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Regulation of adipose tissue lipolysis revisited

Symposium on ‘Frontiers in adipose tissue biology’

Published online by Cambridge University Press:  24 August 2009

Véronic Bézaire
Affiliation:
Inserm U858, Laboratoire de Recherches sur les Obésités, F-31432 Toulouse, France Université de Toulouse, UPS, Institut de Médecine Moléculaire de Rangueil, IFR150, F-31432 Toulouse, France
Dominique Langin*
Affiliation:
Inserm U858, Laboratoire de Recherches sur les Obésités, F-31432 Toulouse, France Université de Toulouse, UPS, Institut de Médecine Moléculaire de Rangueil, IFR150, F-31432 Toulouse, France Laboratoire de Biochimie, Institut Fédératif de Biologie de Purpan, F-31059 Toulouse, France
*
*Corresponding author: Professor Dominique Langin, fax +33 561325623, email Dominique.Langin@inserm.fr
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Abstract

Human obesity and its complications are an increasing burden in developed and underdeveloped countries. Adipose tissue mass and the mechanisms that control it are central to elucidating the aetiology of obesity and insulin resistance. Over the past 15 years tremendous progress has been made in several avenues relating to adipose tissue. Knowledge of the lipolytic machinery has grown with the identification of new lipases, cofactors and interactions between proteins and lipids that are central to the regulation of basal and stimulated lipolysis. The dated idea of an inert lipid droplet has been appropriately revamped to that of a dynamic and highly-structured organelle that in itself offers regulatory control over lipolysis. The present review provides an overview of the numerous partners and pathways involved in adipose tissue lipolysis and their interaction under various metabolic states. Integration of these findings into whole adipose tissue metabolism and its systemic effects is also presented in the context of inflammation and insulin resistance.

Type
Research Article
Copyright
Copyright © The Authors 2009

Abbreviations:
AMPK

AMP-activated protein kinase

AR

adrenergic receptors

ATGL

adipose TAG lipase

CGI-58

comparative gene identification 58

DAG

diacylglycerols

FABP

fatty acid-binding protein

HSL

hormone-sensitive lipase

LD

lipid droplet

MGL

monoacylglycerol lipase

PK

protein kinase

PLIN

perilipin

WAT

white adipose tissue

Hormonal regulation of adipocyte lipolysis

White adipose tissue (WAT) essentially represents an unlimited pool of energy. In WAT NEFA originating from dietary intake or de novo synthesis are stored as TAG in highly-structured hydrophobic lipid droplets (LD). With its storage capacity and ability to hydrolyse TAG (a process termed lipolysis) WAT provides a NEFA buffering system for other organs(Reference Frayn1). Lipolysis is the breakdown of one TAG molecule to three energy-rich NEFA and one glycerol molecule, which are released into the bloodstream and are available for uptake by other tissues. NEFA are not only an energy source, they are also signalling molecules. Overabundance of NEFA can interfere with normal metabolism, as is the case in obesity and type 2 diabetes. Chronically-elevated NEFA alter glucose and lipid metabolism in skeletal muscle and liver and may lead to insulin resistance(Reference Arner2).

Tight regulatory control of lipolysis is provided by catecholamines and insulin (Fig. 1). The hormone adrenaline and neurotransmitter noradrenaline stimulate lipolysis through the activation of β1- and β2-adrenergic receptors (AR). Coupling of β1- and β2-AR to stimulatory GTP-binding protein receptors activate adenylyl cyclase, increasing cAMP production. A rise in cAMP activates protein kinase (PK) A, which phosphorylates hormone-sensitive lipase (HSL) and LD-coating protein perilipin (PLIN) to stimulate lipolysis. Conversely, catecholamines can inhibit lipolysis via the activation of α2-AR and their coupling to inhibitory GTP-binding protein receptors. The latter inhibit adenylyl cyclase action and cAMP production. Thus, AR-dependent lipolysis is dictated by the combined effects of pro-lipolytic β-AR and anti-lipolytic α2-AR. Impairment in PKA-stimulated lipolysis observed in obesity is thought to result from accentuated stimulation of α2-AR(Reference Jensen, Haymond and Rizza3Reference Stich, De Glisezinski and Crampes5). Insulin also regulates lipolysis when binding to its receptor on adipocytes. Insulin binding to insulin receptor substrate 1 leads to phosphodiesterase 3B activation, which degrades cAMP, and consequently reduces PKA activation. Thus, in a postprandial state insulin not only favours substrate uptake and storage but also minimizes TAG breakdown in adipocytes.

Fig. 1. Signal transduction pathways implicated in hormonal control of human adipocyte lipolysis. Coupling of β1 and β21/2)- and α2-adrenergic receptors (AR) respectively stimulate and inhibit cAMP production by adenylyl cyclase (AC) and protein kinase A (PKA) activation. Insulin favours cAMP degradation through activation of protein kinase (PK) B and phosphodiesterase 3B (PDE-3B) activity. Natriuretic peptides promote cGMP accumulation and PKG activation via type A receptor. PKA and PKG phosphorylate hormone-sensitive lipase (HSL) and perilipin A (PLINA). Adipose TAG lipase (ATGL) and monoacylglycerol lipase (MGL) are not thought to be directly hormonally-regulated. Gs, stimulatory GTP-binding protein; Gi, inhibitory GTP-binding protein; IRS, insulin receptor substrate; PI3-K phosphatidylinositol-3 phosphate kinase; GC, guanylyl cyclase; LD, lipid droplet.

In human fat cells an additional signal transduction pathway, independent of catecholamines and insulin, is implicated in pro-lipolytic events. Natriuretic peptides bind type A receptors, which possess intrinsic guanylyl cyclase activity (Fig. 1). Rises in cGMP activate PKG, which similarly to PKA phosphorylates HSL and PLIN(Reference Sengenes, Berlan and De Glisezinski6). Stimulation of lipolysis by natriuretic peptides is of similar magnitude to that of catecholamines and is particularly pronounced during exercise(Reference Moro, Crampes and Sengenes7, Reference Lafontan, Moro and Sengenes8).

Natriuretic peptides, catecholamines and insulin provide the main regulatory control of lipolysis in human adipocytes. Additional hormones and factors such as growth hormone, TNFα, and IL-6 also influence lipolysis by altering the signalling pathways or lipolytic machinery described earlier. There is also a wealth of anti-lipolytic systems activated by catecholamines, adenosine, PG and metabolites for which the physiological relevance is still unknown.

Lipases in lipolysis regulation

Tremendous progress has been made in the regulation of lipolysis over the past 10 years. For approximately three decades HSL was thought to be the rate-limiting step in lipolysis. It is now established that other lipases, cofactors and lipid-associated proteins each participate in the regulation of lipolysis.

Hormone-sensitive lipase

In the 1960s HSL was characterized as a lipolytic enzyme sensitive to adrenaline(Reference Bjorntorp and Furman9, Reference Rizack10). For the following 30 years HSL remained the undisputed regulator of lipolysis. HSL is highly expressed in WAT(Reference Holm, Belfrage and Fredrikson11) and displays in vitro hydrolysis activity for TAG, diacylglycerols (DAG), monoacylglycerols(Reference Fredrikson, Stralfors and Nilsson12), cholesterol and retinyl esters(Reference Grober, Lucas and Sorhede-Winzell13, Reference Strom, Gundersen and Hansson14). Its relative affinity is ten times greater for DAG than TAG(Reference Fredrikson, Stralfors and Nilsson12, Reference Langin, Lucas and Lafontan15) and shows a preference for fatty acids in the sn-1 and sn-3 position of TAG molecules(Reference Raclot, Langin and Lafontan16).

The cloning of HSL in the rat and human subjects(Reference Holm, Kirchgessner and Svenson17, Reference Langin, Laurell and Stenson Holst18) has provided an insight into its gene and protein structure. The carboxy terminal of HSL harbours the active site and regulatory module of the enzyme(Reference Osterlund19). The amino terminal, although less characterized, appears to be required for protein–protein interaction, notably with fatty acid-binding protein (FABP) 4 (detailed later)(Reference Shen, Sridhar and Bernlohr20). As alluded to earlier, HSL action is in part regulated by PKA. Three PKA phosphorylation sites have been identified in rat HSL: Ser563; Ser659; Ser660(Reference Anthonsen, Rönnstrand and Wernstedt21). The corresponding sites in human HSL are Ser552, Ser649 and Ser650(Reference Contreras, Danielsson and Johansson22). PKA phosphorylation of rat HSL residue Ser563 appears to regulate intrinsic activity(Reference Shen, Patel and Natu23) while residues Ser659 and Ser660 favour the translocation of a predominantly cytosolic HSL to LD(Reference Su, Sztalryd and Contreras24Reference Clifford, Londos and Kraemer27). In human HSL PKA phosphorylation of residues Ser649 and Ser650 has been shown to be the most important in increasing enzymic activity(Reference Krintel, Osmark and Larsen28). The pro-lipolytic effect of PKA on HSL is therefore two-pronged: increasing the enzyme's intrinsic activity; promoting its access to TAG molecules in a whole-cell context.

Additional HSL regulatory pathways include the extracellular signal-regulated kinase and AMP-activated PK(AMPK) pathways. HSL is positively regulated by the extracellular signal-regulated kinase pathway via phosphorylation of Ser660(Reference Greenberg, Shen and Muliro29, Reference Zhang, Halbleib and Ahmad30) and negatively regulated by AMPK. AMPK, the cellular energy sensor, is activated by increasing AMP:ATP to restore energy levels(Reference Kahn, Alquier and Carling31). Once activated AMPK phosphorylates HSL on Ser565 in human adipocytes(Reference Roepstorff, Vistisen and Donsmark32, Reference Garton and Yeaman33), resulting in an anti-lipolytic effect(Reference Daval, Diot-Dupuy and Bazin34).

Doubt on the lone regulatory role of HSL in lipolysis slowly grew over the years. First, puzzlement revolved around an important mismatch between HSL activity and adipocyte lipolysis in response to PKA activation. PKA-dependent phosphorylation of HSL leads to a two- to three-fold increase in TAG hydrolase activity, while whole-cell lipolysis increases ⩽100-fold. These contrasting observations suggested additional, yet unidentified, regulatory steps in lipolysis. The critical role of the LD structural protein PLIN would later shed light on this issue (described later). Additionally, DAG accumulation in adipose tissue of HSL-null mice(Reference Haemmerle, Zimmermann and Hayn35) suggested the presence of an alternative lipase targeting TAG molecules, possibly to complement the strong affinity of HSL for DAG. The identification of adipose TAG lipase (ATGL) in 2004 (see later) supports more recent findings obtained from HSL manipulation; for example, residual TAG hydrolase activity and lipolysis despite HSL silencing(Reference Kershaw, Hamm and Verhagen36Reference Bezaire, Mairal and Ribet38) or specific pharmacological inhibition(Reference Schweiger, Schreiber and Haemmerle39Reference Mairal, Langin and Arner41) and the failure of HSL overexpression to promote whole-cell lipolysis(Reference Bezaire, Mairal and Ribet38, Reference Lucas, Tavernier and Tiraby42).

Adipose TAG lipase

In 2004 three groups independently identified an additional lipase with TAG hydrolase activity(Reference Zimmermann, Strauss and Haemmerle43Reference Villena, Roy and Sarkadi-Nagy45). ATGL (also known as desnutrin or phospholipase A2ξ) belongs to the family of patatin-like phospholipase domain-containing proteins. It is highly expressed in WAT and brown adipose tissue and to a lower extent in testes, skeletal and cardiac muscle(Reference Kershaw, Hamm and Verhagen36, Reference Zimmermann, Strauss and Haemmerle43, Reference Villena, Roy and Sarkadi-Nagy45, Reference Lake, Sun and Li46). The carboxy-terminal region of ATGL contains a hydrophobic section permitting protein–lipid interactions(Reference Schweiger, Schoiswohl and Lass47). Accordingly, in mouse models and COS-7 cell lines native or ectopic ATGL is mostly associated with LD(Reference Zimmermann, Strauss and Haemmerle43, Reference Schweiger, Schoiswohl and Lass47, Reference Kobayashi, Inoguchi and Maeda48). Also within the carboxy-terminal region of ATGL are two phosphorylation sites, Ser404 and Ser428(Reference Bartz, Zehmer and Zhu49). The nature of the PK targeting ATGL and the functional role of such sites are unknown. Last, the enzymic activity of ATGL and its interaction with co-activator comparative gene identification 58 (CGI-58) are dependent on the carboxy-terminal region(Reference Schweiger, Schoiswohl and Lass47).

Studies with ATGL-null mice have revealed the importance of ATGL in energy homeostasis(Reference Haemmerle, Lass and Zimmermann50). ATGL-null mice display increased WAT mass and ectopic TAG storage in several tissues, including heart tissue, resulting in premature death. A strong body of evidence has further established the central role of ATLG in lipolysis in murine adipocytes or non-adipocyte cell lines. Overexpression of ATGL increases TAG hydrolysis(Reference Villena, Roy and Sarkadi-Nagy45, Reference Lake, Sun and Li46) and basal and isoproterenol-stimulated lipolysis(Reference Kershaw, Hamm and Verhagen36) while its silencing decreases TAG hydrolase activity(Reference Kershaw, Hamm and Verhagen36, Reference Zimmermann, Strauss and Haemmerle43), TAG storage and LD size(Reference Miyoshi, Perfield and Obin37). Unlike HSL, ATGL hydrolysis capacity is mainly targeted towards TAG. In human adipocytes, however, the in vitro TAG hydrolase capacity of ATGL is lower than that of HSL(Reference Mairal, Langin and Arner41). Nonetheless, ATGL plays a crucial role in orchestrating lipolysis in human adipocytes(Reference Bezaire, Mairal and Ribet38). Modulation of ATGL with adenoviral transduction and gene silencing dictates basal and PKA-stimulated lipolysis(Reference Bezaire, Mairal and Ribet38). The latter study has also demonstrated, in response to PKA-stimulation, translocation of ATGL from the cytosol to LD and consequently its enrichment with HSL. Collectively, these findings suggest that ATGL and HSL act sequentially, despite their common capacity for TAG hydrolysis. HSL remains the lone enzyme capable of DAG hydrolysis, but DAG supply by ATGL controls PKA-stimulated lipolysis in human adipocytes.

Monoacylglycerol lipase

Monoacylglycerol lipase (MGL) was purified from rat adipose tissue in the 1970s(Reference Tornqvist and Belfrage51). This enzyme is expressed in WAT, lung, liver, kidney, testes, brain and heart(Reference Karlsson, Contreras and Hellman52). Despite the in vitro capacity of HSL to hydrolyse monoacylglycerols, the presence of MGL in vivo is required for complete lipolysis(Reference Fredrikson, Tornqvist and Belfrage53). MGL hydrolyses the 1(3) and 2-ester bonds of monoacylglycerols at equal rates but has no affinity for DAG, TAG or cholesteryl esters. Site-directed mutagenesis has confirmed the importance of Ser122, Asp239 and His269 in the lipase and esterase activities of MGL(Reference Karlsson, Contreras and Hellman52). MGL is not thought to be rate limiting in lipolysis because of its abundance(Reference Fredrikson, Tornqvist and Belfrage53).

Lipid droplet-associated proteins and lipid-binding proteins

It is now widely accepted that lipases do not act alone in regulating lipolysis. Several proteins interact with LD, lipases and NEFA to offer additional regulatory control of lipolysis and lipid homeostasis.

Perilipins

Over the past 15 years it has become clear that LD are not simple aggregates of lipids but rather dynamic and highly-structured organelles, important for cellular homeostasis and the synthesis of lipid signalling molecules. Providing structure to LD is a family of lipid-coating proteins termed PAT. The PAT family in human adipocytes includes perilipin, adipophilin, tail-interacting protein of 47 kDa, S3-12 and oxidative tissues-enriched PAT protein. The proportion of each lipid-coating protein on LD is altered as LD mature(Reference Wolins, Quaynor and Skinner54, Reference Wolins, Skinner and Schoenfish55). Perilipin, which was discovered in 1991(Reference Greenberg, Egan and Wek56), is highly expressed in WAT and brown adipose tissue(Reference Greenberg, Egan and Wek56Reference Tansey, Sztalryd and Gruia-Gray59) and is the most abundant lipid-coating protein on mature LD(Reference Wolins, Quaynor and Skinner54). Three isoforms arise from alternate splicing of a single mRNA transcript, PLINA being most abundant in WAT LD(Reference Greenberg, Egan and Wek56, Reference Greenberg, Egan and Wek57). Ectopic expression of PLINA in 3T3 L1 preadipocytes naturally devoid of PLIN suggests that PLINA forms a physical barrier around LD to reduce lipase access(Reference Brasaemle, Rubin and Harten60). Three hydrophobic sequences play a major role in anchoring PLINA to LD(Reference Subramanian, Garcia and Sekowski61) yet it is the amino and carboxy terminals that are critical in promoting TAG storage(Reference Garcia, Subramanian and Sekowski62).

Investigations with PLIN-null mice clearly illustrate the regulatory role of PLIN in lipolysis. PLIN-ablated mice are lean, have smaller adipocytes and are resistant to diet-induced obesity(Reference Martinez-Botas, Anderson and Tessier58, Reference Tansey, Sztalryd and Gruia-Gray59, Reference Sztalryd, Xu and Dorward63). In addition, they exhibit elevated basal lipolysis and attenuated stimulated lipolysis. Interestingly, experiments with mouse embryonic fibroblasts from PLIN–/– mice and COS-7 cells lacking PLIN have shown that HSL fails to translocate to LD in response to β-adrenergic stimulation(Reference Sztalryd, Xu and Dorward63). Additionally, live culture cell experiments have demonstrated that PKA activation facilitates fluorescence resonance energy transfer between fluorescent probes fused to HSL and PLIN(Reference Granneman, Moore and Granneman64). Together, these results not only highlight the regulatory role of PLIN as a physical barrier to HSL, but also suggest that PLIN may provide an HSL-docking site on LD.

PLINA has six serine phosphorylation sites targeted by PKA(Reference Clifford, Londos and Kraemer27, Reference Greenberg, Egan and Wek56, Reference Nishiu, Tanaka and Nakamura65, Reference Egan, Greenberg and Chang66). Of those sites, residue Ser517 has been demonstrated to be essential to ATGL-dependent lipolysis in stimulated conditions(Reference Miyoshi, Perfield and Souza67). However, specific phosphorylation of Ser492 in murine adipocytes is also of importance as it causes a remodelling of large LD into a myriad of microLD, independently of lipolysis(Reference Marcinkiewicz, Gauthier and Garcia68). On phosphorylation PLINA remains on the surface of LD but increased LD surface area following fragmentation facilitates lipolysis. Thus, PLINA limits lipase access to LD in the basal state but provides greater access to lipases in stimulated conditions by docking HSL and promoting fragmentation of LD.

Caveolin-1

Caveolae are small invaginations on cell plasma membranes(Reference Palade69, Reference Patel, Murray and Insel70). They are common to many cell types but highly expressed in adipocytes(Reference Thorn, Stenkula and Karlsson71). Caveolin is the marker protein for these structures such that ectopic expression of caveolin results in the formation of invaginations on cellular membranes(Reference Parton, Hanzal-Bayer and Hancock72). Caveolae have several putative functions, including participation in signal transduction(Reference Drab, Verkade and Elger73), membrane trafficking pathways and NEFA binding and transport(Reference Trigatti, Anderson and Gerber74). Interestingly, caveolin-1 also associates with LD(Reference Fujimoto, Kogo and Ishiguro75Reference Brasaemle, Dolios and Shapiro78), hinting at a role for caveolin-1 in lipolysis. Accordingly, caveolin-1-deficient mice display a blunted response to pharmacological and physiological lipolytic stimuli(Reference Cohen, Razani and Schubert79). Surprisingly, PKA activity is not impaired in this genotype, but rather increased(Reference Cohen, Razani and Schubert79) as a result of the absence of aromatic residues within the caveolin scaffolding domain that mediate PKA inhibition(Reference Razani, Rubin and Lisanti80). Despite accentuated PKA activity, PLIN phosphorylation is dramatically reduced in the absence of caveolin-1. A likely explanation has arisen from the in vivo and in vitro evidence that caveolin-1 facilitates the interaction between the catalytic subunit of PKA and PLIN(Reference Razani, Rubin and Lisanti80). The heavy representation of caveolae on plasma membranes therefore suggests an important pro-lipolytic function for caveolin-1, via PLIN phosphorylation. Importantly, the contribution of caveolin-1 in the regulation of lipolysis has yet to be explored in human fat cells but certainly warrants attention.

Fatty acid-binding protein 4

FABP4, also known as adipocyte lipid-binding protein, belongs to the large family of lipid-binding proteins. This low-molecular-mass soluble protein is highly expressed in WAT and displays a high affinity for hydrophobic species such as NEFA and retinoic acids(Reference Bernlohr, Doering and Kelly81, Reference Matarese and Bernlohr82). FABP are thought to provide solubility to NEFA and facilitate their intracellular trafficking between metabolic enzymes and membranes(Reference Coe and Bernlohr83, Reference Hertzel and Bernlohr84). FABP4 physically binds to HSL in vitro and in vivo. The first 300 amino acids of HSL provide a docking domain for FABP4(Reference Shen, Sridhar and Bernlohr20). HSL and FABP4 bind 1:1 in the cytosol in response to accentuated lipolysis(Reference Jenkins-Kruchten, Bennaars-Eiden and Ross85). As demonstrated by fluorescence resonance energy transfer analysis, this complex translocates to LD on PKA activation(Reference Smith, Sanders and Thompson86).

Comparative gene identification 58

CGI-58, also known as α/β-hydrolase domain-containing protein 5, is yet another protein associated with LD. CGI-58 is a α/β-hydrolase fold-containing protein that resembles a lipase(Reference Schrag and Cygler87). However, the putative catalytic triad of CGI-58 contains an asparagine in place of the usual serine residue. CGI-58 in itself therefore lacks lipase activity. In the mouse CGI-58 is highly expressed in WAT and testes, and to lower levels in liver, skin, kidney, heart, stomach, and lung(Reference Subramanian, Rothenberg and Gomez88). CGI-58 stimulates lipolysis by potently and selectively activating ATGL(Reference Lass, Zimmermann and Haemmerle89). In mature murine adipocytes CGI-58 is localized to the surface of LD via association with PLINA(Reference Subramanian, Rothenberg and Gomez88, Reference Yamaguchi, Omatsu and Matsushita90). On β-AR stimulation CGI-58 is rapidly dispersed to the cytosol, an event reversible with the addition of β-AR antagonists. Under these conditions CGI-58 and ATGL co-localization is greatly accentuated and tends to migrate to small LD(Reference Granneman, Moore and Granneman64). Interestingly, CGI-58 has recently been found to exert lysophosphatidic acid acyltransferase activity(Reference Ghosh, Ramakrishnan and Chandramohan91). This activity is independent of its functions as an activator of ATGL. Thus, while CGI-58 overexpression in yeast increases overall phospholipid content, it reduces neutral lipid content.

In human subjects CGI-58 has been identified as a causal gene of the Chanarin-Dorfman syndrome, a disorder characterized by the accumulation of abnormally large amounts of LD in several organs(Reference Lefevre, Jobard and Caux92). In total, nine mutations of CGI-58 have been identified in patients with Chanarin-Dorfman syndrome(Reference Lefevre, Jobard and Caux92, Reference Akiyama, Sawamura and Nomura93). CGI-58 mutants with Chanarin-Dorfman syndrome point mutations are not recruited to LD as expected and display weak interactions with PLIN(Reference Yamaguchi, Omatsu and Matsushita90). This outcome may be physiologically relevant to basal and PKA-stimulated lipolysis. Recently, the importance of CGI-58 in both basal and PKA-stimulated lipolysis has been shown in human adipocytes. Gene silencing of CGI-58 not only reduces basal lipolysis by half but also completely abrogates PKA-stimulated lipolysis in hMADS adipocytes (a human white adipocyte model)(Reference Bezaire, Mairal and Ribet38). The precise whole-cell dynamics involving CGI-58, PLINA and ATGL in basal and PKA-stimulated lipolysis have not been fully elucidated but CGI-58 appears important in both states.

Models of lipolysis activation

The recent identification of an additional lipase and its co-activator, as well as the characterization of novel protein–protein and lipid–protein interactions have drastically changed the working model of basal and PKA-stimulated lipolysis. Fig. 2 presents a hypothetical model of human adipocyte lipolysis.

Fig. 2. Hypothetical model of basal and protein kinase A (PKA)-stimulated lipolysis in human adipocytes. In the basal state (a) adipose TAG lipase (ATGL) is found both in the cytosol and on the surface of lipid droplets (LD). On LD ATGL is activated by comparative gene identification 58 (CGI-58), which is also bound to perilipin A (PLINA). During basal lipolysis ATGL and CGI-58 facilitate the hydrolysis of TAG to diacylglycerols (DAG). Hormone-sensitive lipase (HSL) is mainly cytosolic but also is involved in DAG degradation provided by ATGL action. In PKA-stimulated conditions (b) PLINA phosphorylation (P) promotes LD fragmentation and the release of CGI-58. ATGL and CGI-58 form a highly-active complex on small LD where they catalyse TAG degradation. Phosphorylated HSL associates with FABP4 and translocates to LD where it hydrolyses DAG produced by ATGL. Monoacylglycerol (MAG) lipase (MGL) completes lipolysis by hydrolysing DAG to a fatty acid (FA) and glycerol molecule. FABP4 ensures the intracellular trafficking of FA from LD to the plasma membrane.

A model has been proposed that integrates the newly-identified ATGL into lipolysis(Reference Granneman and Moore94). It is hypothesized that in the basal state ATGL is mostly located on the surface of LD and exerts little activity because of the association between CGI-58 and PLINA. HSL is mainly found in the cytosol and has limited access to TAG or DAG. Only on phosphorylation of PLINA would CGI-58 dissociate from the latter to bind and activate ATGL on LD and initiate TAG hydrolysis. HSL translocation to the surface of LD via its docking on PLINA would allow the enzyme to participate in PKA-stimulated lipolysis by catalysing DAG hydrolysis. This model supports ATGL- and HSL-dependent lipolysis in PKA-stimulated conditions but offers limited insight into the control of basal lipolysis.

A model has been proposed that addresses more explicitly the role of ATGL in basal lipolysis(Reference Brasaemle95). It is suggested that in the basal state ATGL is associated with LD in a PLINA-independent manner. It is bound to its co-activator CGI-58 despite the latter's docking on PLINA. Together ATGL and CGI-58 dictate the rate of basal lipolysis by hydrolysing TAG to DAG. HSL is largely cytosolic and has minimal access to TAG or DAG. On PKA activation HSL and PLINA are phosphorylated. HSL translocates to LD via phosphorylated PLINA and hydrolyses DAG. PLINA phosphorylation also leads to the release of CGI-58 in the cytosol. Two scenarios are envisaged for ATGL and CGI-58 in PKA-stimulated conditions; cytosolic CGI-58 is either not involved in stimulated lipolysis or it forms a complex with cytosolic ATGL and migrates to LD in a PLINA-independent manner. Together ATGL and CGI-58 participate in PKA-stimulated TAG hydrolysis. Generated DAG are further hydrolysed by HSL. MGL completes lipolysis by generating NEFA and glycerol.

Results generated from a human adipocyte cell line provide additional information(Reference Bezaire, Mairal and Ribet38). First, the data demonstrate a 50% reduction in basal lipolysis following single and dual gene silencing of ATGL and CGI-58, while HSL silencing has no effect. This finding strongly suggests that ATGL and CGI-58 govern basal lipolysis through TAG hydrolysis. Second, immunofluoresence results indicate important amounts of cytosolic ATGL in the basal state, with translocation to small LD on PKA activation. In this condition a specific HSL inhibitor reduces NEFA release by 60–65%, which suggests that in the whole adipocyte uniquely ATGL hydrolyses TAG (HSL and MGL releasing the second and third NEFA). This notion is further supported by complete abrogation of PKA-stimulated lipolysis with single and dual silencing of ATGL and CGI-58. Thus, it is believed that the increased number of ATGL–CGI-58 complexes formed following PLINA phosphorylation and docked on small LD govern PKA-stimulated lipolysis. Overall, it is the sequential effect of ATGL-accentuated TAG hydrolysis, phosphorylated HSL and MGL action that yields massive increases in NEFA release in response to PKA activation.

A regulatory step is also provided by the association between FABP4 and HSL. NEFA binding to FABP4 and HSL phosphorylation precede the association between FABP4 and HSL(Reference Smith, Thompson and Sanders96). Thus, in addition to supporting NEFA trafficking to the plasma membrane in a reaction that is independent of physical association with HSL, FABP4 bound to fatty acids associates with activated phosphorylated HSL on the surface of LD. Fatty acid–FABP4–HSL association could either limit HSL activity or alter the formation of the complex on LD(Reference Smith, Thompson and Sanders96). However, in the absence of FABP4 lipolysis is decreased and the NEFA content within adipocytes is three times greater than that in wild-type littermates(Reference Coe, Simpson and Bernlohr97). As NEFA need to be trafficked from the site of hydrolysis (LD) to the plasma membrane, the loss of FABP4 may explain reduced NEFA release.

Integration of lipolysis into adipose tissue biology

Lipolysis and re-esterification

Attention in WAT metabolism thus far has been mainly directed towards catabolic pathways but WAT mass is also dependent on NEFA esterification. Lipolysis and esterification are not limited to fasted and postprandial states respectively, but rather undergo constant cycling in both anabolic and catabolic states(Reference Newsholme98). In postprandial states glucose is the main source of the glycerol backbone. The abundance of both NEFA and glucose facilitates esterification. In catabolic states glucose levels cannot support esterification; rather, phosphoenolpyruvate carboxykinase provides glycerol backbones from pyruvate via the glyceroneogenesis pathway (for review, see Forest et al. (Reference Forest, Tordjman and Glorian99)). Accordingly, phosphoenolpyruvate carboxykinase expression and activity are increased with fasting(Reference Reshef, Hanson and Ballard100) and β-AR agonist treatment(Reference Franckhauser, Antras-Ferry and Robin101), both highly catabolic states.

Re-esterification is the esterification of NEFA on existing acylglycerol molecules. Similarly to esterification, re-esterification occurs concurrently with lipolysis(Reference Vaughan102Reference Hammond and Johnston104). The regulation of re-esterification is unclear. Strong correlations between re-esterification and lipolysis rates over a wide range of lipolytic flux have been observed in mature adipocytes(Reference Vaughan102) and a human adipocyte cell line(Reference Bezaire, Mairal and Ribet38). In hMADS adipocytes altering lipase content quantitatively changes lipolysis and re-esterification fluxes, the coupling of the two variables remaining constant and elevated at 86%(Reference Bezaire, Mairal and Ribet38). In human subjects re-esterification is estimated at 50–75%(Reference Reshef, Olswang and Cassuto105, Reference Wang, Zang and Ling106) but can decrease to 20–35% with fasting and exercise(Reference Coppack, Frayn and Humphreys107, Reference Wolfe, Klein and Carraro108).

It was previously thought that re-esterification of NEFA occurs through an extracellular route(Reference Edens, Leibel and Hirsch109). With current knowledge of LD structure, questions relating to trafficking dynamics extend beyond NEFA. They also apply to acylglycerol species that are synthesized in association with the smooth endoplasmic reticulum but stored and hydrolysed in LD. Preferential hydrolysis or esterification of one acylglycerol species over another is therefore of interest. It has previously been shown that DAG are preferentially hydrolysed over TAG during PKA-stimulated lipolysis(Reference Edens, Leibel and Hirsch110). Despite overall activation of lipolysis, this preferential hydrolysis occurs because of the strong capacity and affinity of HSL for DAG in human WAT(Reference Bezaire, Mairal and Ribet38, Reference Mairal, Langin and Arner41). Conversely, it has been found that DAG are preferentially re-esterified in the basal state and crucial to the preservation of a fixed fractional re-esterification rate in hMADS adipocytes. While forskolin uncouples re-esterification from lipolysis, inhibition of HSL restores the coupling(Reference Bezaire, Mairal and Ribet38). The implication of these findings in human adipocytes could be favoured re-esterification in obese individuals, for whom PKA-activated DAG breakdown by HSL is challenged(Reference Jensen, Haymond and Rizza3, Reference Langin, Dicker and Tavernier40, Reference Large, Reynisdottir and Langin111).

Lipolysis and adipose tissue inflammation

The past 15 years have provided evidence of the endocrine function of WAT. WAT secretes numerous proteins implicated in the control of energy homeostasis, blood pressure and coagulation, vasculature and the immune system. Immune system proteins are not only intrinsically produced and secreted by adipocytes but also by WAT-resident macrophages. As adiposity increases, so does WAT infiltration of macrophages(Reference Weisberg, McCann and Desai112, Reference Xu, Barnes and Yang113). WAT-resident macrophages express and secrete pro-inflammatory factors and establish the low-grade inflammation state observed in WAT with obesity and believed to be an important mediator of insulin resistance(Reference Xu, Barnes and Yang113, Reference Hotamisligil, Shargill and Spiegelman114). FABP are involved in linking WAT inflammation and systemic effects. Targeting FABP with a small-molecule inhibitor reduces WAT macrophage infiltration and the expression of inflammatory products by macrophages(Reference Furuhashi, Tuncman and Gorgun115). Moreover, FABP deficiency in either macrophages or adipocytes improves insulin action and signalling(Reference Furuhashi, Fucho and Gorgun116). This process is thought to occur as a consequence of a unique lipid profile in FABP-null mice(Reference Cao, Gerhold and Mayers117).

A selected group of pro-inflammatory cytokines directly promote lipolysis. The resulting elevated circulating levels of NEFA further aggravate insulin resistance. TNFα is a pro-inflammatory cytokine highly expressed in obesity. Chronic TNFα treatment induces a process termed adipocyte de-differentiation, whereby PPARγ expression levels are drastically reduced(Reference Zhang, Berger and Hu118). Consequently, expression of its target genes is reduced, including HSL(Reference Sumida, Sekiya and Okuda119) and ATGL(Reference Kralisch, Klein and Lossner120, Reference Kim, Tillison and Lee121). However, TNFα exerts pro-lipolytic effects independently of lipase content. First, TNFα interferes with the anti-lipolytic action of insulin. Specifically, TNFα inhibits insulin receptor substrate 1 activation by promoting its serine phosphorylation through the p42-44 mitogen-activated PK pathway(Reference Engelman, Berg and Lewis122, Reference Fujishiro, Gotoh and Katagiri123). Second, TNFα increases stimulatory GTP-binding protein-coupled receptors:inhibitory GTP-binding protein-coupled receptors by markedly reducing the protein content of all three inhibitory GTP-binding protein subtypes on fat cells(Reference Gasic, Tian and Green124). Although this effect is limited to rodent fat cells(Reference Ryden, Arvidsson and Blomqvist125), TNFα-induced degradation of inhibitory GTP-binding proteins by the proteasomal pathway(Reference Botion, Brasier and Tian126) mitigates the anti-lipolytic action of adenosine. Last, TNFα treatment reduces total PLINA content in adipocytes(Reference Zhang, Halbleib and Ahmad30, Reference Souza, Vargas and Yamamoto127) and their phosphorylation by PKA(Reference Souza, Palmer and Kang128). This effect promotes lipolysis by increasing exposure of lipids to ATGL and HSL.

IL-6 is a pro-inflammatory cytokine heavily secreted from visceral WAT(Reference Fontana, Eagon and Trujillo129). Its expression is elevated in patients suffering from obesity and type 2 diabetes(Reference Bastard, Jardel and Bruckert130, Reference Vozarova, Weyer and Hanson131). IL-6 stimulates basal(Reference Petersen, Carey and Sacchetti132) and PKA-activated lipolysis(Reference Päth, Bornstein and Gurniak133) and induces insulin resistance(Reference Rotter, Nagaev and Smith134, Reference Lagathu, Bastard and Auclair135). Stimulation of lipolysis is thought to take place independently of PKA, through the extracellular signal-regulated kinase pathway, resulting in diminished PLINA content(Reference Yang, Ju and Zhang136). However, IL-6 also promotes fatty acid oxidation(Reference Petersen, Carey and Sacchetti132, Reference van Hall, Steenberg and Sacchetti137) via the AMPK pathway(Reference Al-Khalili, Bouzakri and Glund138, Reference Carey, Steinberg and Macaulay139). Thus, despite the pro-inflammatory status of IL-6, its overall systemic effects have been rather challenging to discern(Reference Kristiansen and Mandrup-Poulsen140, Reference Carey, Petersen and Bruce141). Conversely, the action of IL-1β is better defined. IL-1β stimulates lipolysis in cultured adipocytes(Reference Feingold, Doerrler and Dinarello142, Reference Doerrler, Feingold and Grunfeld143) and inhibits lipogenesis in bone marrow adipocytes(Reference Delikat, Galvani and Zuzel144). These effects are thought to partially occur as a result of impaired phosphorylation of insulin receptor substrate 1(Reference Lagathu, Yvan-Charvet and Bastard145).

While certain pro-inflammatory cytokines stimulate lipolysis, products of lipolysis have been shown to mediate inflammation in adipose tissue(Reference Suganami, Nishida and Ogawa146). Using co-cultures of adipocytes and macrophages it has been demonstrated that saturated NEFA can activate macrophages and lead to the up-regulation of macrophage-related genes(Reference Suganami, Tanimoto-Koyama and Nishida147). Saturated NEFA can therefore be defined as adipocyte-derived paracrine mediators of WAT inflammation. This response is thought to take place through the mitogen-activated PK and NF-κB pathways(Reference Suganami, Tanimoto-Koyama and Nishida147, Reference Lee, Sohn and Rhee148). Thus, the presence of a paracrine loop between adipocytes and macrophages probably aggravates adipose tissue inflammation. The existence of a cross talk between adipocyte fat metabolism and macrophage activation is supported by in vivo clinical data on the regulation of WAT gene expression during a dietary weight-loss programme(Reference Capel, Klimcakova and Viguerie149).

Summary

Knowledge about adipose tissue lipolysis has been considerably expanded in the recent years. The hormonal regulation of lipolysis is no longer limited to HSL. Other key players have been characterized. ATGL, CGI-58 and PLIN each play an important role in the regulation of basal and stimulated lipolysis. Co-activation mechanisms, e.g. CGI-58 action on ATGL, have been identified. Protein–protein interactions such as FABP4–HSL and caveolin–PLIN have been shown to influence cellular lipid stores. Cellular trafficking and distribution of the lipolytic machinery under various physiological conditions is of current interest and should provide an important insight into whole-adipocyte lipolysis. The understanding of the cross talk within adipose tissue between metabolism and inflammation may constitute a promising avenue for the understanding of obesity- and type 2 diabetes-related complications.

Acknowledgements

The authors declare no conflict of interest. V. B. produced the first draft of the manuscript, suggested and included corrections and prepared the Figures. D. L. planned the manuscript, proposed corrections and additions and edited the final version. This work was supported by Inserm andYSL Beauté/BRI, the Commission of the European Communities (Integrated Project HEPADIP, contract no. LSHM-CT-2005-018734, the Collaborative Project ADAPT contract no. HEALTH-F2-2008-2011 00) and the Natural Sciences and Engineering Research Council of Canada (NSERC-PDF).

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Figure 0

Fig. 1. Signal transduction pathways implicated in hormonal control of human adipocyte lipolysis. Coupling of β1 and β21/2)- and α2-adrenergic receptors (AR) respectively stimulate and inhibit cAMP production by adenylyl cyclase (AC) and protein kinase A (PKA) activation. Insulin favours cAMP degradation through activation of protein kinase (PK) B and phosphodiesterase 3B (PDE-3B) activity. Natriuretic peptides promote cGMP accumulation and PKG activation via type A receptor. PKA and PKG phosphorylate hormone-sensitive lipase (HSL) and perilipin A (PLINA). Adipose TAG lipase (ATGL) and monoacylglycerol lipase (MGL) are not thought to be directly hormonally-regulated. Gs, stimulatory GTP-binding protein; Gi, inhibitory GTP-binding protein; IRS, insulin receptor substrate; PI3-K phosphatidylinositol-3 phosphate kinase; GC, guanylyl cyclase; LD, lipid droplet.

Figure 1

Fig. 2. Hypothetical model of basal and protein kinase A (PKA)-stimulated lipolysis in human adipocytes. In the basal state (a) adipose TAG lipase (ATGL) is found both in the cytosol and on the surface of lipid droplets (LD). On LD ATGL is activated by comparative gene identification 58 (CGI-58), which is also bound to perilipin A (PLINA). During basal lipolysis ATGL and CGI-58 facilitate the hydrolysis of TAG to diacylglycerols (DAG). Hormone-sensitive lipase (HSL) is mainly cytosolic but also is involved in DAG degradation provided by ATGL action. In PKA-stimulated conditions (b) PLINA phosphorylation (P) promotes LD fragmentation and the release of CGI-58. ATGL and CGI-58 form a highly-active complex on small LD where they catalyse TAG degradation. Phosphorylated HSL associates with FABP4 and translocates to LD where it hydrolyses DAG produced by ATGL. Monoacylglycerol (MAG) lipase (MGL) completes lipolysis by hydrolysing DAG to a fatty acid (FA) and glycerol molecule. FABP4 ensures the intracellular trafficking of FA from LD to the plasma membrane.