Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice

Abstract

Leptin is a circulating protein involved in the long-term regulation of food intake and body weight. Cholecystokinin (CCK) is released postprandially and elicits satiety signals. We investigated the interaction between leptin and CCK-8 in the short-term regulation of food intake induced by 24-hr fasting in lean mice. Leptin, injected intraperitoneally (i.p.) at low doses (4-120 g͞kg), which did not influence feeding behavior for the first 3 hr postinjection, decreased food intake dose dependently by 47-83% during the first hour when coinjected with a subthreshold dose of CCK. Such an interaction was not observed between leptin and bombesin. The food-reducing effect of leptin injected with CCK was not associated with alterations in gastric emptying or locomotor behavior. Leptin-CCK action was blocked by systemic capsaicin at a dose inducing functional ablation of sensory afferent fibers and by devazepide, a CCK-A receptor antagonist but not by the CCK-B receptor antagonist, L-365,260. The decrease in food intake which occurs 5 hr after i.p. injection of leptin alone was also blunted by devazepide. Coinjection of leptin and CCK enhanced the number of Fos-positive cells in the hypothalamic paraventricular nucleus by 60%, whereas leptin or CCK alone did not modify Fos expression. These results indicate the existence of a functional synergistic interaction between leptin and CCK leading to early suppression of food intake which involves CCK-A receptors and capsaicin-sensitive afferent fibers.

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

“…In the current study, we were unable to p<0.001 compared with combined therapy group could help determine whether increased insulin secretion or decreased liver clearance is involved. By contrast, the synergistic interaction between leptin and CCK to reduce shortterm food intake is well established [31][32][33]. Thus, as expected, in the current study combined administration of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 exhibited significantly enhanced acute feeding-suppressive effects compared with either peptide alone.…”

No evidence of an additive inhibitory feeding effect following PP and PYY3−36 administration

“…For example, pairs of appetite inhibitory hormones that have been reported to inhibit feeding additively, such as CCK-8 and leptin, 11 PYY 3À36 and GLP-1 7À36 , 12 and PYY 3À36 and exendin-4, 17 consist of two peptides from different families.…”

“…The gut hormone cholecystokinin-8 (CCK-8) potentiated the appetite inhibitory effects of the adipocyte hormone, leptin, in rodents. 11 More recently, the gut hormones, PYY 3À36 and GLP-1 7À36 , were reported to inhibit feeding additively in rodents and humans at low doses at which neither peptide significantly altered feeding when administered individually. 12 Low-dose combined peptide administration could have the therapeutic advantage of greater inhibition of feeding with a more favourable side-effect profile.…”

Anticipatory physiological regulation in feeding biology: Cephalic phase responses

“…Indeed, leptin and CCK appear to act synergistically to reduce both long and short-term food intake (Matson and Ritter, 1999;Barrachina et al, 1997).…”