CAMP- and cGMP-dependent control of lipolysis and lipid mobilization in humans: putative targets for fat cell management

Abstract

The mobilization of triglycerides stored in adipose tissue (AT) plays a major role in supplying non-esterified fatty acids (NEFA) to working muscle. Lipolysis, the hydrolysis of fat cell triacylglycerols by hormone-sensitive lipase (HSL), promotes the release of NEFA and glycerol by fat cells. HSL regulation is under the potent control of cAMP and the cAMP-dependent protein kinase, protein kinase A (PKA). In human fat cells, adenylyl cyclase activity and cAMP production are under the positive control of β1-, β2- and, to a lesser extent, β3-adrenergic-receptor (AR)-dependent stimulation and α2-AR-mediated inhibition. The links between β- and α2-ARs and adenylyl cyclase activity operate through the activationof Gs and GiGTP binding proteins respectively. The adrenergic regulation of lipolysis in vitro is complex because of the heterogeneity of the distribution of α2-/β-ARs in fat cells. A number of in vitro studies have clearly established that the repertoire and the level of expression of ARs in human fat cells differ largely according to the anatomical location and the extent of AT, the sex, the age as well as genetic determinants of the subjects. Fat cells from visceral deposits exhibit the highest β-adrenergic responsiveness and lowest α2-adrenergic response. Reduced adrenaline-induced lipid mobilization has been reported in the AT of obese subjects. Physiological stimulation of adipocyte α2-ARs strongly impairs exercise-induced lipolysis in the subcutaneous AT of obese subjects. It is completely reversed by the local administration of an α2-AR antagonist. Oral administration of an α2-AR antagonist (yohimbine or idazoxan) promotes sympathetic nervous system (SNS) activation and increased lipid mobilization.