Synergistic effect of CART (cocaine- and amphetamine-regulated transcript) peptide and cholecystokinin on food intake regulation in lean mice

In fasted C57BL/6 mice, the anorexigenic effect of CART(61-102) in the doses of 0.1 or 0.5 μg/mouse was significantly enhanced by low doses of CCK-8 of 0.4 or 4 μg/kg, while 1 mg/kg dose of CCK-A receptor antagonist devazepide blocked the effect of CART(61-102) on food intake. After simultaneous administration of 0.1 μg/mouse CART(61-102) and of 4 μg/kg of CCK-8, the number of Fos-positive neurons in NTS, PVN, and DMH was significantly higher than after administration of each particular peptide. Besides, CART(61-102) and CCK-8 showed an additive effect on inhibition of the locomotor activity of mice in an open field test.The synergistic and long-lasting effect of the CART peptide and CCK on food intake and their additive effect on Fos immunoreactivity in their common targets suggest a co-operative action of CART peptide and CCK which could be related to synergistic effect of leptin on CCK satiety.Information on the metabolic status of the organism enters and is processed in the hypothalamus and in the nucleus tractus solitarii (NTS) of the brainstem (hindbrain). In the hypothalamic arcuate nucleus (ARC), adiposity signal leptin influences expression of peptides affecting food intake such as anorexigenic cocaine- and amphetamine-regulated transcript (CART). ARC neurons project to other hypothalamic areas such as the paraventricular nucleus (PVN) and the lateral hypothalamic area (LHA) (for reviews, see [1-5]). Both PVN and LHA convey neuronal signals to the brainstem where they are integrated with afferent input of cholecystokinin (CCK) [2], satiety peptide of gut origin. For the satiety effect of CCK, leptin signaling in ARC was found necessary [6]. Recently, CCK was shown to facilitate access of leptin to hypothalamic areas and modulate body weight [7].Satiety effect of CCK is mediated by cholecystokinin A (CCK-A or CCK-1) receptors [8] expressed abundantly not only in the brainstem but also in the hypothalamus [9,10]. Unlike CCK receptors, receptors of CART peptid