Pulsatility Of Ffa Release

Oscillations in lipolysis have been described in omental tissue of dogs (57). Electrical stimulation of the sympathetic nerve endings stimulates lipolysis and FFA release from adipose tissue, whereas denervation reduces lipolysis. Studies in dogs (57), and more recently in humans (58), confirmed that the pulsatility of FFA release is linked to neuronal activity, as ^3-receptor blockade partly abrogated FFA and glycerol oscillations. Recently Karpe and colleagues confirmed pulsatility of FFA and glycerol release from subcutaneous depots in humans during euglycemic hyperinsulinemic clamps, thus demonstrating that the oscillations in fatty acid release are not dependent on insulin (59). Oscillations of plasma norepinephrine as an index of sympathetic nervous system activity were not well correlated with fluctuations in FFAs release (59).

The parasympathetic nervous system also participates in the release of FFAs, as demonstrated by Kreier et al., who showed that denervation of the peritoneal fat leads to decreased insulin-stimulated uptake of FFAs and glucose (60), and enhanced HSL activity. Finally, it has been suggested that oscillations are conserved in isolated adipocytes, suggesting cell-autonomous oscillations of FFA release (46). Glucose metabolism may participate in lipolytic oscillations ex vivo in rat adipocytes by generating fluctuations in LCFA-acylCoA, and oscillations are abolished in cases of glucose depletion (46,61). Additional studies are required to elucidate the mechanism involved in these oscillations and to determine their physiological significance.

Total Fat Mass and Regional Fat Depots: What are the Differences between these Fat Depots?

Because FFAs are released into the circulation by lipolysis of adipose tissue triglycerides in relation to the size of the fat depot, the greater overall fat mass of adipose tissue in obese individuals will result in an elevation of fatty acid flux to nonadipose tissues, even in the absence of a qualitative abnormality in adipose tissue metabolism (62). It is worth noting that not all fat depots make an identical contribution to the plasma pool of FFAs. Upper body fat (ie fat in the visceral and subcutaneous abdominal region), but not lower body fat is strongly associated with insulin resistance and increased risk of cardiovascular events (63-67) although the causal nature of this relationship and the relative importance of visceral versus subcutaneous abdominal fat (68,69) are still debated (70,71).

There are differences in lipolysis between visceral and subcutaneous fat, with visceral fat shown to have higher lipolytic activity and lower sensitivity to the antilipolytic action of insulin (71). Quantification of FFA fluxes using labeled FFA has suggested that postprandial FFA is derived mostly from nonsplanchnic areas, with only a small quantity from visceral adipose tissue, suggesting increased visceral adipose tissue as a marker rather than a cause of increased insulin resistance (72). On the other hand, FFAs released by visceral fat depots are delivered directly to the liver via the portal vein, resulting in greater FFA flux to the liver in viscerally obese individuals than in those with predominantly subcutaneous obesity, perhaps contributing to hepatic insulin resistance and enhanced gluconeogenesis. Along these lines, increased FFA elevation in dogs via portal venous delivery of an intravenous synthetic lipid emulsion and heparin impairs insulin action and clearance to a greater extent than systemic delivery (73).

Bergman and co-workers have recently shown that expression of genes involved in lipid accumulation and lipolysis (PPAR7, SREBP-1, HSL and LPL) were increased in visceral compared to subcutaneous fat in insulin-resistant fat-fed rats, suggesting an increased metabolic turnover of fatty acids in visceral fat (74). This effect may induce lipid delivery to, and deposition of fat in, the liver, because lipogenic as well as gluconeogenic programs were induced (74). In humans, a correlation was demonstrated between visceral adipose mass and hepatic FFA delivery (75). However, the same study also indicated that the contribution of viscerally released FFAs to the total liver delivery represented only 5-20% (75). The pathophysiological relevance of this small additional FFA supply from expanded visceral fat stores remains to be elucidated. Moreover, the contribution of subcutaneous adipose tissue has been poorly characterized, and further studies are required to resolve this issue. Of note however, total splanchnic blood supply increases postprandially (76) because of increased insulin and sympathetic activation after meals, as might the proportion of lipolysis from spanchnic versus subcutaneous fat. Thus, the contribution of visceral fat to hepatic FFA uptake and systemic FFA appearance could be more substantial in the postprandial than in the fasting state.

Fukuhara and coworkers have identified a new adipocytokine (77), which they named visfatin, previously identified as a growth factor for B-cells (or PBEF) (78). Visfatin is highly expressed in visceral fat compared to subcutaneous fat depots, and its expression increases during adipocyte differentiation and in obesity (77). These investigators further demonstrated that injection of recombinant visfatin or chronic adenoviral-mediated overexpression of this protein lowers plasma glucose and insulin levels in control and streptozotocin-induced or genetically induced (KKAy mice) models of diabetes. Moreover this protein is able to bind to the insulin receptor and mimic insulin action (77). Additional interest in visfatin has come from human studies showing that plasma visfatin levels are increased in type 2 diabetes (79). In addition, administration of the lipid lowering PPARa activator fenofibrate, or the insulin sensitizer PPAR7 ligand rosiglitazone, increased visfatin expression levels in OLETF rats (80). Some caution is advised, however, because no association was found between plasma visfatin levels in humans and parameters of insulin sensitivity or visceral fat mass calculated from computer-assisted tomography (81). The physiological role of visfatin still needs to be established, and further studies are necessary to determine whether it is indeed a marker of visceral fat accumulation or plays a causative role in the metabolic manifestations of insulin resistance or type 2 diabetes.

Impaired Adipose Tissue Trapping/Uptake of Fatty Acids (Fig. 2)

Uptake and sequestration of FFAs in adipose tissue, although promoting expansion of fat mass, can be viewed in a sense as a protective mechanism to prevent exposure of other tissues to excessive FFAs and their deleterious effects in situations of positive net energy balance (82). Lipoprotein lipase (LPL), anchored to the endothelial surface of capillaries in tissues such as skeletal muscle and fat, hydrolyzes TGs in the core of intestinally derived chylomicrons and hepatically derived VLDL particles. This process releases FFAs and glycerol into the local microcirculation, which must be rapidly and efficiently taken up and disposed of to prevent spillover of FFAs to nonadipose tissue with consequent lipotoxicity. In the fasting state, LPL activity is low in adipose tissue and higher in muscle, to respond to muscle energy requirements. Reciprocal changes occur in the fed state, contributing to the highly regulated partitioning of FFAs among tissues. Insulin has been shown to stimulate adipose tissue LPL activity and to reduce LPL activity in muscle, implying a preferential postprandial partitioning of lipoprotein-derived fatty acids towards adipose tissue and away from muscle (83). After a meal, trapping of LPL-derived FFAs in subcutaneous fat increases from near zero to near maximal uptake within 1h, whereas FFA released by muscle LPL are taken up continuously (84). Although adipose tissue of lean individuals can efficiently switch from a negative to a positive FFA balance during the transition from fasting to the postprandial state, the adipose tissue FFA balance remains negative postprandially in insulin-resistant obese individuals, despite the presence of hyperinsulinemia (85). Lean, glucose tolerant relatives of patients with type 2 diabetes have an increase in postprandial glucose and triglyceride excursion, and less suppression of plasma FFA, following a mixed meal, compared with matched control subjects without a family history of diabetes (32). In obesity and type 2 diabetes, insulin activation of LPL in adipose tissue is delayed and LPL activity in skeletal muscle is increased instead of decreased by hyperinsulinemia (70,86). The importance of LPL in tissue FFA uptake has recently been demonstrated by experiments in which either muscle-specific or liver-specific overexpression in mice induces marked tissue lipid accumulation in either muscle or liver, respectively, with consequent insulin resistance developing in the affected organ (87). Although LPL may be viewed as a first step leading to the uptake of FFA by adipose tissue, it is clear that the deposition of FFA is also regulated downstream of LPL (88). Endothelial lipase (EL), a more recently discovered lipase with sequence homology to LPL and predominant phospholipase A2 activity, may also participate in FFA uptake, as demonstrated in LPL-deficient mice (89).

Once taken up by the cell, FFAs are esterified, a process which is dependent on the supply of glycerol-3-phosphate derived from insulin-mediated glucose uptake by the adipocyte, which is diminished in insulin resistance (90). Impaired disposal of fatty acids taken up by adipocytes will have the effect of inhibiting further uptake of fatty acids along the concentration gradient among plasma, extracellular, and intracellular fluid (91). Less is known about insulin stimulatory effects on esterification enzymes than is known about its effects on LPL, but insulin may directly stimulate the enzyme that catalyzes the final step in triglyceride synthesis, acyl coenzyme A:diacylglycerol acyltransferase (DGAT) (92,93). Riemens et al. have suggested that the main abnormality of fatty acid trapping is an elevated rate of escape of FFAs from esterification in adipose tissue (91).

The question as to whether the transport of FFA into cells occurs through a passive diffusion process or by a facilitated mechanism involving fatty acid transport protein (FATP) remains controversial. Both processes are probably involved, although their relative importance may vary as a function of free albumin-bound FFAs versus lipoprotein-packaged TG availability (94,95). In the adipocyte, aP2 may interact with HSL to facilitate FFA binding (96). The "scavenger" receptor CD36/FAT is a fatty acid receptor/transporter, with particular abundance in adipose tissue, heart, and skeletal muscle, but with low expression in kidney and liver (97). A deficiency of CD36 has been associated with functionally significant impairment of intracellular FFA transport (98,99). Furthermore, transgenic expression of CD36 in hypertensive SHR rats ameliorates insulin resistance and lowers serum FFAs (100), perhaps by improving FFA uptake in adipose tissue. Muscle-specific CD36 overexpression in mice reduces body fat and lowers serum FFAs and VLDL triglycerides, but results in elevated plasma glucose and insulin, suggesting that these mice are insulin resistant (101). One may speculate that the increased FFA uptake and oxidation in muscle tissues of these animals impairs muscle glucose utilization, thereby inducing insulin resistance in a fashion analogous to that seen in mice with muscle-specific LPL overexpression (87). Amelioration of insulin resistance has been seen after muscle CD36 overexpression in diabetic mice (102). In contrast, the uptake of fatty acids by heart, skeletal muscle, and adipose tissues from CD36 null mice is markedly reduced (by 50-80%), whereas that of glucose is increased several fold (103). CD36 deficiency is present in 2-3% of the

Japanese population, and recent evidence suggests that it may be associated with insulin resistance, dyslipidemia (104), and reduction in myocardial uptake of FFA tracers in vivo (105).

Fatty acid trapping is also regulated by acylation stimulating protein (ASP), a proteolytic cleavage product of the third component of complement (C3). ASP production is upregulated by insulin and by chylomicrons (106). Fasting ASP correlates with postprandial TG clearance (107). Postprandially, ASP is produced by adipose tissue, where it stimulates adipocyte fatty acid esterification by increasing the activity of diacylglycerol acyltransferase through a protein kinase C (PKC)-dependent pathway (108). There is controversy in the literature regarding the physiological importance of ASP in controlling postprandial lipoprotein metabolism, because some (109) but not others (110) have described abnormalities of postprandial lipoprotein metabolism in ASP null mice. ASP exerts additional activities, as it increases glucose uptake in human adipocytes, decreases FFA release from those cells, and has a lipogenic effect (1).

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