Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome.

Adipose tissue lipolysis is the catabolic process leading to the breakdown of triglycerides stored in fat cells and release of fatty acids and glycerol. Recent work has revealed that lipolysis is not a simple metabolic pathway stimulated by catecholamines and inhibited by insulin. There have been new discoveries on the endocrine and paracrine regulation of lipolysis and on the molecular mechanisms of triglyceride hydrolysis. Catecholamines modulate lipolysis through lipolytic beta-adrenoceptor and antilipolytic alpha2-adrenoceptor. Recent studies have allowed a better understanding of the relative contribution of the two types of receptors and provided evidence for the in vivo involvement of alpha2-adrenoceptors in the physiological control of subcutaneous adipose tissue lipolysis. A puzzling observation is the characterization of a residual catecholamine-induced lipolysis in mice deficient in beta-adrenoceptors. A novel lipolytic system has been characterized in human fat cells. Natriuretic peptides stimulate lipolysis through a cGMP-dependent pathway. There are other lipolytic pathways active in human fat cells which importance is not fully understood. Forty years after the description of the antilipolytic effect of nicotinic acid, the receptors have been identified. Adrenomedullin which is produced by adipocytes exert an antilipolytic effect through an indirect mechanism involving nitric oxide. The molecular details of the lipolytic reaction are not fully understood. The role of the lipases has been re-evaluated with the cloning of adipose triglyceride lipase. Hormone-sensitive lipase appears as the major lipase for catecholamine and natriuretic peptide-stimulated lipolysis whereas adipose triglyceride lipase mediates the hydrolysis of triglycerides during basal lipolysis. Translocation of hormone-sensitive lipase bound to the adipocyte lipid binding protein to the lipid droplet seems to be an important step during lipolytic activation. Re-organization of the lipid droplet coating by perilipins facilitates the access of the enzyme. The role of other lipid-interacting proteins in lipolysis is still unclear. The proteins involved in the lipolytic process constitute drug targets for the treatment of obesity and the metabolic syndrome. The oldest example is nicotinic acid (niacin) used as a hypolipidaemic drug. A first approach consists in molecules stimulating lipolysis and oxidation of the released fatty acids to decrease fat stores. A second approach is a chronic inhibition of lipolysis to diminish plasma fatty acid level which is a central feature of the metabolic syndrome.