Recent developments on lipolysis regulation in humans and discovery of a new lipolytic pathway M Lafontan 1 *, C Sengenes 1 , J Galitzky 1 , M Berlan 1 , I De Glisezinski 1 , F Crampes 1 , V Stich 1 , D Langin 1 , P Barbe 1 and D Rivie `re 1 1 Unite ´ 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-esterified 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 Hormone-sensitive lipase (HSL) is the rate-limiting enzyme in the hydrolysis of stored triglycerides in adipose tissue and lipolysis regulation. HSL functions together with monoglyceride lipase (MGL), which is required to obtain a complete hydrolysis of the mono- glycerides produced by HSL action. 1 In contrast to HSL, MGL is not believed to be under acute hormonal or neural control. Basically, short-term regulation of adipocyte lipolysis is under the control of a number of stimulatory and inhibitory pathways leading to the control of hormone-sensitive lipase (HSL) activity. In human adipocyte, the major hormones controlling the lipolytic function are insulin (inhibition of lipolysis) and catecholamines (stimulation of lipolysis). Insulin is regarded as the most important antilipolytic hor- mone in mammals. Its ability to antagonize hormone- induced lipolysis can, to a large extent, be explained by its ability to activate phosphodiesterase 3B and lower cAMP production in fat cells. 2 Catecholamines are of major importance for the regulation of lipid mobilization in human adipose tissue (AT) and for the increase of non-esterified fatty acid (NEFA) supply to the working muscle. The simplified scheme of regula- tion of HSL activity by catecholamines follows the well-known sequence: the binding of agonists to the b-adrenergic receptors (b-ARs) coupled to adenylyl cyclase via the stimulatory Gs protein, increment of cAMP production which leads to activation of protein kinase A (PKA) and phosphorylation of HSL, result- ing in increased enzyme activity and NEFA and glycerol release by fat cells. HSL-derived fatty acids are bound by adipocyte lipid-binding protein (ALBP) to facilitate intracellular trafficking of hydrophobic lipids. Until recently, HSL activation was believed to be exerted via the phosphorylation of a serine residue, Ser-563 (corresponding to Ser-552 in human HSL), by PKA. Another site known to be phosphorylated by cAMP-independent mechanisms in non-stimulated adipocytes, Ser-565 (corresponding to Ser-554 in human HSL), does not appear to directly affect enzyme activity. This site, often referred to as the basal site, is presumably phosphorylated by the 5 0 AMP-activated protein kinase and prevents subse- quent phosphorylation of HSL by PKA. Two novel sites, Ser-659 and Ser-660, which are phosphorylated 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 in human fat cells. Recent data also suggest that in addition to PKA other kinases may also be involved in the activation of HSL. *Correspondence: M Lafontan, Unite ´ INSERM 317, Institut Louis Bugnard, CHU Rangueil, Universite ´ Paul Sabatier, 31403 Toulouse cedex, France. E-mail: lafontan@rangueil.inserm.fr 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