Cholecystokinin is involved in triglyceride fatty acid uptake by rat adipose tissue.

The incorporation of plasma triglyceride (TG) fatty acids to white adipose tissue (WAT) depends on lipoprotein lipase (LPL), which is regulated by angiopoietin-like protein-4 (ANGPTL-4), an unfolding molecular chaperone that converts active LPL dimers into inactive monomers. The production of ANGPTL-4 is promoted by fasting and repressed by feeding. We hypothesized that the postprandial hormone cholecystokinin (CCK) facilitates the storage of dietary TG fatty acids in WAT by regulating the activity of the LPL/ANGPTL-4 axis and that it does so by acting directly on CCK receptors in adipocytes. We report that administration of CCK-8 (a bioactive fragment of CCK) to rats: (i) reduces plasma ANGTPL-4 levels; (ii) represses Angptl-4 expression in WAT and (iii) simultaneously enhances LPL activity in this tissue without inducing Lpl expression. In vivo CCK-8 effects are specifically antagonized by the CCK-2 receptor (CCK-2R) antagonist, L-365,260. Moreover, CCK-8 downregulates Angptl-4 expression in wild-type pre-adipocytes, an effect that is not observed in engineered pre-adipocytes lacking CCK-2R. These effects have functional consequences as CCK-8 was found to promote the uptake of dietary fatty acids by WAT, as demonstrated by means of proton nuclear magnetic resonance (1H-NMR). The efficacy of acute CCK-8 administration was not reduced after chronic CCK-8 treatment. Moreover, the effects of CCK-8 on WAT were not associated to the increase of circulating insulin. Our results show that cholecystokinin promotes lipid storage in WAT by acting on adipocyte CCK-2R, suggesting a pivotal role for CCK in TG homeostasis.

Effect of adrenaline and glucocorticoids on monocyte cAMP-specific phosphodiesterase (PDE4) in a monocytic cell line.

An increase in phosphodiesterase 4 (PDE4) in blood mononuclear white cells of patients with atopic dermatitis (AD) has been described. This and other skin disorders worsen during stress, during which there are increased circulating levels of adrenaline and glucocorticoids. The aim of this study was to analyse the effect of both these hormones on PDE4 in inflammatory cells. The human monocyte cell line U-937 was used as a model of blood mononuclear leucocytes. For this purpose, (1) the effect of adrenaline on PDE4 activity was determined, (2) the receptor mediating adrenaline actions was characterized, (3) the role of intracellular cAMP in PDE4 activation was investigated and (4) the effect of glucocorticoids on PDE4 activity was also ascertained. Adrenaline at a concentration of 1 micro M produced a two- to threefold selective increase in PDE4 activity in U-937 cells after 4 h of incubation with the hormone. This stimulation was reversible, as well as concentration- and time-dependent. Cycloheximide (10 micro M) induced a blockade of adrenaline-induced stimulation of PDE4. The stimulatory effect was inhibited by propranolol, but not by atenolol or phentolamine, in a concentration-dependent manner and was mimicked by salbutamol. The stimulation of PDE4 was paralleled by an increase in intracellular levels of cAMP. 8-Br-cAMP and forskolin also increased PDE4 activity. After 4 h of incubation in the presence of adrenaline, inhibition of cAMP degradation by rolipram further increased cAMP levels by about 300% and also enhanced PDE4 activity. These results suggest that adrenaline-induced stimulation of PDE4 is mediated by the beta(2)-adrenoceptor and is related to intracellular levels of cAMP, which might trigger expression and synthesis of the enzyme. The synthetic glucocorticoid dexamethasone (in the concentration range 10(-8) to 10(-6) M) showed no effect on PDE4 activity or on the cAMP accumulation induced by adrenaline, even after prolonged (24 h) incubation with the cells. Of the two stress hormones assayed, PDE4 activity was shown to be sensitive to adrenaline elevation but resistant to changes in glucocorticoid levels in the U-937 monocytic cell line.