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Recent Developments on Lipolysis Regulation in Humans and Discovery of a New Lipolytic Pathway

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Recent Developments on Lipolysis Regulation in Humans and Discovery of a New Lipolytic Pathway 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
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