Individuals with peripheral obesity possess fat distribution subcutaneously in glu-teofemoral areas and the lower part of the abdomen, and are at little risk of metabolic complications, such as NIDDM. Conversely, individuals with upper-body obesity accumulate fat in subcutaneous and visceral deposits and are more susceptible to metabolic problems, in particular when visceral fat deposits are abundant. Visceral fat deposits, located in the body cavity, are composed of the omental and mesenteric fat, and comprise the minor component of total body fat, representing ~ 20% and ~ 5-8% of total body fat in men and women, respectively. In upper-body obesity, fat excess is present in the visceral abdominal regions but also in the subcutaneous abdominal regions. There are several explanations but no clear proof why upper-body obesity is more at risk of developing metabolic disease than lower-body obesity . Since the visceral deposit is in direct contact with the liver through the portal circulation and considering the alterations of hormonal control of lipolysis of its adipocytes (insulin vs. catecholamines, see below), the "portal paradigm" was postulated on the basis that visceral adipocytes, through enhancement of lipolysis due to both reduced insulin-induced anti-lipolysis and enhanced catecholamine-induced lipolysis, will release portal NEFA that disturb liver metabolism . Chronic NEFA excess will in turn lead to glucose intolerance, hyperinsulinemia, insulin resistance and dyslipidemia. However, experimental evidence is accumulating that non-visceral upper-body fat rather than visceral fat deposits is the predominant source of excess postprandial systemic NEFA availability in upper-body obese women and NIDDM patients [501, 502]. This raises the question as to whether the extent of visceral fat just represents another marker of ectopic fat distribution (i.e. fat present at the wrong place in tissues such as muscle, heart, liver and pancreatic /5-cells). Alternatively, visceral adipocytes may possess properties that could be the origin of metabolic disturbances. In fact, striking adipose-location-related differences have been reported in adipocyte responsiveness to insulin and catecholamines. Moreover, differences have been described in the characteristics of various biochemical pathways regulating TAG storage and mobilization between subcutaneous and visceral fat deposits (Tab. 11.2).
In detail, adipocytes from visceral adipose tissue are more resistant to insulin-induced anti-lipolysis and re-esterification of NEFA than those from leg and non-visceral body fat both in vitro [503, 504] and in vivo . Various functional differences in these cells have been identified at the level of the insulin receptor and the post-receptor insulin signaling cascade [503, 504]. PDE3B involved in lipolysis regulation by insulin (see above, Fig. 11.7) and protein tyrosine phosphatases de-phosphorylating the insulin receptor, such as PTP1b, could be affected in differen-
Tab. 11.2 Differences in the regulation ofTAG mobilization and storage between fat cells from visceral (vAT) and subcutaneous adipose tissue (scAT). The extent of some of these differences depends on the adipocyte hyperplasie (total fat mass) and hypertrophy as well as on the sex. Adapted from Ref.  with modifications (see  for references).
Effects and factors
TAG mobilization ^¿-Adrenoceptor number jS-Adrenoceptor-dependent stimulation ofTAG mobilization
Isoproterenol-induced stimulation of AC
Basal rat of lipolysis
HSL protein level and activity
ALBP mRNA and protein levels
Leptin mRNA and protein secretion
TAG Storage a2-Adrenoceptor number a2-Adrenoceptor-dependent inhibition of TAG storage Insulin receptor expression (exon 11 deleted) IRS-1 mRNA and protein levels
Insulin-induced insulin receptor tyrosine phosphorylation
Insulin-induced IRS-1 tyrosine phosphorylation
Insulin-induced PI3K activation
ASP mRNA levels
LPL mRNA and protein levels
FA Transport by human preadipocytes vAT > scAT vAT > scAT scAT=vAT scAT > vAT scAT > vAT scAT > vAT scAT > vAT vAT=scAT
scAT > vAT scAT > vAT vAT > scAT scAT > vAT scAT > vAT scAT > vAT scAT > vAT vAT > scAT scAT > vAT scAT > vAT scAT > vAT
tial fashion in visceral vs. subcutaneous adipocytes. This concurs with the endogenous PTP1b activity found to be elevated in visceral adipose tissue and might contribute to the relative insulin resistance of this fat deposit . Exacerbating the impairment of insulin inhibition of lipolysis, the lipolytic response toward cate-cholamines is more pronounced in isolated adipocytes from visceral adipose tissue than from subcutaneous gluteal, femoral and abdominal adipose tissue . This higher lipolytic activity can be explained by altered expression or function of HSL (increase) and/or proteins interacting with either HSL, such as ALBP (increase), or the LD, such as perilipin (decrease) (see above, Fig. 11.6). An enhanced a2-adrenoceptor responsiveness associated with a concomitant decrease in /5-adre-noceptor responsiveness explains the lower lipolytic effect of catecholamines in gluteal and femoral adipocytes of normal and obese women and abdominal adipo-cytes of obese men compared with visceral adipocytes. Conversely, visceral adipocytes exhibit the highest /512-adrenoceptor-mediated and the weakest a2-adrenocep-tor-mediated lipolytic and anti-lipolytic responsiveness, respectively, to catecholamines, which seems to correlate with decreased expression of ^-adrenoceptors and concomitantly increased expression of ^-adrenoceptors [508, 509]. In obese subjects, unrestrained lipolysis leads to excessive NEFA release from visceral hy-
pertrophied adipocytes and may prevent their further enlargement in contrast to subcutaneous adipocytes, which actually represent the largest ones. The search for adipose tissue-specific local differences in the expression of genes that regulate the differentiation and expansion of adipose tissue as well as the regulation of TAG storage and mobilization is underway using genomic and proteomic approaches.
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