Importance of TNFa and neutral lipases in human adipose tissue lipolysis

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1 Review TRENDS in Endocrinology and Metabolism Vol.17 No.8 Importance of TNFa and neutral lipases in human adipose tissue lipolysis Dominique Langin 1,2,3,4 and Peter Arner 5 1 Inserm, U586, Unité de Recherches sur les Obésités, Toulouse, F France 2 Université Paul Sabatier, Institut Louis Bugnard IFR31, Toulouse, F France 3 CHU de Toulouse, Laboratoire de Biochimie, Institut Fédératif de Biologie de Purpan, Toulouse, F France 4 Inserm, Franco-Czech Laboratory for Clinical Research on Obesity, Prague, CZ-10100, Czech Republic 5 Karolinska Institute at the Department of Medicine, Karolinska University Hospital, Huddinge, Stockholm, S-14186, Sweden Catecholamines and natriuretic peptides stimulate human adipocyte lipolysis through an increase in camp and cgmp levels, resulting in phosphorylation and activation of hormone-sensitive lipase. A defect in hormonesensitive lipase expression might contribute to the resistance to catecholamine-induced lipolysis observed in obesity. The respective roles and regulation of hormone-sensitive lipase and adipose triglyceride lipase in spontaneous and hormone-stimulated lipolysis remain to be determined. Tumor necrosis factor a stimulates triglyceride hydrolysis by multiple intracellular pathways acting on insulin signaling, G proteins and perilipins, and might contribute to enhanced plasma fatty acid levels in obesity. Characterization of the lipolytic pathways might provide novel strategies to decrease free fatty acid production and reverse insulin resistance and other obesity-related metabolic complications. Introduction Adipose tissue is the most important organ in the body for the storage and release of energy. During lipolysis, triglycerides (TGs), which constitute >95% of the lipid droplet in fat cells, are broken down to energy-rich free fatty acids (FFAs) and glycerol. The turnover of the TG pool in fat cells is rapid. Therefore, relatively small variations in lipolysis (or TG synthesis) can, in a relatively short time, have profound effects on fat mass and the metabolic fate of FFAs. The circulating FFA level is increased in obesity and type 2 diabetes. FFAs are not only energy substrates, but are also signaling molecules that influence metabolic regulation and hormone action. Elevated FFA levels impair glucose and lipid metabolism in liver and skeletal muscle, and might induce insulin resistance [1]. The camp pathway has long been considered as the only important regulator of adipocyte lipolysis, with hormone-sensitive lipase (HSL) being the only regulated lipase in the lipolytic cascade [2] (Figure 1). Hormones, which bind to Gs-proteincoupled receptors, stimulate lipolysis by activating adenylate cyclase so that more camp is produced. Some antilipolytic factors bind to Gi-protein-coupled receptors, which inhibit adenylate cyclase, thereby reducing camp production. However, the most important antilipolytic hormone, Corresponding author: Langin, D. (langin@toulouse.inserm.fr). Available online 30 August insulin, activates a different camp-dependent pathway. This hormone stimulates the enzyme phosphodiesterase 3B (PDE-3B), which lowers the camp content by catalyzing the breakdown of this cyclic nucleotide to inactive 5 0 AMP. camp activates the protein kinase A (PKA) complex so that HSL is phosphorylated and thereby is able to break down TGs to FFAs and glycerol. Unlike the case in most other species, catecholamines have antilipolytic properties in human fat cells that are mediated by the Gi-coupled a 2A - adrenoceptor subtype (Table 1). In humans, catecholamines and insulin are physiologically the most important hormones regulating adipocyte lipolysis by the camp pathway [3,4]. As regards the lipolytic adrenoceptors in fat cells, the b 3 - and b 2 -adrenoceptors are the dominant subtypes in rodents and in man, respectively. Insulin can also inhibit catecholamineinduced lipolysis through the disruption of PKA scaffolding induced by b-adrenoceptor signaling [5]. A few years ago, a novel lipolytic pathway, found only on primate fat cells, that does not involve camp was discovered [6]. Natriuretic peptides bind to specific receptors on human fat cells, which possess guanylate cyclase activity. The increase in intracellular cgmp levels leads to protein kinase G (PKG) activation, which, in turn, phosphorylates and activates HSL. These peptides stimulate lipolysis to the same extent as do catecholamines acting via b-adrenoceptor activation. However, their lipolytic effect is not modulated by catecholamines and insulin. Recently, alternative ways of activating adipocyte lipolysis have been described, indicating that the regulation of lipid mobilization is much more complex than was originally thought. One such factor is tumor necrosis factor a (TNFa), which has multiple signaling pathways in adipocytes. Another factor is a novel TG-specific lipase, named adipose TG lipase (ATGL) [7]. Here, we focus on these novel regulators of lipolysis in human fat cells. Animal data are mentioned to fill in gaps in our knowledge and to highlight possible species differences. TNFa regulation of lipolysis The interest in TNFa as a regulator of adipose tissue storage of lipids originates from cachexia disorders. The cytokine was originally termed cachectin because of its association with loss of fat mass in malignancy and heart failure. TNFa is a strong promoter of the hydrolysis of /$ see front matter ß 2006 Elsevier Ltd. All rights reserved. doi: /j.tem

2 Review TRENDS in Endocrinology and Metabolism Vol.17 No Figure 1. The control of adipocyte lipolysis. Three signal transduction pathways for lipolytic (e.g. catecholamines and natriuretic peptides) and antilipolytic (e.g. insulin, catecholamines, prostaglandine2, adenosine, nicotinic acid, and neuropeptidey and peptideyy) factors activatevarious proteinkinases and modulate the lipolytic reaction (i.e. the breakdown of TGs into fatty acids and glycerol) controlled by lipases and a nonenzymatic component (e.g. perilipins). Abbreviations: AC, adenylate cyclase; ALBP, adipocyte lipid binding protein; DG, diglycerides; Gi, inhibitory GTP-binding protein; Gs, stimulatory GTP-binding protein; MGL, monoglyceride lipase; PI3-K, phosphatidylinositol-3-phosphate kinase; PLIN, perilipins; PKB, protein kinase B. intracellular TGs in fat cells [8]. It can stimulate lipolysis by at least three separate mechanisms (Figure 2). One is by inhibiting insulin receptor signaling, thereby counteracting the antilipolytic effect of the hormone. Another is by inhibiting signaling through the Gi-protein-coupled adenosine receptor to counteract the antilipolytic effect of adenosine. The third way is via direct stimulation of basal (nonhormonal) lipolysis through interactions with the lipid-binding protein perilipin. TNFa signaling is complex, involving two receptors and multiple intracellular pathways [9]. Only TNFa receptor 1 and mitogen-activated protein (MAP) kinases promote lipolytic effects in fat cells [10]. Three MAP kinases (p44/42, Jun kinase (JNK) and p38) are activated by TNFa in fat cells but only the first two are linked to lipolysis. Interaction of TNFa with insulin The early insulin receptor signaling events are common to the various metabolic effects of the hormone [11]. Therefore, the effects of insulin TNFa interactions on glucose metabolism are relevant for lipolysis as long as they concern early signaling. The initial events after the binding of insulin to its receptor are tyrosine phosphorylation of the insulin receptor and of insulin receptor substrates (IRS-1, IRS-2), which leads to activation of phosphatidylinositol 3-kinase, so that PDE-3B is activated and camp is broken down [11,12]. The most important effect of TNFa is inactivation of IRS-1. This can be caused by inhibition of tyrosine phosphorylation and by a reduction in the amount of IRS-1 in fat cells. TNFa counteracts tyrosine phosphorylation by promoting serine phosphorylation of IRS-1. The most important TNFa effect on adipocyte IRS-1 is mediated through the p42 44 MAP kinase [13,14]. Interaction of TNFa with adenosine The rate of basal lipolysis is low in rodent fat cells. This might be caused by chronic inhibition through the intracellular release of adenosine. In human fat cells, there is higher basal lipolytic activity, probably owing to much less active adenosine regulation. Adenosine binds to specific Gi-protein-coupled receptors. TNFa markedly decreases the protein content of all three Gia subtypes in rodent fat cells, without changing the amount of Gs protein or b-subunit of the G-protein complex [15]. This decrease in Table 1. Species differences in adipose tissue lipolysis Mice Predominant role of b 3 -adrenoceptors Lack of effect of natriuretic peptides Lipolytic action of adrenocorticotropic hormone and other peptides Low a 2 -adrenoceptor expression No effect of neuropeptide Y and peptide YY Humans Predominant role of b 2 - (and b 1 -)-adrenoceptors Low b 3 -adrenoceptor expression Strong lipolytic effect of natriuretic peptides No effect of peptides except for natriuretic peptides Strong a 2 -adrenoceptor antilipolytic effect Antilipolytic effect of neuropeptide Y and peptide YY

3 316 Review TRENDS in Endocrinology and Metabolism Vol.17 No.8 Figure 2. The action of TNFa on HSL-mediated adipocyte lipolysis. The different pathways are represented. The elements of the TNFa transduction pathway involved in the control of HSL-mediated lipolysis are shown in red. The TNFa receptor and kinases are shown in red boxes. The endpoint targets IRS-1 and PLIN, colored in yellow, are regulated both by phosphorylation and at the expression level. CIDEA, PDE3 and Gi are regulated at the expression level and are shown in orange boxes. Abbreviations: AC, adenylate cyclase; Gi, inhibitory GTP-binding protein; IR, insulin receptor; PI3-K, phosphatidylinositol-3-phosphate kinase; PLIN, perilipins; PKB, protein kinase B; R, receptor; TNFR, tumor necrosis factor a receptor. Gi protein mitigates the antilipolytic effect of adenosine. TNFa decreases Gi-protein content through an induction of protein degradation by the proteasomal pathway [16]. However, the TNFa Gi interaction appears to be specific for rodents because it was not observed in human fat cells [17]. Effect of TNFa on lipase expression TNFa treatment of rodent adipocytes results in a comprehensive alteration of the adipocyte gene expression profile, a process called adipocyte dedifferentiation, which includes the downregulation of HSL expression [18]. However, the lipolytic effect of TNFa occurs independently of changes in HSL expression [19]. Recently, TNFa was shown to downregulate ATGL mrna expression [20,21]. This decrease is paralleled by a downregulation of peroxisome proliferator-activated receptor g, supporting the notion that ATGL regulation by TNFa is part of the dedifferentiation process. Therefore, there is no evidence to date that the lipolytic action of TNFa is related to a regulation of adipocyte lipase expression. Interaction of TNFa with perilipin Perilipins are a family of phosphoproteins located at the surface of the fat-cell lipid droplet [22]. Adipocytes contain perilipins A and B, which protect TGs from being hydrolyzed by HSL. Studies in human and mouse fat cells suggest that TNFa activates lipolysis both by phosphorylation of perilipin and by decrease of its expression [10,17,23,24]. The effect of TNFa on perilipin phosphorylation is probably indirect and is mediated by a TNFainduced decrease in the expression of PDE-3B. As a result, the camp content is elevated, more PKA is activated and more perilipin becomes phosphorylated. Perilipin phosphorylation enables the lipases to access the lipid droplet. Similarly, a decrease in perilipin content unmasks TGs for the lipases. During early signaling events, the p44/42 MAP kinase mediates the indirect effect via PDE-3B [24], whereas p44/42 and JNK mediate the direct effect on perilipin expression [10,17,25]. Physiological and pathophysiological importance of TNFa signaling to lipolysis Unlike most hormonal regulators of lipolysis, which exert their effects within minutes, the TNFa effect on lipolysis is slow, taking 6 12 h to be detectable and up to 48 h to be maximal [8,10]. Therefore, TNFa serves as a chronic regulator of the lipolytic tone. The existence of several endpoint targets for TNFa on lipolysis (Gi protein, perilipin, IRS-1) gives rise to different forms of lipolysis modulation. The Gi-protein effect (only present in rodents) modulates adenosine action. The perilipin effect could influence basal lipolysis, regardless of the nutritional status. However, the effect on IRS-1 could alter lipolysis in the postprandial state when insulin levels are high and the antilipolytic effect of the hormone maximal. Similarly, this TNFa effect could be observed in chronic hyperinsulinemic states. The influence of TNFa signaling on lipolysis is markedly modified in obesity. The production of TNFa by adipose tissue is increased in obese rodents and humans, and normalized following weight reduction [26,27]. The mechanisms by which obesity increases TNFa production in adipose tissue are not known but they are most likely to be of multiple nature. Decreased processing, combined with increased production of TNFa, is of importance for human and rodent obesity. Hyperinsulinemia, which usually accompanies obesity, could be one important factor for enhanced production of the cytokine. For example,

4 Review TRENDS in Endocrinology and Metabolism Vol.17 No in vitro exposure of human adipose tissue to insulin markedly increases the local production of TNFa [28]. A human-specific mechanism for the control of lipolysis is mediated by a gene termed cell death-inducing DNA fragmentation factor-a-like effector A (CIDEA) [29]. In rodents, CIDEA is expressed in brown but not white fat cells, and the expression is not influenced by dietaryinduced obesity. By contrast, in humans, CIDEA expression is abundant in white fat cells. The expression is markedly decreased in obese humans and is normalized following weight reduction. DNA microarray analysis revealed that CIDEA expression is sensitive to moderate long-term caloric restriction [30]. Moreover, gene silencing with small interference RNA against CIDEA increases basal lipolysis and TNFa production by human fat cells [29]. Thus, CIDEA inhibits TNFa production and thereby protects lipolysis from being increased in human obesity. There is also a feedback mechanism involved because TNFa can downregulate CIDEA expression in human fat cells through the action of JNK. Role of lipases in the hydrolysis of fat cell TGs Following the characterization of HSL activity in the fat cell during the 1960s, the activation of lipolysis was thought to follow the sequence: activation of stimulatory receptors, increase in camp levels and phosphorylation of HSL by PKA, resulting in enzyme activation. However, the hydrolysis of stored TGs is a more complex phenomenon, involving several lipases, fatty acid-binding proteins and proteins associated with the lipid droplet. Activation of HSL HSL is a multifunctional enzyme that possesses TG, diglyceride (DG), cholesterol ester and retinyl ester hydrolase activities [2]. In white adipocytes, its main metabolic role is to hydrolyze TGs and DGs. HSL is highly regulated, mainly by reversible phosphorylation of serine residues by PKA and PKG. Phosphorylation of HSL by PKA has been shown to increase its activity in vitro, although not to the same extent that cellular lipolysis can be increased by catecholamines. This implies mechanisms other than conformational change leading to increased enzyme activity. The mechanisms for lipolysis activation during b-adrenoceptor stimulation are not entirely characterized. HSL and perilipin both have a major role. It has recently been proposed that stimulated lipolysis occurs on small peripheral lipid storage droplets, which, unlike the central core large droplets, are coated with perilipin [31]. In basal conditions, perilipin suppresses lipolysis by blocking access of the lipases to the lipid droplet [22]. As expected from cellular studies, basal lipolysis is highly elevated in perilipin-null mice. In unstimulated cells, HSL is diffusively distributed throughout the cytosol but some molecules are found associated with the lipid droplets. Upon phosphorylation by PKA, HSL is translocated from a cytosolic compartment to the surface of lipid droplets coated with perilipin [31 33]. The dependence of HSL translocation on perilipin phosphorylation is debated [33,34]; however, perilipin phosphorylation seems to be essential for full lipolytic stimulation. Adipocyte lipid-binding protein (ALBP) interacts with the amino-terminal region of HSL and increases the lipolytic activity of HSL through its ability to bind and sequester fatty acids via specific protein protein interaction [35]. A prelipolysis complex containing ALBP and HSL is formed [36]. The complex translocates to the surface of the lipid droplet upon lipolytic stimulation. Consistent with such a role for ALBP is the observation that knockout mice exhibit decreased lipolytic capacity [37]. Respective roles of ATGL and HSL in lipolysis Data from HSL-null mice have led to a reassessment of the role of HSL in fat mobilization. Catecholamine-induced lipolysis is markedly blunted, as expected, in these mice but basal lipolysis is unaltered in isolated adipocytes, suggesting the existence of lipases other than HSL [38 41]. A novel lipase, ATGL, has been identified [42 44]. ATGL belongs to a family of closely related hydrolases that contain a patatin-like domain [43,45]. Using antibodies directed against ATGL, it was suggested that ATGL is responsible for a large part of the cytosolic acyl-hydrolase activity in white adipose tissue of HSL-deficient mice [42]. Furthermore, in a mouse fat cell line, overexpression of ATGL stimulates basal and catecholamine-induced lipolysis, whereas knockdown of the enzyme has the opposite effect [46]. ATGL-null mice show blunted lipolysis and have increased adipose mass [47]. Therefore, together with HSL, ATGL participates in mouse adipose tissue lipolysis. At present, the respective roles of HSL and ATGL in human fat cell lipolysis have not been fully established. Whether HSL and ATGL possess comparable TG lipase activity is a debated question [42,48]. ATGL is activated by a cofactor, comparative gene identification (CGI)-58 [49]. Mutations in the CGI-58 gene are associated with Chanarin Dorfman syndrome, a genetic disease characterized by neutral lipid accumulation in many tissues. Because CGI-58 interacts with perilipins on the surface of the lipid droplet, a complex interplay between ATGL, perilipins and CGI-58 can be envisaged [50,51]. Interestingly, mutations of CGI-58 found in Chanarin Dorfman syndrome patients abolish both interaction with perilipins and coactivation of ATGL [49,51]. HSL, but not ATGL, shows significant DG lipase activity [48,52]. The DG lipase activity of HSL is tenfold higher than its TG lipase activity. TGs are hydrolyzed at a lower rate than are DGs, indicating that the first step of lipolysis is rate limiting. Both PKA and PKG phosphorylate and activate HSL. Use of a specific HSL inhibitor suggests that the catecholamine and natriuretic peptide pathways converge on HSL to induce lipolysis in human fat cells, and that ATGL participates in basal lipolysis [53]. However, in mice, ATGL seems to participate in stimulated lipolysis because ATGL deficiency causes a drastic reduction in stimulated lipolysis [42,47]. Although ATGL seems to have an important role in basal lipolysis in humans [53], it cannot be excluded that other adipose tissue enzymes with the capacity to hydrolyze TGs, such as other members of the patatin or the TG hydrolase families, have a role [45,54,55]. The potential importance for ATGL in regulating lipolysis in humans is suggested by the demonstration that polymorphism in the ATGL gene is associated with plasma FFA levels [56].

5 318 Review TRENDS in Endocrinology and Metabolism Vol.17 No.8 HSL and human obesity Resistance to catecholamine-induced lipolysis in subcutaneous adipose tissue has been demonstrated in vivo in obese adults and children [57,58]. Alterations at various levels of the lipolytic pathway have been shown in obesity [59]. The defect in HSL expression observed in obese subjects is likely to have a major role in the impaired lipolysis [60]. Indeed, the defect is also observed in firstdegree relatives of obese subjects [61] and in newly formed adipocytes from obese subjects, when preadipocytes that were differentiated in vitro are used [53]. Moreover, there is a strong correlation between lipolytic capacity and HSL expression in human subcutaneous fat cells, and a high adipose tissue lipase activity is associated with increased maximal lipolysis and HSL mrna levels [4,48]. The link between HSL and obesity is also supported by genetic studies that show an association between obesity and impaired lipolytic activity of subcutaneous fat cells [62 64]. The defect might constitute an early, possibly primary, event in obesity that protects against excessive FFA release. Accordingly, HSL deficiency in mice causes a reduction in plasma FFA levels and favors an antiatherogenic lipid profile [38,39]. Conclusion and therapeutic perspectives It is apparent from the discovery of novel lipases and TNFa that, first, HSL is not the sole endpoint target of the lipolytic cascade, and, second, that nonhormonal lipolysis is subject to regulation. Although TNFa can influence HSL phosphorylation through its effects on Gi protein and IRS- 1, and thereby modulate hormone-regulated lipolysis, the effect on perilipin is of importance for basal lipolysis, at least in humans. It is likely that adipose TNFa partially contributes to enhanced circulating levels of FFA in obesity. Neutralization of TNFa in vivo in obese rodents decreases circulating FFA levels [65]. Antidiabetic therapy with glitazones has the same effect [1]. One potential mechanism is the inhibition of TNFa-mediated lipolysis in fat cells. Human obesity is associated with a state of lowgrade inflammation in which adipose tissue itself is a source and site of inflammation [66,67]. TNFa produced by macrophages might induce inflammatory markers in adipose tissue, in addition to its effect on lipolysis. In turn, FFAs can activate macrophages. Therefore, targeting the TNFa signaling pathways to decrease FFA levels offers new potential therapeutic strategies. Attempts to improve insulin sensitivity in obese type 2 diabetic patients by neutralizing TNFa, using anti-tnfa antibodies or recombinant TNF receptors, have so far proven unsuccessful [68,69]. The lack of efficacy might be attributable to the treatment strategy because only a single injection was evaluated. Furthermore, in humans, TNFa acts locally in the adipose tissue [70]. However, targeting p44/42 and JNK and/or CIDEA in fat cells might provide novel ways to decrease FFA production and thereby reverse insulin resistance in obesity and its associated conditions. The interest in the inhibition of lipases in the treatment of insulin-resistant conditions has led to the synthesis of several HSL inhibitors. The rationale for the development of these drugs is somewhat similar to that for the use of nicotinic acid. The hypolipidemic action of nicotinic acid is chiefly mediated through inhibition of lipolysis [71]. One potent specific inhibitor of HSL has been shown to decrease plasma FFA levels and also to reduce hyperglycemia in diabetic rats [53,72,73]. Further evidence for the therapeutic potential of HSL, and possibly also ATGL inhibitors, will await data showing an improvement in plasma lipid profiles and insulin sensitivity. Whether inhibition of adipocyte lipases will lead to an increase in fat mass warrants further study. In the context of insulinresistant states characterized by impaired adipose tissue deposition, such as lipodystrophy, cachexia and chronic inflammation, a putative effect on fat storage would prove beneficial. In the recent years, adipose tissue has been shown to produce an increasing number of peptides known as adipokines, with putative roles in insulin resistance. However, many of these molecules might have local but not systemic effects. FFAs remain prime candidates in the development of insulin resistance. Therefore, targeting adipose tissue lipolysis at the level of the TNFa signaling pathway, or at the level of HSL and ATGL, constitutes a plausible therapeutic strategy. Acknowledgements The authors work is supported by Inserm, the Swedish Research Council, the Programme National de Recherche en Nutrition Humaine, the Programme National de Recherche sur le Diabète, the Agence National de la Recherche program on Cardiovascular disease, Diabetes and Obesity, the Swedish Diabetes Association, the Novo Nordic Foundation, the Swedish Heart and Lung Foundation, the Bergvall Foundation, the Tore Nilsson Foundation, the King Gustaf V and Queen Victoria Foundation, and the project Hepatic and adipose tissue and functions in the metabolic syndrome (HEPADIP, see which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT ). References 1 Arner, P. (2003) The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones. Trends Endocrinol. Metab. 14, Langin, D.et al. (2000) Millenium fat cell lipolysis reveals unsuspected novel tracks. Horm. Metab. 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