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

Abstract

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 expression in WAT and (iii) simultaneously enhances LPL activity in this tissue without inducing expression. CCK-8 effects are specifically antagonized by the CCK-2 receptor (CCK-2R) antagonist, L-365,260. Moreover, CCK-8 downregulates 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 (H-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.

The cholecystokinin receptor agonist, CCK‐8, induces adiponectin production in rat white adipose tissue

“…Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny, Browne, Cuthill, Emerson, & Altman, ) and with the recommendations made by the British Journal of Pharmacology . The in vivo studies were carried out in adult male Sprague–Dawley rats during the nocturnal period of the circadian cycle, under similar experimental conditions to those used in our laboratory to investigate the role of CCK‐8 on other aspects of energy metabolism (Merino, Cano, Guzman, Somoza, & Ruiz‐Gayo, ; Merino, Somoza, Ruiz‐Gayo, & Cano, ; Plaza, Merino, Cano, et al, ). The dose of CCK‐8 (10 μg·kg −1 ) was chosen on the basis of previous studies (Merino, Cano, et al, ; Plaza, Merino, Cano, et al, ).…”

“…The in vivo studies were carried out in adult male Sprague–Dawley rats during the nocturnal period of the circadian cycle, under similar experimental conditions to those used in our laboratory to investigate the role of CCK‐8 on other aspects of energy metabolism (Merino, Cano, Guzman, Somoza, & Ruiz‐Gayo, ; Merino, Somoza, Ruiz‐Gayo, & Cano, ; Plaza, Merino, Cano, et al, ). The dose of CCK‐8 (10 μg·kg −1 ) was chosen on the basis of previous studies (Merino, Cano, et al, ; Plaza, Merino, Cano, et al, ). This dose did not significantly increase total CCK immunoreactivity in plasma and was able to activate CCK receptors in adipocytes (Plaza, Merino, Cano, et al, ).…”

“…The dose of CCK‐8 (10 μg·kg −1 ) was chosen on the basis of previous studies (Merino, Cano, et al, ; Plaza, Merino, Cano, et al, ). This dose did not significantly increase total CCK immunoreactivity in plasma and was able to activate CCK receptors in adipocytes (Plaza, Merino, Cano, et al, ). The time of CCK‐8 administration (10 p.m.) was selected because CCK‐8 has been shown to be more effective when administered earlier in the night (Kraly, ).…”

“…The CCK 2 receptors (also previously called gastrin receptors) are widely expressed in the CNS (Dufresne, Seva, & Fourmy, ) and, in the periphery; these receptors play a major role in maintaining the normal function of gastric mucosa (Chen et al, ). A recent study carried out in our laboratory has shown that activation of CCK 2 receptors facilitates the uptake of dietary triglycerides by white adipocytes, suggesting that CCK is involved in regulating homeostasis in white adipose tissue (WAT) (Plaza, Merino, Cano, et al, ; Plaza, Merino, Sánchez‐Pernaute, et al, ). Related with that, studies carried out by Flatt's group have provided evidence of the effect of CCK in alleviating symptoms of insulin resistance (Irwin et al, ; Irwin, Montgomery, O'harte, Frizelle, & Flatt, ), which supports the concept of an insulin/CCK drive of energy metabolism.…”

“…Taking into account (a) the role of CCK in regulating WAT homeostasis (Plaza, Merino, Cano, et al, ), (b) the existence of a complete CCK system in WAT (Plaza, Merino, Sánchez‐Pernaute, et al, ), and (c) the already reported interaction between CCK and insulin in driving energy metabolism (Irwin et al, ; Irwin et al, ; Pathak, Flatt, & Irwin, ), we aimed at investigating the effect of the C‐terminal bioactive fragment of CCK, CCK‐8, on both adiponectin gene ( Adipoq ) expression and adiponectin production in rat WAT.…”