PCSK2-null mice exhibit delayed intestinal motility, reduced refeeding response and altered plasma levels of several regulatory peptides

Aims: To examine the effects of global lack of proprotein convertase subtilisin/kexin 2 (PCSK2) in mouse on intestinal motility, post-fast refeeding response and levels of several PCSK-generated peptides known to regulate food intake and processing. Main methods: Using male and female PCSK2 knockout (KO) and wild-type (WT) mice, intestinal motility was assessed by determining the percent of intestinal length travelled by a charcoal-dyed meal following an oral gavage; the refeeding response by measuring the amount of meal consumed following an overnight fast; the levels of the regulatory peptides by enzyme immunoassays or immunoblotting. Key findings: Relative to same-gender WT mice, KO mice exhibited delayed intestinal transit (P<0.001 in females; P<0.05 in males). Their post-fast feeding response was reduced in females during the first hour of refeeding (P<0.05). The circulating level of substance P (SP) was lower (P<0.001 in females; P<0.05 in males); it was higher for somatostatin (SS) (P<0.001 in females; P<0.05 in males) and GLP-1 (P<0.001 in females; P<0.01 in males) and GLP-2 (P<0.001 in both genders); it was higher for peptide YY (PYY) in female mice only (P<0.01). Processing of brain proneuropeptide Y was impaired in both genders. Significance: The alterations in intestinal motility and post-fast refeeding response observed in PCSK2-KO mice correlate with changes in the circulating and tissue levels of the regulatory peptides tested, suggesting that PCSK2 is needed for normal food intake and processing. (C) 2010 Elsevier Inc. All rights reserved.