaneous adipose tissue, but the receptor-dependent inhibition of lipolysis is, as indicated before , less pronounced in the former than in the latter depot However, despite strong antilipolytic effect of adenosine analogs, human adipocytes contain few adenosine type A l receptors, regardless of the fat depot considered According to Arner , the α2-, β l -,β 2 -, and β 3 -adrenoreceptors and receptors for insulin, adenosine, and glucocorticoids, as well as for PGE 2 , a potent antilipolytic agent with high affinity receptors identified in adipocytes , have a major functional role, as shown by relevant biological receptor-mediated effects, the presence of a receptor molecule, and receptor regulation.

The receptors for GH, thyroid hormones, estrogen, and testosterone, as well as for acetylcholine and TSH, probably have an important functional role but complete evidence, indicated in the previous group of receptors, is not present so far; however, there is little doubt of a regulatory role.

Genetic epidemiology: heritability and segregation analysis. Studies performed in individuals from families of French descent living in Quebec City [Quebec Family Study QFS ] allowed the estimation of the fraction of the phenotypic variance that could be attributed to the genetic and environmental factors among the obesity phenotypes or in the distribution of the adipose tissue, taking into account the BMI and amount of subcutaneous fat by the sum of the measurement of skinfolds in six different sites , lean body mass, fat mass, percentage of fat derived from underwater weighing, and visceral fat by CT , The residual variance corresponded to environmental factors, but some factors cultural, nongenetic could be transmitted from parents to descendents and sometimes were confounded by genetic effects Segregation analysis studies have recently concluded that visceral fat is similarly influenced by a gene with a major effect in the QFS and HERITAGE families , However, after adjustment of the visceral adipose tissue for the fat mass, the effect of the gene with the major effect was not more compatible with a mendelian transmission.

These results suggested the presence of a pleiotropism: the gene with the major effect, identified by the fat mass , could similarly influence the amount of visceral fat Similar results were obtained with the same type of analysis in the HERITAGE cohort To test the hypothesis of a genetic pleiotropism, Rice et al.

The results of this study Fig. These results have confirmed the presence of a genetic pleiomorphism and suggested the presence of genes affecting simultaneously the amounts of fat mass and visceral abdominal fat.

Schematic representation of the genetic effects on total fat mass and visceral fat adjusted for the fat mass and on the co-variation between the two phenotypes Quebec Family Study, G 1 and G 2 represent the genetic effects specific for the total fat mass and visceral fat, respectively.

E 1 and E 2 represent the specific effects of the environment on total fat mass and visceral fat, respectively. G 3 and E 3 indicate the genetic and environment effects common to both phenotypes.

Pérusse et al. The interactions of the effects of genotype and environment evaluated in monozygotic twins, when the energy balance is manipulated, indicated that even though there were large interindividual differences in the response to excess or negative energy balance, there was a significant within-pair resemblance in response 96 , In effect, in response to overfeeding, there was at least 3 times more variance in response between pairs than within pairs for the gains in body weight, fat mass, and fat-free mass In relation to the response to the negative energetic balance, at least 7 times more variation was observed in response between pairs than within members of the same pair of twins, with respect to the same variables This intrapair similarity in the response to either excess or deficient energy balance is also observed in relation to the abdominal visceral fat Thus, the interaction between genotype and environment is important to consider in the study of the genetics of obesity since the propensity to fat accumulation is influenced by the genetic characteristics of the subject.

Molecular genetics: association and linkage studies. Several candidate genes as well as random genetic markers were found to be associated with obesity as well as body fat and fat distribution in humans. The current human obesity gene map, based on results from animal and human studies, indicates that all chromosomes, with the exception of the Y chromosome, include genes or loci potentially involved in the etiology of obesity Initial findings from the QFS showed that significant but marginal associations with body fat were found with LPL and the α2-subunit of the sodium-potassium ATPase genes The Trp64Arg mutation of the β 3 -adrenergic receptor gene β 3 AR , prevalent in some ethnic groups, is associated with visceral obesity and insulin resistance in Finns as well as increased capacity to gain weight This mutation was also shown to be associated with abdominal visceral obesity in Japanese subjects, with lower triglycerides in the Trp64Arg homozygotes but not heterozygotes It has been suggested that those with the mutation may describe a subset of subjects characterized by decreased lipolysis in visceral adipose tissue.

On the other hand, Vohl et al. Previously, it was reported by the same group that apo-B gene Eco R-1 polymorphism appeared to modulate the magnitude of the dyslipidemia generally found in the insulin-resistant state linked with visceral obesity These studies are a demonstration of a significant interaction between visceral obesity and a polymorphism for a gene playing an important role in lipoprotein metabolism.

When the genes related to the hormonal regulation of body fat distribution studied in the QFS families sex hormone-binding globulin, 3β-hydroxysteroid dehydrogenase, and glucocorticoid receptor genes were considered along with the knowledge that body fat distribution is influenced by nonpathological variations in the responsiveness to cortisol, it was shown that the less frequent 4.

However, the association with abdominal visceral fat area was seen only in subjects of the lower tertile of the percent body fat level.

The consistent association between the glucocorticoid receptor polymorphism detected with Bcl I and abdominal visceral fat area suggested that this gene or a locus in linkage disequilibrium with the Bcl I restriction site may contribute to the accumulation of abdominal visceral adipose tissue With respect to the linkage studies, only a few studies of body fat or fat distribution with random genetic markers or candidate genes have been reported using the sibling-pair linkage method.

One of the few reported studies relative to the visceral fat mass was the evaluation of a sib-pair linkage analysis from the QFS between five microsatellite markers encompassing about 20 cM in the Mob-1 region of the human chromosome 16pp These results suggested to the authors that this region of the human genome contains a locus affecting the amount of visceral fat and lipid metabolism as also shown by the association studies indicated above.

The other population and intrafamily association study used a polymorphic marker LIPE in the hormone-sensitive lipase gene, located on chromosome 19q In conclusion, despite the fact that the genetic architecture of obesity has just begun, the results obtained so far suggest that a great number of genes, loci, or chromosomal regions distributed on different chromosomes could play a role in determining body fat and fat distribution in humans.

This reflects the complex and heterogeneous nature of obesity. The accumulation of adipose tissue in the abdominal region is at least partially influenced by genes, which becomes more evident as the number of involved genes are identified.

The concept that adipocytes are secretory cells has emerged over the past few years. Adipocytes synthesize and release a variety of peptide and nonpeptide compounds; they also express other factors, in addition to their ability to store and mobilize triglycerides, retinoids, and cholesterol.

These properties allow a cross-talk of adipose tissue with other organs as well as within the adipose tissue. The important finding that adipocytes secrete leptin as the product of the ob gene has established adipose tissue as an endocrine organ that communicates with the central nervous system.

As already mentioned, LPL is the key regulator of fat cell triglyceride deposition from circulating triglycerides. LPL is found, after transcytosis, associated with the glycosaminoglycans present in the luminal surface of the endothelial cells.

The regulation of LPL secretion, stimulated by the most important hormonal regulator, insulin, is related to posttranslational changes in the LPL enzyme, at the level of the Golgi cisternae and exocytotic vesicles, insulin possibly having a positive role in this secretory process Genes encoding LPL were not differentially expressed in omental when compared with subcutaneous adipocytes However, in very obese individuals omental adipocytes express lower levels of LPL protein and mRNA than do subcutaneous fat cells The regulation of LPL in obesity has been presented in the Section on correlations of abdominal visceral fat.

With respect to the hormonal regulation of LPL, insulin and glucocorticoids are the physiological stimulators of the LPL activity, and their association plays an important role in the regulation of body fat topography.

In effect, omental adipose tissue is known to be less sensitive to insulin, both in the suppression of lipolysis and in the stimulation of LPL However, when exposed to the combination of insulin plus dexamethasone in culture for 7 days, large increases in adipose LPL were observed because of increases in LPL mRNA Significant differences were observed between men and women.

The increase in LPL in response to dexamethasone suggests that the well known steroid-induced adipose redistribution especially in the abdomen may be caused by increases in LPL, which would lead to a preferential distribution of plasma triglyceride fatty acids to the abdominal depot.

Therefore, these data suggest that LPL is central to the development of abdominal visceral obesity On the other hand, catecholamines, GH, and testosterone in males reduce adipose tissue LPL Acylation-stimulating protein ASP.

ASP is considered the most potent stimulant of triglyceride synthesis in human adipocytes yet described. Its generation is as follows Human adipocytes secrete three proteins of the alternate complement pathway: C3 the third component of the complement , factor B, and factor D adipsin , which interact extracellularly to produce a amino-terminal fragment of C3 known as C3a.

Excess carboxypeptidases in plasma rapidly cleave the terminal arginine from C3a to produce the amino acid peptide known as C3a desarg or ASP, which then acts back upon the adipocyte, causing triglyceride synthesis to increase. As fatty acids are being liberated from triglyceride-rich lipoproteins and chylomicrons as the result of the action of LPL, ASP is also being generated and triglyceride synthesis increased concurrent with the need to do so.

In human adipose tissue, in the postprandial period, ASP secretion and circulating triglycerides clearance are coordinated in accordance with the suggestion that ASP in sequence to LPL would have a paracrine autoregulatory role. The adipsin-ASP pathway, therefore, links events within the capillary space to the necessary metabolic response in the subendothelial space, thus avoiding the excess buildup of fatty acids in the capillary lumen.

The generation of ASP is triggered by chylomicrons. While insulin decreases gene expression of C3, B, and adipsin, it enhances the secretion of ASP as expected from the concurrent action of LPL and ASP.

However, more intensely and independent of insulin, ASP is capable of stimulating triglyceride synthesis in adipocytes and fibroblasts.

Thus, from the reduced sensitivity to insulin in the suppression of lipolysis and stimulation of LPL by the omental adipose tissue, omental obesity may represent an example of impaired activity of the ASP pathway even if dysfunction of the pathway is a secondary feature.

As a consequence, omental adipose tissue, as compared with subcutaneous fat tissue, would have a limited capacity to prevent fatty acids from reaching the liver, which may contribute to the abnormalities in metabolism observed in visceral obesity Cholesteryl-ester transfer protein CETP.

Human adipose tissue is rich in CETP mRNA, probably one of the major sources of circulating CETP in humans. CETP promotes the exchange of cholesterol esters of triglycerides between plasma lipoproteins. In this way, the adipose tissue is a cholesterol storage organ in humans and animals; peripheral cholesterol is taken up by HDL species, which act as cholesterol efflux acceptors, and is returned to the liver for excretion , The few studies of circulating CETP in obesity have shown that activity and protein mass of CETP are both significantly increased in obesity, being negatively correlated with HDL cholesterol and the cholesteryl ester-triglyceride ratio of HDL2 and HDL3, thus exhibiting an atherogenic lipoprotein profile.

Furthermore, there was a positive correlation with fasting plasma insulin and blood glucose, suggesting a possible link to insulin resistance — From an observation of Angel and Shen , it could be suggested that the CETP activity of omental adipose tissue is greatly increased in comparison with subcutaneous fat.

Retinol-binding protein RBP. Adipose tissue is importantly involved in retinoid storage and metabolism. RBP is synthesized and secreted by adipocytes , the rate of RBP gene transcription being induced by retinoic acid The mRNA encoding RBP is expressed at a relatively high level in adipocytes with no difference between subcutaneous and omental fat cells There are no data regarding retinol mobilization from adipose stores in humans; however, in vitro studies with murine adipocytes showed that the cAMP-stimulated retinol efflux from fat cells was not the result of increased RBP secretion but instead due to the hydrolysis of retinyl esters by the cAMP-dependent hormone-sensitive lipase PAI-1 is a serine protease inhibitor and evidence suggests that it is a major regulator of the fibrinolytic system, the natural defense against thrombosis.

It binds and rapidly inhibits both single- and two-chain tissue plasminogen activator tPA and urokinase plasminogen activator uTPA , which modulate endogenous fibrinolysis. The major sources of PAI-1 synthesis are hepatocytes and endothelial cells, but platelets, smooth muscle cells, and adipocytes are also contributors The increased gene expression and secretion of PAI-1 by adipose tissue contribute to its elevated plasma levels in obesity, presenting a strong correlation with parameters that define the insulin resistance syndrome, in particular with fasting plasma insulin and triglycerides, BMI, and visceral fat accumulation: omental adipose tissue explants produced significantly more PAI-1 antigen than did subcutaneous tissue from the same individual, and transforming growth factor-βl increased PAI-1 antigen production In a premenopausal population of healthy women with a wide range of BMI, there was a positive correlation of PAI-1 activity with CT-measured visceral fat area, independent of insulin and triglyceride levels.

Weight loss confirmed this link. PAI-1 diminution was correlated only with visceral adipose tissue area loss and not with total fat, insulin, or triglyceride decrease Results from in vitro studies have shown that insulin — stimulates PAI-1 production by cultured endothelial cells or hepatocytes.

Attempts to extrapolate these in vitro data to in vivo proved difficult. Acute 2-h hyperinsulinemia modulation of plasma insulin in humans did not affect PAI-1 levels, and hypertriglyceridemia from several origins was not always associated with increased PAI-1 levels In the same way, exogenous short-term insulin infusion with triacylglycerol and glucose failed to demonstrate elevations of PAI-1 The augmentation of PAI-1 by insulin probably requires concomitant elevation of lipids and glucose and perhaps other metabolites in blood, as suggested by the strikingly synergistic effects when Hep G2 cells are exposed to both insulin and fatty acids in vitro Accordingly, a hyperglycemic hyperinsulinemic clamp associated with an intralipid infusion for 6 h, to induce hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia, produced an increase in PAI-1 concentrations in blood for as long as 6 h after cessation of the infusion However, the extent to which elevation of any one constituent or any given combination of elevations is sufficient to induce the phenomenon has not yet been elucidated in insulin-resistant patients.