Effects of diet on lipolysis and its regulation.

Acute control. Hydrolysis of triacylglycerols is catalysed by hormone-sensitive lipase. The activity of this enzyme is enhanced by phosphorylation by cyclic-AMP-dependent kinase (A-kinase). Hormone-sensitive lipase, and hence lipolysis, is thus acutely stimulated by a variety of hormones (e.g. adrenaline, glucagon, adrenocorticotrophic hormone (ACTH)) and the neurohumoral transmitter, noradrenaline, which increase the adenylate cyclase-A-kinase signal transduction system. Each peptide hormone interacts with its own receptor in the plasma membrane while adrenaline and noradrenaline interact with the P-adrenergic receptor. These hormone-receptor interactions lead to dissociation and activation of the GTP-binding protein, G,, which in turn leads to activation of adenylate cyclase (also located in the plasma membrane) and the synthesis of cyclic-AMP (Fig. 1). Cyclic-AMP activates A-kinase which in turn phosphorylates and activates hormone-sensitive lipase. Signal transduction through this system is modulated by noradrenaline and adrenaline acting via a second receptor, the 1x2-adrenergic receptor, and by prostaglandins (El and E2) and adenosine, both produced within adipose tissue, and acting via their own receptors. These receptors are coupled to a second GTP-binding protein, Gi. Receptor activation leads to dissociation of Gi which inhibits adenylate cyclase (Fig. 1). Catecholamines can, thus, both stimulate and inhibit lipolysis, the net effect depending on the relative numbers of pand cx2-adrenergic receptors of the fat cells. Insulin also modulates lipolysis acutely. The mechanisms have not been fully elucidated but include activation of a cyclic-AMP phosphodiesterase, possibly by increased phosphorylation (Degerman et al. 199Oj, which catalyses the degradation of cyclic-AMP and so reduces A-kinase activity. Insulin is also thought to activate the phosphatases which dephosphorylate and inactivate hormone-sensitive lipase (Stralfors & Honnor, 1989). Recent research is revealing further forms of control for what was once a relatively simple system. A-kinase, and a specific p-adrenergic receptor kinase phosphorylate and uncouple the P-adrenergic receptor from G, (Roth et al. 1991). A-kinase can also phosphorylate and activate cyclic-AMP phosphodiesterase, providing a feedback loop (Degerman etal. 1990). Another kinase has been discovered which is stimulated by AMP (Hardie, 1989). This kinase phosphorylates hormone-sensitive lipase on a serine next but one to that phosphorylated by A-kinase; phosphorylation on either serine prevents phosphorylation on the other (Garton et al. 1989). Since increased concentrations of palmitoyl-CoA lead to activation of this AMP-stimulated kinase (Hardie, 1989), this