Regulation of plasma fatty acid metabolism

Regulation of plasma fatty acid metabolism

Clinica Chimica Acta 286 (1999) 163–180 Regulation of plasma fatty acid metabolism Jumana Saleh, Allan D. Sniderman, Katherine Cianflone* Mike Rosenb...

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Clinica Chimica Acta 286 (1999) 163–180

Regulation of plasma fatty acid metabolism Jumana Saleh, Allan D. Sniderman, Katherine Cianflone* Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, Montreal, PQ , Canada H3 A 1 A1 Received 21 December 1998; accepted 25 March 1999

Abstract Although adipose tissue serves a crucial function in energy storage, excess adipose tissue – that is, obesity – is often associated with diabetes and cardiovascular disease. A common thread in the weave of complications is increased plasma concentrations of fatty acids. In the present review, we have focused on two specific points that relate to obesity: (i) What are the metabolic consequences of increased free fatty acid concentrations? and (ii) What are the physiological factors that are involved in the regulation of fatty acid uptake or release from adipose tissue? We have tried to emphasize new factors that act as hormones on adipose tissue and in so doing regulate the net concentration of circulating free fatty acids.  1999 Elsevier Science B.V. All rights reserved.

1. Introduction The main function of adipose tissue is to store and release energy in the form of fatty acids. The body’s supply of fatty acids originate from the diet or through endogenous fatty acid synthesis, primarily in the liver. Fatty acids are chains of hydrocarbon groups attached to a carboxyl group. They vary in chain length and saturation and can be nonessential or essential (unable to be synthesized within the body). Oxidation of fatty acids is our major metabolic source of energy to *Corresponding author. Tel.: 1 1-514-842-1231; fax: 1 1-514-982-0686. E-mail address: [email protected] (K. Cianflone) 0009-8981 / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0009-8981( 99 )00099-6


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support our biological survival. Dietary fatty acids are esterified to form triglyceride (TG), and assembled into large lipoprotein particles (chylomicrons), secreted from intestinal cells into the lymph and from there enter the general circulation. Triglyceride rich VLDL are assembled in a similar manner in the liver and secreted from there into the general circulation. Both of these triglyceride rich particles (chylomicrons and VLDL) are substrates for the lipolytic action of lipoprotein lipase as they pass through the capillary space (Fig. 1). Energy in excess of the body’s needs is assimilated by fat cells in the form of fatty acids and stored as triglycerides in lipid droplets. Upon demand, intracellular triglyceride stores are hydrolysed by the action of hormone sensitive lipase to release free fatty acids that are transported to different tissues and oxidized to generate energy (Fig. 1), [1]. The balance between lipogenesis (TG storage) and lipolysis (TG breakdown) in adipocytes is of critical importance and regulation of these processes is under complex hormonal and neuronal influence. Dysregulation of the lipogenesis-lipolysis balance in adipose tissue leads to significant metabolic complications. A positive imbalance between storage and utilization leads to obesity in which

Fig. 1. Adipose tissue extracellular free fatty acid (FFA) concentrations are influenced by (i) intracellular hormone-sensitive lipase hydrolysis of storage triglyceride (TG); (ii) lipoprotein lipase lipolysis of triglyceride rich lipoproteins, (chylomicrons and VLDL); and (iii) fatty acid uptake and esterification in adipose tissue to form storage TG.

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there are increased numbers (hyperplasia) as well as increased size (hypertrophy) of adipocytes. Obesity is a major health problem associated with serious complications and, in humans, is generally divided into (i) subcutaneous obesity (female type or gynoid obesity) which is characterized by an accumulation of fat under the skin, especially in lower body parts; and (ii) omental (male type or android obesity) which is characterized by the accumulation of fat within the omentum [2]. Many studies have investigated the regional variations in adipocyte morphology and the relation to metabolic profiles and disease. The first scientific evidence that showed a link between abdominal body fat distribution and disease was provided by Vague et al. [3]. Since then, many studies have shown that abdominal obesity, particularly excess visceral (or omental) fat, is associated with a series of metabolic complications including abnormal glucose metabolism [4,5], hyperinsulinemia [4], familial combined hyperlipidemia [6], increased VLDL and small dense LDL production [7], all of which are associated with cardiovascular disease and diabetes [8]. A common underlying feature of these subjects is an increase in circulating free fatty acid levels [9–11]. This has been demonstrated in many studies exemplified by those of Despres and colleagues [8,12], as summarized in a number of reviews [13].

2. Consequences of increased fatty acid The concentration of plasma fatty acids may be regulated by the utilization or release of fatty acids by a number of tissues such as adipose tissue, muscle and liver. In the present discussion, we will focus on the regulation of fatty acid storage and release by the adipose tissue as one factor which can influence net plasma fatty acid concentrations. Nonetheless, regardless of the cause of increased plasma fatty acids, the consequence is significant perturbations at the level of many tissues. At the immediate site of generation of fatty acids, that is on the endothelial cell surface where lipoprotein lipase is located, high levels of free fatty acids can inhibit lipoprotein lipase activity through product inhibition [14], interfere with interaction of lipoprotein lipase with its cofactor apoCII [15], or dislodge lipoprotein lipase from its endothelial cell anchorage in adipose tissue and muscle [16]. Consequently postprandial TG clearance may be delayed. The increased circulating fatty acids (FFA) also affect liver, muscle, pancreas, arterial wall and adipose tissue. Many in vitro studies have shown that increased hepatic availability of circulating FFA and partially hydrolyzed chylomicrons will result in enhanced production of apoB lipoproteins [17,18]. The net result is an increase in VLDL and LDL production and increased plasma LDL, and therefore an increased risk for atherosclerosis. In addition, fatty acids stimulate hepatic glucose production [13] and modulate gene expression in positive or


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negative ways of enzymes such as fatty acid synthase, acetyl CoA carboxylase, malic enzyme, pyruvate kinase and PEPCK [19–21]. The increased fatty acids interfere with insulin extraction by the liver [5] and stimulate secretion of other factors by the liver such as plasminogen activator inhibitor (PAl-I) [22]. In muscle, increased plasma FFA also interfere with normal glucose utilization in several ways. An increased flux of fatty acids decreases muscle glycogen synthase [13] and increases muscle triglyceride stores [23], thereby reducing glucose oxidation. Whether these effects are accompanied by increased or decreased fatty acid oxidation is controversial [23,24]. In some cases, no change in fatty acid oxidation has been noted in obese vs. normal subjects [25]. The reduction in glucose utilization and the reduced insulin stimulation of glucose transport and uptake into this tissue are associated with increases in both plasma glucose and insulin (insulin resistance) [5,12]. Can this be a direct result of increased fatty acid levels? In fact, these same physiological consequences which are termed ‘‘insulin resistance’’ when plasma glucose remains within the normal range can be generated experimentally in vivo by administering infusions of fatty acids which results in both increased insulin levels and decreased muscle glucose uptake [26]. Fatty acids can also affect the pancreas by promoting insulin secretion [13] and, with chronic exposure, lead to beta cell apoptosis [27]. Within the arterial wall, fatty acids have been shown to promote the growth of smooth muscle cells [28,29] and the activation of T lymphocytes [30], both processes involved in the development of atherosclerosis. Finally, in adipose tissue, fatty acids serve as more than just a substrate for triglyceride synthesis. For example, fatty acids directly increase glycerol-3phosphate acyltransferase activity which enhances triglyceride storage [31]. At the same time, fatty acids can also interfere with insulin stimulated glucose transport [32,33], even though there is no effect on insulin stimulated glycogen synthesis [32]. Fatty acids have a profound influence on adipocyte membrane composition [33], gene regulation [19,20], and adipocyte differentiation [31]. These effects are mediated by specific fatty acids themselves (polyunsaturated fatty acids, arachidonic acid), or via molecules which are derived from fatty acids (as described below). These effects may be transduced in part through direct interaction with PPARs (peroxisome proliferator activated receptors), which are members of the steroid / thyroid nuclear receptor superfamily of ligand activated transcription factors [31]. The gamma isotype (PPARg) is mainly expressed in adipose tissue and appears to play a critical role in adipocyte differentiation and lipid storage [31]. Although the identification of native PPAR ligands is still underway, both fatty acids and eicosanoids (such as PGJ 2 ) have been identified as potential PPAR activators [34,35]. Fatty acids are precursors for other cellular effectors such as lysophosphatidic acid, prostaglandins and arachidonic acid which, in turn, can affect both cell

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differentiation and lipolysis [36]. Phosphoinositolglycan-peptide (PIG-P), isolated from insulin sensitive tissue, has been demonstrated to exert partial insulin like effects on glucose and lipid metabolism. Treatment of rat adipocytes with PIG-P as well as with other agents that have partial insulin-mimetic activity, such as phosphatidyl inositol-specific phospholipase C and sulfonylurea glimepiride, trigger protein tyrosine phosphorylation which correlates with stimulation of lipogenesis and TG storage in adipose tissue [37]. Fatty acids also have potent regulatory effects on key adipocyte enzymes and secreted hormones. Fatty acids stimulate the secretion of angiotensin II [38] and leptin [26,39] by adipocytes. Of note, dietary lipoproteins (chylomicrons) increase the production of acylation stimulating protein (ASP) from adipocytes both in vitro and in vivo [40–42]. Thus the consequences of increased circulating fatty acids are many and result in metabolic changes which promote increased obesity, insulin resistance and hyperlipidemia.

3. Causes of increased plasma fatty acids Many studies have been performed in order to understand the basic mechanisms regulating fatty acid movement into and out of adipose tissue, the major TG storage site (Fig. 1). The size of the extracellular pool of fatty acids is a balance between (i) the rate of intracellular lipolysis by hormone sensitive lipase and release of fatty acids from the cells; (ii) lipoprotein lipase hydrolysis (independent of cellular fatty acid uptake); and (iii) adipose tissue FFA uptake and esterification of fatty acids. Each of these three aspects is discussed below. Firstly, many studies have demonstrated increased hormone-stimulated lipolysis in omental adipocytes as compared to subcutaneous adipocytes (for review see [43–46]). However, the basal (unstimulated) lipolytic rate is, in fact, lower in omental than subcutaneous adipocytes. Furthermore, in vitro studies have shown that the maximum lipolytic rate of glycerol release following adrenergic stimulation was higher in subcutaneous than in omental fat cells and this was parallelled by increases in hormone sensitive lipase activity and mRNA expression [47]. However, unlike other fat depots, omental fat tissue has direct access to the liver through the portal vein and the metabolic complications that accompany excess visceral fat may reflect direct fatty acid input to the liver. Secondly, the general view that lipoprotein lipase is the rate limiting step that determines the rate of hydrolysis of plasma triglyceride and consequently uptake of free fatty acid by fat cells was re-examined by Olivecrona and colleagues [48]. They showed that the amount of lipoprotein lipase appears to be in excess of normal requirements and thus not rate limiting [48]. In addition, the correlation between plasma triglyceride clearance and lipoprotein lipase activity was poor [48,49]. Although lipoprotein lipase is essential for efficient clearance


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of plasma triglycerides and normal adipose tissue composition, other factors may also be important determinants of TG clearance such as tissue uptake and esterification of free fatty acids.

4. Basal fatty acid esterification: influence of size, sex and site Fatty acid cellular uptake and intracellular fatty acid esterification to triglyceride are two tightly coupled processes. Fatty acid uptake itself (independent of esterification) is regulated by differentiation [50], is variable in different adipose tissue sites [51], and is influenced by the presence or absence of ap2, the adipocyte fatty acid binding protein [52]. Studies have shown that fatty acid incorporation into adipose tissue (FIAT) increases linearly with increasing concentrations of a physiological spectrum of fatty acids in vitro [53]. FIAT and glucose (GLIAT) incorporation activities per cell were positively correlated with fat cell diameter but not fat cell number [54]. The basal capacity to synthesize triglyceride in a mature adipocyte is not only influenced by cell size but also by the sex of the donor as well as the site of sampling. For example, in fat tissue from morbidly obese patients, triglyceride synthesis in subcutaneous adipose tissue from women had higher triglyceride synthetic capacity compared to omental tissue and was greater than the triglyceride synthesis in both adipose tissue depots in males [55]. It is true that subcutaneous adipocytes are larger than omental adipocytes [56], and since larger cells appear to have greater triglyceride synthetic capacity than smaller cells [55] these differences may simply be a function of cell size. However, even in preadipocytes which have not yet differentiated to contain a triglyceride droplet, in vitro studies showed that basal triglyceride synthesis was greater in subcutaneous than omental preadipocytes [57]. Studies also suggest a major role of sex steroids in determining the anatomical distribution of fat. Their function may be exerted through both androgen and estrogen receptors which have been demonstrated recently on adipose tissue [58]. The level of androgen receptors in omental tissue is twice as high as in subcutaneous preadipocytes [58]. Testosterone inhibits lipoprotein lipase activity but can stimulate hormone sensitive lipolysis markedly [46,58], and this may enhance fatty acid release in male omental tissue. Female sex steroids (estrogens) appear to have similar effects to testosterone [45,46]. On the other hand, progesterone inhibits lipolysis by decreasing cAMP levels probably mediated through phosphodiesterase IV [59] and counteracts the stimulatory effect of estrogen. The anti-lipolytic effect of insulin also appears to be greater in women than in men [60].

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5. Insulin and catecholamines as regulators Both insulin and catecholamines have long been recognized to have profound influences on lipolysis / lipogenesis and these effects have been reported widely [43,44,61–65]. Insulin activates phosphodiesterase, reducing the intracellular levels of cAMP, thus reducing the activation of hormone sensitive lipase. Insulin increases glucose transport through its effects on translocation of Glut 4 [66] and has direct, although less marked, effects on the triglyceride synthetic enzymes [67] as well as lipoprotein lipase [68]. Since insulin is an effective lipogenic factor, could it play a role in enhancing obesity? Although obesity is often associated with insulin resistance, nonetheless, it is evident that fat storage is still effective in obese and insulin resistant subjects. Arner et al. studied the anti-lipolytic effect of insulin in obese subjects. There was no change in insulin responsiveness or sensitivity compared to the normal controls. When the obese subjects were divided into hyperinsulinemic and normal fasting serum insulin levels, a similar anti-lipolytic effect of insulin was observed in both groups [69]. However, other studies have suggested that there is a decrease in insulin responsiveness in fat cells from obese subjects [70]. The second well known lipolytic regulators are norepinephrine / epinephrine. Their effects on hormone sensitive lipase mediated release of fatty acids have been extensively studied. The effects appear to be mediated through interaction with a number of adrenergic receptors: b1, b2, al and a2 receptors. Recently, however, a new member of this family, the b3 receptor has been described. Although this receptor appears to be specific to fat tissue [44], it appears to play a minor role in stimulation of overall lipolysis [63]. The variable expression of these multiple receptors on adipose tissue from different depots will influence the overall response to a lipolytic stimulus.

6. Lipolysis and lipogenesis: new regulators There are a number of recently described endocrine and autocrine factors that are emerging as additional potential regulators of lipid turnover in adipocytes. Several of them exert pronounced effects in vitro on lipolysis or lipogenesis and their effects may vary significantly in different adipose depots. For the purposes of this discussion, in the references indicated, lipolysis is measured experimentally as the mass of fatty acid or glycerol released from adipose tissue or by increases in hormone sensitive lipase activity or mRNA. Lipogenesis is measured as radio-labelled glucose or fatty acid incorporation into intracellular triglyceride, increases in fatty acid synthesis or glucose transport, increases in activity or mRNA of any of the enzymes or transporters inherent to these


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Table 1 Endocrine and autocrine hormones which influence lipolysis Endocrine



Adenosine Testosterone Estrogen Progesterone Growth hormone Neuropeptide Y Prostaglandins

⇓ ⇑ ⇓ ⇓ ⇑ ⇑ ⇓ ⇑ ⇓ ⇓

activates PDE (decreases cAMP), inhibits HSL activates b1, b2, b3, al receptors, activates HSL (OM d . SC e) activates a2 receptors, inhibits HSL (OM . SC) inhibits lipolysis (SC . OM) interacts with androgen receptor, increases lipolysis interacts with estrogen receptors, increases lipolysis (OM . SC) decreases lipolysis and cAMP by increasing PDE (type IV) interacts with growth hormone receptor (OM . SC) decreases lipolysis (SC 5 OM) inhibits lipolysis (SC . OM)

[62,63,103] [43] [58] [45,48] [50] [48,71] [73,104] [43,105]

Autocrine TNFa f NO g Leptin Agouti

⇑ ⇑ ⇑ ⇓

increases lipolysis increases lipolysis increases lipolysis decreases lipolysis

[74] [75,76] [77–79] [80]

Insulin NE/EP c





PDE: phosphodiesterase. HSL: hormone sensitive lipase. c NE / EP: Norepinephrine / epinephrine. d OM: omental. e SC: subcutaneous. f TNFa: tumor necrosis factor a. g NO: nitric oxide. b

processes (including lipoprotein lipase), or by an increase in cell fat content. A summary of endocrine and autocrone factors and their effects on lipolysis and lipogenesis is described in Tables 1,2 respectively. As described above, factors known to influence lipolysis include insulin, catecholamines and sex hormones such as estrogen, testosterone and progesterone. Growth hormones [46,71] also increase lipolysis and growth hormone receptors are present at a higher density in omental tissue vs. subcutaneous depots [45]. In addition to insulin, prostaglandins and adenosine also inhibit lipolysis and have greater effects in subcutaneous compared to omental adipose tissue [43]. Finally, neuropeptide Y, in addition to its neuronal effects, has been shown to have direct peripheral effects and also inhibits lipolysis equally in both subcutaneous and omental adipose tissue [72,73]. Within the adipocyte itself, several secreted autocrine regulators of lipolysis have been described. These include TNFa [74], NO [75,76] and leptin [77–79], all of which stimulate lipolysis. Agouti, by contrast, inhibits lipolysis [80]. Factors that influence lipogenesis have been studied less intensely. In addition to its anti-lipolytic activities, insulin is known to be a major lipogenic hormone (as described above). However, new factors are regularly being proposed as

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Table 2 Endocrine and autocrine hormones which influence lipogenesis Endocrine



Testosterone Estrogen Growth hormone

⇓ ⇓ ⇓

Cortisol DHEAe GLP-1 f

⇑ ⇓ ⇑ ⇑

Autocrine ASP g

Angiotensin II

TNFa h NO i Leptin Agouti

⇓ ⇓ ⇓ ⇑

Ref. a


increases LPL (SC ), increases glucose transport (GLUT 4 c), increases fatty acid esterification interacts with androgen receptor, inhibits lipoprotein lipase interacts with estrogen receptor, inhibits lipoprotein lipase interacts with growth hormone receptor (OM d . SC), inhibits insulin stimulated lipogenesis, decreases fat content increases lipoprotein lipase decreases fatty acid synthase increases lipoprotein lipase increases lipoprotein lipase, fatty acid incorporation, enhances insulin effect on glucose uptake & lipid synthesis (decreases cAMP) increases fatty acid incorporation and glucose transport in adipocytes and muscle cells, additive to insulin increases triglyceride content, fatty acid synthase, glycerol-3-phosphate acyltransferase decreases lipogenesis decreases insulin mediated glucose uptake decreases lipid synthesis (acetyl CoA carboxylase) increases mRNA fatty acid synthase, additive to insulin

[66–68] [48,58] [45] [71] [45,48,71] [81] [82,83]

[93] [87,88] [85] [86] [84,85] [80,89]


LPL: lipoprotein lipase. SC: subcutaneous. c GLUT 4: glucose transporter 4. d OM: omental. e DHEA: dehydroepiandrosterone. f GLP: glucagon-like peptide. g ASP: acylation stimulating protein. h TNFa: tumor necrosis factor a. i NO: nitric oxide. b

lipogenic modifiers. Thus, as described above, testosterone and estrogen interact with specific receptors and decrease lipoprotein lipase activity [45,46,58]. Growth hormones act through specific receptors and inhibit insulin stimulated lipogenesis and decrease fat content [71]. Cortisol inhibits de novo fatty acid synthesis, but increases lipoprotein lipase activity [45,46,71]. DHEA and GLP-I also both stimulate lipoprotein lipase [81,82]. GLP-1 also stimulates FIAT and enhances insulin-mediated effects on glucose uptake and lipid synthesis [82,83]. An array of adipocyte-derived secreted autocrine factors also influence lipogenesis. Both TNFa and leptin decrease lipid synthesis, through, for example, inhibition of acetyl CoA carboxylase [84,85]. NO also appears to inhibit insulin mediated glucose uptake [86].


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Recently, it was found that angiotensin II was synthesized and secreted by adipocytes, and increases the triglyceride content of adipocytes and the activities of two lipogenic enzymes: fatty acid synthase and glycerol-3-phosphate dehydrogenase [87]. These appear to be mediated through the type-2 angiotensin II receptor and the effect can be blocked by specific receptor blockade [88]. Moreover, angiotensin II increased the transcription rate of fatty acid synthase and leptin (obese) genes in 3T3 and human adipocytes [87,88]. Increased fat stores in obese yellow mice triggered studies to investigate the role of the agouti protein in lipogenesis. It was shown that agouti and agoutirelated proteins increased adipocyte fatty acid synthase gene expression in a Ca 21 dependent manner. Agouti and insulin exert similar but additive effects on adipocyte lipogenesis, indicating different signalling pathways [80,89]. A major autocrine lipogenic factor is ASP, the factor on which we have focused our studies. ASP is produced via the interaction of the complement proteins C3, factor B and adipsin. All three of these proteins are synthesized and secreted by adipocytes in a differentiation dependent manner [90,91], resulting in increased ASP production [92]. ASP is a potent stimulant of both triglyceride synthesis and glucose transport in adipocytes (for review see [93]). The autoregulatory effect of ASP on its principal physiological target, adipose tissue, may serve as a critical factor in determining regional adipose distribution and related metabolic disorders. ASP levels were shown to be increased in gynoid obesity and levels drop after a prolonged fast [94]. Although ASP levels are increased in obesity, the adipocytes from patients with morbid obesity remain as responsive to ASP as adipocytes from normal weight subjects [95]. This contrasts with the resistance to insulin action in some studies of obese subjects [96,97]. In addition to their greater capacity to store triglyceride, in vitro studies have shown that larger adipocytes can produce more ASP than smaller ones [90], thus higher circulating levels of ASP may enhance further TG storage. These studies and other evidence point to ASP as a major player in the pathophysiology of obesity, hyperlipidemia and related lipid disorders. Recently it was shown that a functional ASP knockout mouse had delayed triglyceride clearance [98] and intraperitoneal administration of ASP in genetically obese mice (ob /ob and db /db) increased triglyceride clearance markedly [99].

7. Positive feedback regulation There are two interesting properties which characterize many of these lipolytic / lipogenic factors. The first is that in many instances the hormones have opposite effects on lipolysis vs. lipogenesis (Tables 1,2). For example, insulin and agouti protein both decrease lipolysis but increase lipogenesis. Similarly, testosterone, estrogen, growth hormone, TNFa, NO and leptin all increase

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lipolysis, but decrease lipogenesis. The second feature is that a number of these factors, both endocrine and autocrine (such as insulin, leptin, angiotensin II and ASP), are stimulated by fatty acids or dietary lipids and they, in turn, then regulate the processes of lipolysis and lipogenesis which control the tissue disposition of these fatty acids and lipids. Certain fatty acids influence leptin secretion [26,39], and the secreted leptin not only has neuronal effects, but also appears to enhance lipolysis peripherally in adipocytes. Fatty acids increase angiotensin II [38] secretion from adipose tissue and insulin secretion from the pancreas [13]. Dietary chylomicrons increase ASP secretion from adipose tissue [40–42] and all of these hormones then stimulate lipogenesis in adipocytes enhancing storage of triglycerides. Thus a number of factors, especially autocrine factors, demonstrate positive / negative feedback regulation in adipocytes by the substrates which they influence.

8. Pharmacologic targets A consequence of the recent advances in adipose tissue biology is the development of a number of pharmacologic agents which target the pathways of lipolysis and / or lipogenesis directly or through the hormone effectors described above for the treatment of obesity and or diabetes. For example, AOD4O1 is an anti-obesity drug which is a synthetic analogue of growth hormones. It increases lipolysis and decreases lipogenesis in adipose tissue (both esterification of fatty acids and de novo fatty acid synthesis). This occurs in both subcutaneous and omental adipose tissue, however the effects were more pronounced in subcutaneous adipose tissue [100]. Vanadate and peroxovanadate, which act as insulinmimetic drugs, inhibit tyrosine phosphatases resulting in increased lipoprotein lipase secretion and decreased hormone-sensitive lipolysis [72,101]. Compound UK-14304 acts as an alpha-2 adrenergic agonist to decrease lipolysis in adipose tissue [64]. Thiazolidinediones (TD) are a new family of insulin sensitizing agents and appear to have multiple effects (for review see [34,35]). They improve the secretory response of beta cells to insulin secretagogues, improve insulin sensitivity in skeletal muscles, adipose tissue and hepatocytes and activate glycolysis in hepatocytes, thus reducing fasting hyperglycemia and insulinemia. In adipose tissue, TD increase expression of GLUT 1 and GLUT 4, increase lipoprotein lipase activity [102], and block the lipolytic effect of TNFa but not catecholamines [74]. TD markedly influence lipid metabolism by decreasing plasma triglyceride. Beyond triglyceride, there are limited data suggesting possible effects on fatty acids, LDL cholesterol and HDL cholesterol. Thiazolidinediones act directly through binding to the nuclear receptor PPARg, activating the receptor and influencing the lipogenic process as well as adipocyte differentiation. Thus many new pharmacologic opportunities are available which

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can target hormone receptor interactions (endocrine and autocrine) through the use of agonist / antagonist compounds, the intracellular pathways (signal transduction or nuclear receptors) or the enzymes directly involved in lipolysis / lipogenesis.

9. Summary In this review we have summarized briefly the multiple metabolic consequences of increased circulating fatty acids, and focused on the cellular processes which can influence this fatty acid trafficking in adipose tissue. One of the most interesting recent developments in adipose tissue biology has been the recognition that there are multiple autocrine and endocrine factors produced by adipose tissue. Preliminary data suggests that several of these newly described hormones may demonstrate potential lipolytic or lipogenic functions with positive / negative feedback regulation. Future experimental data will certainly define these pathways, and explore their interactions with each other as well as their potential as pharmacologic targets.

10. Abbreviations Ap2: ASP: DHEA: EP: FFA: FIAT: GLIAT: GLP-1: GLUT 1: GLUT 4: HDL: HSL: LDL: LPL: NE: NO: OM: PAl-I: PDE: PGJ 2 :

adipocyte fatty acid binding protein acylation stimulating protein dehydroepiandrosterone epinephrine free fatty acids fatty acid incorporation into adipose tissue glucose incorporation into adipose tissue glucagon like peptide glucose transporter 1 glucose transporter 4 high density lipoprotein hormone sensitive lipase low density lipoprotein lipoprotein lipase norepinephrine nitric oxide omental plasminogen activator inhibitor-1 phosphodiesterase prostaglandin J 2

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phosphoinositolglycan-peptide peroxisome proliferator activated receptors subcutaneous thiazolidinedione triglyceride tumor necrosis factor a very low density lipoprotein

Acknowledgements This work was supported by grants from the Medical Research Council of Canada (KC), Heart and Stroke Foundation of Quebec (KC), and Servier Pharmaceuticals (ADS). KC is a research scholar of the Heart and Stroke Foundation of Canada.

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