PEGylated cholecystokinin prolongs satiation in rats: dose dependency and receptor involvement

Abstract

Background and purpose: Acute intraperitoneal (i.p.) administration of cholecystokinin (CCK) is known to induce a significant, but short-lasting, reduction in food intake, followed by recovery within hours. Therefore, we had covalently coupled CCK to a 10 kDa polyethylene glycol and showed that this conjugate, PEG-CCK 9 , produced a significantly longer anorectic effect than unmodified CCK 9 . The present study assessed the dose-dependency of this response and the effect of two selective CCK 1 receptor antagonists, with different abilities to cross the blood-brain barrier (BBB), on PEG-CCK 9 -induced anorexia. Experimental approach: Food intake was measured, for up to 23 h, after i.p. administration of different doses (2, 4, 8, 16 and 32 mg kg À1 ) of CCK 9 or PEG-CCK 9 in male Wistar rats. Devazepide (100 mg kg À1 ), which penetrates the BBB or 2-NAP (3 mg kg À1 ), which does not cross the BBB, were coadministered i.p. with PEG-CCK 9 (6 mg kg À1 ) and food intake was monitored. Key results: In PEG-CCK 9 -treated rats, a clear dose-dependency was seen for both the duration and initial intensity of the anorexia whereas, for CCK 9 , only the initial intensity was dose-dependent. Intraperitoneal administration of devazepide or 2-NAP, injected immediately prior to PEG-CCK 9 , completely abolished the anorectic effect of PEG-CCK 9 . Conclusions and implications: The duration of the anorexia for PEG-CCK 9 was dose-dependent, suggesting that PEGylation of CCK 9 increases its circulation time. Both devazepide and 2-NAP completely abolished the anorectic effect of i.p. PEG-CCK 9 indicating that its anorectic effect was solely due to stimulation of peripheral CCK 1 receptors.

Metabolic effects of activation of CCK receptor signaling pathways by twice-daily administration of the enzyme-resistant CCK-8 analog, (pGlu-Gln)-CCK-8, in normal mice

“…Moreover, knockout rather than upregulation of the CCK 1 receptor has been shown to predispose to anxiety-like behavior in rats (Schroeder & Weller 2010). Body weights of (pGlu-Gln)-CCK-8-treated mice were substantially lower than controls by day 28 accompanied by predictable inhibitory effects on food intake, highlighting the therapeutic potential of (pGlu-Gln)-CCK-8 for obesity-diabetes (Verbaeys et al 2007, Irwin et al 2012. Interestingly, effects of the peptide were recently shown not to be associated with changes in energy expenditure (Irwin et al 2012), highlighting the plasticity of signaling pathways involved in energy intake and weight regulation and suggesting multiple actions of (pGlu-Gln)-CCK-8.…”

“…As such, numerous studies have shown notable therapeutic effectiveness of longer-acting CCK-based compounds (O'Harte et al 1998, Verbaeys et al 2007, 2008, 2009a. In particular, the recently characterized N-terminally modified, enzymatically stable CCK-8 analog, (pGlu-Gln)-CCK-8, causes sustained weight loss and improves both insulin resistance and glucose tolerance in mice with genetically and environmentally induced forms of obesity-diabetes (Irwin et al 2012).…”

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

“…The fact that CCK 2 receptor inhibition did not perturb the satiating effect of (pGlu-Gln)-CCK-8 is interesting since CCK 2 receptor deletion has been associated with increased body weight and hypothalamic neuropeptide Y content [26]. CCK-8 does not cross the blood-brain barrier [2], making accumulation in the brain unlikely even following repeated dosing. Nonetheless, lack of effect of (pGlu-Gln)-CCK-8 on CCK 2 receptor action is encouraging given that activation of this receptor has been associated with panic and anxiety attacks [27,28].…”

“…It is generally now accepted that the major physiological role of the gut-derived peptide cholecystokinin (CCK) is in the short-term regulation of energy balance through stimulation of satiety [1,2]. CCK exists in multiple molecular forms ranging from 58 to 39, 33, 22, 8 and 4 amino acids in length [3], but the carboxy-terminal octapeptide, CCK-8, is well conserved among species and is the smallest form that retains the full range of biological actions [4].…”

“…CCK exists in multiple molecular forms ranging from 58 to 39, 33, 22, 8 and 4 amino acids in length [3], but the carboxy-terminal octapeptide, CCK-8, is well conserved among species and is the smallest form that retains the full range of biological actions [4]. The biological actions of CCK are mediated through two receptors, CCK 1 and CCK 2 , which are predominantly located in the periphery and central nervous system, respectively [5]. Intestinally released CCK-8 cannot cross the blood-brain barrier and the potent short-term effect of CCK-8 on inhibiting food intake is believed to be mediated peripherally via the vagus nerve [2].…”