Long-acting CCK analogue NN9056 lowers food intake and body weight in obese Göttingen Minipigs

Abstract

Background/Objectives Cholecystokinin (CCK) is a regulator of appetite and energy intake in man. The aim of this study was to determine the effect of NN9056, a long-acting CCK-1 receptor-selective CCK analogue, on food intake and body weight (BW) in obese Göttingen Minipigs. Subjects/Methods Tolerability of NN9056 and acute effects on food intake, pancreas histology, amylase and lipase levels were assessed in lean domestic pigs in doses up to 100 nmol/kg (n = 3-4). Subsequently, obese Göttingen Minipigs were treated subcutaneously (s.c.) once daily for 13 weeks with vehicle, NN9056 low dose (regulated from 5 to 2 nmol/kg) or NN9056 high dose (10 nmol/kg) (n = 7-8). Food intake was measured daily and BW twice weekly. At the end of the treatment period, an intravenous glucose tolerance test (IVGTT) and a 24-h exposure profile was obtained. Data are mean ± SD. Results The acute studies in domestic pigs showed significant and dose-dependent effect of NN9056 on food intake, acceptable tolerability and no histopathological signs of pancreatitis. Sub-chronic treatment in obese Göttingen Minipigs was also well tolerated and accumulated food intake was significantly lower in both treated groups compared to vehicle, with no significant difference between the dose levels of NN9056 (41.8 ± 12.6, 51.5 ± 13.8 and 86.5 ± 19.5 kg in high-dose, lowdose and vehicle groups, respectively, p = 0.012 and p < 0.0001 for low and high dose vs. vehicle, respectively). Accordingly, there was a weight loss in both treated groups vs. a weight gain in the vehicle group (−7.2 ± 4.6%, −2.3 ± 3.2% and 12.3 ± 3.9% in the high-dose, low-dose and vehicle groups, respectively, p < 0.0001 for both vs. vehicle). IVGTT data were not significantly different between groups. Conclusion NN9056, a long-acting CCK-1 receptor-selective CCK analogue, significantly reduced food intake and BW in obese Göttingen Minipigs after once daily s.c. dosing for 13 weeks.

Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease

“…Combined administration of a CCK1R agonist together with amylin or a GLP-1R agonist over 14–28 days produced considerably greater weight loss relative to monotherapy in mice and rats [ 23 ]. Consistent with these findings, the administration of a long-acting CCK1R agonist for 13 weeks produced sustained reductions in food intake and weight loss in obese Gottingen mini-pigs [ 24 ]. A unimolecular CCK1R agonist AC170222-exenatide analog, designated C2816, was demonstrated to be a full agonist at both the GLP-1R and CCK1R receptors in vitro and produced ∼28% weight loss over 10 days in mice with diet-induced obesity [ 25 ].…”

Determining insulin sensitivity from glucose tolerance tests in Iberian and landrace pigs

“…The IAGTT method allowed the comparison of the insulin responsiveness of an obese (Iberian) and a lean (Landrace) pig breed. It is well established that Iberian pigs have a much greater capacity of lipid deposition in comparison to lean swine breeds ( Nieto et al, 2002 ; Ovilo et al, 2005 ; Muñoz et al, 2009 ) and has since been proposed as a pig model for obesity studies ( Rodriguez Rodriguez et al, 2020 ). For the reason that important differences in for instance protein turnover may take place during development ( Lobley, 1993 ), the study of animal breeds with disparate growth capability is not a simple issue.…”

A Unifying Statistical Framework to Discover Disease Genes from GWAS

“…To our knowledge, the platform is also the first to implicate the well-known satiety hormone CCK (99.1% PPA), its receptor CCKBR (84.3% PPA), and several other neuropeptide hormones and receptors with known roles in food intake regulation. Like GLP-1, cholecystokinin (CCK) has very strong preclinical validation as a regulator of appetite and food intake, and is the target of ongoing drug development for obesity (Christoffersen et al, 2020; Miller et al, 2021). There are as many as three causal variants that alter the expression of CCK (Figure S16), each falling in a distinct enhancer with a different pattern of chromatin accessibility in the brain, intestinal mucosa, and nerve tissue (determined from our atlas of ENCODE open chromatin profiles).…”