International Journal of Obesity (2000) 24, Suppl 4, S47±S52 ß 2000 Macmillan Publishers Ltd All rights reserved 0307±0565/00 $15.00 www.nature.com/ijo Recent developments on lipolysis regulation in humans and discovery of a new lipolytic pathway

M Lafontan1*, C Sengenes1, J Galitzky1, M Berlan1, I De Glisezinski1, F Crampes1, V Stich1, D Langin1, P Barbe1 and D RivieÁre1

1Unite INSERM 317, Institut Louis Bugnard, Universite Paul Sabatier, Toulouse, France

In man, the major hormones controlling the lipolytic function are insulin (inhibition of lipolysis) and catecholamines (stimulation of lipolysis). Catecholamines are of major importance for the regulation of lipid mobilization in human adipose tissue and for the increase of non-esteri®ed fatty acid supply to the working muscle. In vitro studies have shown that there are differences in the catecholaminergic control of fat cells from various fat deposits and a number of physiological and pathological alterations of catecholamine-induced lipolysis have been reported. Lipolytic resistance to catecholamines has been reported in subcutaneous adipose tissue, the major fat depot in obese subjects. Multiple alterations in catecholamine signal transduction pathways have been reported. In situ microdialysis allows a physiological exploration of adipose tissue biology. Recent data obtained on the catecholaminergic regulation of lipolysis and lipid mobilization, using microdialysis in humans, will be analysed. A potent lipolytic and lipomobilizing effect of atrial natriuretic peptide has recently been discovered; the mechanisms of action and physiological relevance will also be discussed. International Journal of Obesity (2000) 24, Suppl 4, S47±S52

Keywords: lipolysis; catecholamines; adipose tissue; atrial natriuretic peptide

Introduction the working muscle. The simpli®ed scheme of regula- tion of HSL activity by catecholamines follows the Hormone-sensitive lipase (HSL) is the rate-limiting well-known sequence: the binding of agonists to the enzyme in the hydrolysis of stored triglycerides in b-adrenergic receptors (b-ARs) coupled to adenylyl adipose tissue and lipolysis regulation. HSL functions cyclase via the stimulatory Gs protein, increment of together with monoglyceride lipase (MGL), which is cAMP production which leads to activation of protein required to obtain a complete hydrolysis of the mono- kinase A (PKA) and phosphorylation of HSL, result- glycerides produced by HSL action.1 In contrast to ing in increased enzyme activity and NEFA and HSL, MGL is not believed to be under acute hormonal glycerol release by fat cells. HSL-derived fatty acids or neural control. Basically, short-term regulation of are bound by adipocyte lipid-binding protein (ALBP) adipocyte lipolysis is under the control of a number of to facilitate intracellular traf®cking of hydrophobic stimulatory and inhibitory pathways leading to the lipids. Until recently, HSL activation was believed to control of hormone-sensitive lipase (HSL) activity. In be exerted via the phosphorylation of a serine residue, human adipocyte, the major hormones controlling the Ser-563 (corresponding to Ser-552 in human HSL), by lipolytic function are insulin (inhibition of lipolysis) PKA. Another site known to be phosphorylated by and catecholamines (stimulation of lipolysis). Insulin cAMP-independent mechanisms in non-stimulated is regarded as the most important antilipolytic hor- adipocytes, Ser-565 (corresponding to Ser-554 in mone in mammals. Its ability to antagonize hormone- human HSL), does not appear to directly affect induced lipolysis can, to a large extent, be explained enzyme activity. This site, often referred to as the by its ability to activate phosphodiesterase 3B and basal site, is presumably phosphorylated by the lower cAMP production in fat cells.2 Catecholamines 50AMP-activated protein kinase and prevents subse- are of major importance for the regulation of lipid quent phosphorylation of HSL by PKA. Two novel mobilization in human adipose tissue (AT) and for the sites, Ser-659 and Ser-660, which are phosphorylated increase of non-esteri®ed fatty acid (NEFA) supply to both in vivo in response to a b-adrenergic stimulation and in vitro by PKA, represent new candidates for HSL activation in rat fat cells.3 The role of the corresponding putative sites requires demonstration *Correspondence: M Lafontan, Unite INSERM 317, Institut Louis in human fat cells. Recent data also suggest that in Bugnard, CHU Rangueil, Universite Paul Sabatier, 31403 Toulouse cedex, France. addition to PKA other kinases may also be involved in E-mail: [email protected] the activation of HSL. Lipolysis regulation M Lafontan et al S48 It is clear that HSL regulation is under the potent Hormone-sensitive lipase function control of cAMP and PKA. In human fat cells, and beta-adrenoceptor-mediated adenylyl cyclase activity and cAMP production are stimulation of lipolysis under the concomitant control of positive b1-, b2- and b3-AR-dependent stimulation and a2-AR-mediated The activity of the sympathetic nervous system (SNS) inhibition. In vitro studies on human fat cells have is related to the three major components of energy clearly shown that the ®ne tuning of cAMP levels and expenditure, that is, resting metabolic rate, thermic lipolysis by catecholamines is dependent on the cross- effect of food and spontaneous physical activity. It is talk between b- and a2-AR-dependent pathways. The considered that a low activity of the SNS is associated level of expression and the repertoire of human fat cell with the development of obesity in rodents and ARs largely differ according to the sex, the anatomi- humans. Alterations of SNS signalling at the target cal location and the size of fat deposits, and the age of cell level (eg the fat cell being one of the privileged the subjects. The variable af®nities of the various b- targets), could have a major effect on metabolic and a2-AR subtypes for catecholamines could explain events controlled by the SNS, especially lipolysis the differential receptor recruitment assessed in a and thermogenesis. The b2-AR is a major lipolytic number of in vitro studies. Usually, fat cells from receptor in human fat cells while the physiological visceral deposits exhibit the highest b-adrenergic and role of the b3-AR remains questionable, although 4 the lowest a2-adrenergic responsiveness. In vitro some drugs, considered b3-agonists, have been studies have suggested that there is lipolytic resistance shown to exert lipolytic effects in human omental to catecholamines in human subcutaneous AT, the fat cells. Various forms of treatment of obesity such as major fat depot in obese subjects.5,6 Multiple altera- low- and very-low-energy diets and physical activity tions in catecholamine signal transduction pathways, remain widely used therapies to promote weight involving decreased expression and function of b2- reduction in obese patients. Alterations of the lipolytic ARs, increased expression and function of a2-AR, responses affecting HSL expression and function and decreased ability of cAMP to stimulate HSL and=or b-AR-mediated events have recently been described reduced expression of the enzyme have been reported. on human isolated fat cells in vitro or when using in The regulation of lipolysis in vitro is complex because situ microdialysis in patients submitted to such thera- of the heterogeneity of fat cell a2-=b-AR adrenoceptor pies (Table 1). Comparison of subcutaneous adipo- ratio according to AT location. Interindividual varia- cytes, with identical sizes but exhibiting high and low tions in catecholamine-induced lipolysis are of impor- lipolytic capacity, has revealed that HSL activity and tance for the rate of weight loss. Concomitant quantity is the lowest in the low lipolytic responders. variations in b2-AR and a2-AR sensitivity in adipo- HSL expression, measured either as total HSL protein cytes may be predictive of weight loss during treat- by Western blot analysis or as total amount of HSL ment with very-low-energy diets. Tissue-speci®c activatable enzyme, is a major determinant of the investigations, using in situ microdialysis, are neces- maximum lipolytic capacity of human fat cells.7 sary to establish the physiological relevance of a large Moderate weight loss leads to improved adipose cell number of in vitro data. lipolytic ef®ciency, which is associated with changes

Table 1 Physiological and pathological modi®cations of the lipolytic responses to catecholamines in human adipocyte and adipose tissue (microdialysis)

Physiological and pathological situations Lipolytic response Modulatory effects

Neonatal period Decreased a2-Adrenergic responsiveness: Aging Decreased Activation of HSL; Sex-related differences Variable Changes in the balance between a2- and b-adrenergic effects HSL expression correlated positively with fat cell size Anatomical differences Variable Changes in the balance between a2- and b-adrenergic effects HSL expression correlated positively with fat cell size Very-low-energy diet Increased HSL expression: Endurance training Increased b-Adrenergic response: Obesity Normal or diminished HSL expression;b2-Adrenoceptor expression;a2-Adrenoceptor expression: Insulin resistance syndrome Decreased HSL activation;b2-Adrenoceptor number; Combined familial hyperlipidemia Decreased HSL expression; Polycystic ovary syndrome Decreased HSL activation;b2-Adrenoceptor number; Hypothyroidism Decreased HSL activation; Hyperthyroidism Increased b-Adrenoceptor number: Cushing syndrome Decreased Unknown Phaeochromocytoma Decreased Unknown Type I diabetes Increased b-Adrenergic response: Head-down bed rest Increased b-Adrenergic response:

HSL, hormone-sensitive lipase.

International Journal of Obesity Lipolysis regulation M Lafontan et al S49 at receptor levels (increased b2- and decreased a2-AR human bAR-2 gene could be of major importance for 8 sensitivities). Hereditary in¯uences have been obesity, energy expenditure and b2-AR-dependent reported in catecholamine-induced lipolysis.9±11 lipolytic function in AT. It should be noticed that, in Recent genetic studies have shown the involvement human fat cells, any reduction of the b2-AR-mediated of genes encoding components of the lipolytic path- lipolytic response will disturb the functional balance ways in obesity. The HSL locus was associated with between a2- and b2-AR-mediated effects and amplify obesity and NIDDM in two independent studies, the reduction of the lipolytic response initiated by the suggesting that the HSL gene could represent a physiological amines. susceptibility gene for both disorders.12 A number of studies have tested whether known polymorphisms in codons 64 for the b3-AR and 16, 27 and 164 for the b2-AR play a role in the control of the lipolytic function of adipocyte and have an incidence Physiological activation of fat cell on the development of obesity-related metabolic a2-adrenoceptors and alterations disorders. A missense mutation of b3-AR gene of lipid mobilization (Trp64Arg) has been reported to be associated with high BMI, abdominal obesity, increased capacity to The regulation of lipolysis in vitro is complex because gain weight and resistance to insulin and early onset of the heterogeneity of fat cell a2-=b-AR adrenoceptor of non-insulin-dependent diabetes mellitus (NIDDM). ratio according to AT location. The coexistence of For the moment a number of controversial studies lipolytic b-ARs and antilipolytic a2-ARs in human fat have been reported and it is dif®cult to reach a cells has been largely demonstrated through in vitro ®nal conclusion.13 Some studies have shown that the studies on isolated fat cells and binding studies. The polymorphism is associated with obesity and altered rate of lipolysis Ð through activation or inhibition of b3-AR function while others did not show any pheno- adenylyl cyclase Ð is relevant from this dual action of typic effect of the polymorphism. catecholamines on lipolysis. In human subcutaneous The b2-AR, Thrl64Ile substitution, leading to fat cells where a2-ARs numerically predominate over alteration of b-AR coupling and function, was not b-ARs, the recruitment of the a2-ARs, leading to detected in the subjects studied. In a group of 140 epinephrine inhibition of lipolysis, has been described women with a large variation in body fat mass, the in vitro. Epinephrine is the preferential amine for fat Gln27Glu substitution was twice as common in obese cell a2-adrenoceptors, suggesting that it is probably subjects as in non-obese; homozygotes for Glu27Glu involved more than norepinephrine in the control of had an average fat mass excess of 20 kg and approxi- lipolysis through the a2-adrenergic pathway. The 9,14 mately 50% larger fat cells than controls. However, physiological relevance of such in vitro a2-AR respon- no signi®cant association with changes in b2-AR siveness to catecholamines is not clearly understood function was observed. The frequency of the Glu27 and has been questioned several times. Interindividual is also higher in patients with NIDDM, but this and anatomical variations in catecholamine-induced association could be secondary to obesity. The poly- lipolysis are of importance for the rate of weight loss. morphisms in codons 16 and 27 are in a strong linkage In vitro studies have shown that concomitant varia- disequilibrium, as two-thirds of the women investi- tions in b2-AR and a2-AR sensitivity in adipocytes gated carried at the same time Gly16 and Glu27 in a may be predictive of weight loss during treatment hetero- or homozygous form. The Arg16Gly poly- with dieting or very-low-energy diets.8,16 Whatever morphism was associated with altered b2-AR func- the mechanistic interest of the in vitro approaches, tion, with Gly16 carriers showing a 5-fold increased tissue-speci®c investigations, using in situ micro- agonist sensitivity and without any change in b2-AR dialysis, are necessary to settle the physiological expression. The frequency of Gly16 homozygotes was relevance of a large number of in vitro studies and lower in obese women when compared with non- the signi®cance of a2-AR-mediated pathways. obese. A recent population study on 1195 subjects The putative physiological relevance of a2-ARs has of the WHO-MONICA project in the North of France recently been investigated more deeply by our group. has shown that men bearing the Gln27Gln genotype Exercise was selected as a perequisite to activate the had higher body weight, body mass index and waist ± SNS and promote increment of circulating catechol- hip ratio and increased risk of obesity; the effect, amines in man. The aim of our studies was: (1) to mainly detected in men, is independent of the reveal the consequences of a physiological activation Gly16Arg polymorphism (Meirhaeghe, 1999, of fat cell b-=a2-ARs in subcutaneous AT in normal personal communication). Physical activity counter- subjects performing exercise, and (2) to delineate the balanced the effect of the genetic predisposition to importance of a2-AR-mediated pathways in the AT of increase body weight, body fat and obesity described obese subjects during exercise. in Gln27Gln subjects. Obese individuals with the b2- The ®rst study, in which the aim was to determine AR Gln27Gln genotype may bene®t from physical the involvement of the antilipolytic a2-adrenergic activity to reduce their weight.15 These ®ndings sug- pathway and the speci®c role of epinephrine in the gest that polymorphisms in the coding sequence in the control of lipolysis during exercise in AT, was

International Journal of Obesity Lipolysis regulation M Lafontan et al S50 performed on healthy male subjects. An in vitro study logical relevance of b- and a2-AR interplay in the carried out on isolated adipocytes showed that the control of lipolysis in subcutaneous adipose tissue weak lipolytic effect of epinephrine was potentiated during exercise in men. The study suggests for the after blockade of a2-AR by an a2-AR antagonist and ®rst time that epinephrine has a speci®c role in vivo in reached that of isoproterenol, a b-AR agonist. The the control of lipolysis in human subcutaneous AT effect of the non-selective a2-AR antagonist phentol- through activation of antilipolytic a2-ARs. It also amine on the response of the extracellular glycerol updates numerous in vitro studies which propose concentration (EGC) in AT during two successive that the activation of a2-ARs by epinephrine could bouts of aerobic exercise (50% VO2max, 60 min dura- play an important role in the control of lipolysis in tion) was evaluated using the microdialysis method. AT, especially in subcutaneous fat deposits. The metabolic responses measured in perfused probes The second study was performed to see if the with Ringer solution were compared to those obtained physiological activation of antilipolytic a2-ARs in perfused probes with Ringer plus 0.1 mmol=l phen- could be an important inhibitory factor for lipid tolamine. Plasma norepinephrine level was not differ- mobilization in subcutaneous AT in exercising obese ent during the two exercise bouts while that of subjects, the adipose tissue of which expresses a epinephrine was 2.5-fold higher during the second higher a2-AR component in vitro. Using the micro- exercise. EGC in AT was 2-fold higher in the second dialysis method, we investigated whether the blockade compared to the ®rst exercise and the same response of a2-ARs can improve lipolysis in subcutaneous pattern was found for plasma glycerol. The exercise- adipose tissue (SCAT) during exercise in healthy induced increase in EGC was higher in the probe young obese and lean men. Changes in extracellular perfused with phentolamine compared to the control glycerol concentrations and in blood ¯ow were mea- probe in both bouts of exercise. However, the poten- sured in SCAT (using microdialysis probes infused tiating effect of phentolamine on EGC was signi®cant with Ringer's solution supplemented with ethanol) at during the second exercise bout but did not reach a rest and during 60 min exercise bouts at 50% of heart 17 signi®cant level during the ®rst. rate reserve. One probe was supplemented with the a2- The present study reveals that epinephrine contri- AR antagonist phentolamine. At rest and during butes to exercise-induced lipolysis although the exis- exercise, plasma norepinephrine and epinephrine con- tence of a2-AR-mediated counteraction was clearly centrations were not different in the two groups. In the revealed with our protocol. Previous studies using basal state, plasma and extracellular glycerol concen- microdialysis have led to con¯icting results. Using trations were higher, while blood ¯ow was lower, in local administration of phentolamine, one study in SCAT of obese subjects. During exercise, the greatest normal subjects has shown that resting lipolysis was increase of plasma glycerol was observed in obese modulated by a2-adrenergic inhibition whereas the a2- subjects (115Æ 35 vs 65Æ 21 mmol=l). Conversely, the adrenergic mechanism did not modulate lipolysis exercise-induced increase EGC was 5 ± 6 fold lower during exercise.18 Our study demonstrates the physio- in obese than in lean subjects (50Æ 14 vs

Figure 1 Time-course of extracellular glycerol concentration changes in subcutaneous adipose tissue, calculated from dialysate glycerol levels, during 60 min cycle-ergometer exercise in lean and obese subjects. The a2-adrenergic receptor antagonist phentol- amine was or was not added to the perfusion medium. Data are meansÆ s.e.m. from seven separate experiments.

International Journal of Obesity Lipolysis regulation M Lafontan et al S51 318Æ 53 mmol=l). The exercise-induced increase in receptors in human fat cells. Activation or inhibition EGC was not signi®cantly modi®ed by phentolamine of cGMP-inhibited phosphodiesterase (PDE-3B) and infusion in lean but was strongly enhanced in the obese inhibition of adenylyl cyclase activity did not alter subjects and reached the concentrations found in lean ANP-induced lipolysis. The data clearly show that subjects (297Æ 46 mmol=l) (Figure 1). The physio- natriuretic peptides are novel activators of human AT logical stimulation of SCAT adipocyte a2-ARs during lipolysis, operating via a cGMP-dependent pathway exercice-induced SNS activation contributes to the which does not involve PDE-3B inhibition and cAMP blunted lipolysis noted in obese men. production.19 The mechanisms explaining the possible In summary these in vivo results provide evidence, cGMP-dependent activation of hormone-sensitive for the ®rst time, of the important contribution played lipase remain to be demonstrated. It must be remem- by a2-ARs in the physiological impairement of lipo- bered that in vitro studies have shown that HSL could lysis in the adipose tissue of obese men. The role of be phosphorylated by cGMP-dependent protein 20 a2-ARs may be explored in other fat deposits, in both kinase. Moreover the results also raise questions men and women, in which the adipocytes express about of the physiological and=or pathological role a high level of a2-ARs greatly outnumbering that of of this new lipolytic pathway. b-ARs. These ®ndings may have important physio- pathologic implications in men developing large sub- cutaneous fat deposits and women with excessive hip and femoral fat deposits. It is tempting to speculate Conclusions and future trends that adipocyte a2-ARs may make a major contribution to the resistance of SCAT to fat loss during very-low- Recent data indicate that genetic factors may modify energy diets and during physical training programmes HSL expression and=or activity and the action of in obese subjects. Local or oral administration of an catecholamines on lipolysis on fat cells and exert a2-AR antagonist could represent a possible strategy a role in the development of obesity. Altered to facilitate mobilization of SCAT when obese SNS impact on its target cells could lead to the subjects are submitted to periods of exercise. development of obesity. Reduced ef®ciency of b- To conclude, these physiological studies have adrenoceptor-dependent lipolysis and=or enhanced demonstrated: (1) that epinephrine is involved in the a2-adrenoceptor-mediated antilipolysis could both control of lipid mobilization through activation of impair lipolysis and lead to catecholamine resistance antilipolytic a2-ARs in human subcutaneous AT, and promote development of obesity. Environmental during exercise; (2) that a physiological stimulation factors such as a sedentary lifestyle may worsen a of adipocyte a2-ARs strongly impairs exercise- hereditary defect affecting b-adrenoceptor-dependent induced lipolysis in subcutaneous AT in obese sub- lipolysis while physical exercise may counterbalance jects. The blunting of lipid mobilization induced by the incidence of the hereditary defect. Much informa- exercise-induced noradrenaline release is completely tion is needed about the disturbances affecting all the suppressed by the local administration of an a2-AR steps of the lipolytic cascade and the genetic factors antagonist. having an effect on these events. Studies associating an approach of the interactions between genetic fac- tors and environmental conditions will be productive in that way. Atrial natriuretic peptides and lipolysis regulation in humans

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