Pharmacokinetics and pharmacodynamics of subcutaneously administered PYY3-36 and its analogues in vivo.

BACKGROUND: Obesity is an emergent epidemic associated with morbidity, mortality, and psychosocial effects. One of the key gut hormones that controls appetite is peptide tyrosine-tyrosine 3-36 (PYY3-36) whose circulating half-life is only 8 min. A long-acting analogue of PYY3-36 would therefore have great potential as an antiobesity agent. The aims of this study were to investigate the effect of various aminoacid modifications of PYY3-36 on pharmacokinetics and their ability to suppress food intake. METHODS: To investigate the pharmacokinetics of PYY3-36 and three modified analogues, serial sampling of plasma peptide levels via cannulation of the jugular vein was performed after subcutaneous injection of the peptide in rats (n=4 per peptide, 80 nmol/kg). To investigate the effect of these peptides on food intake, mice were injected subcutaneously (1000 nmol/kg) and food intake was assessed at timed intervals over 24 h (n=8 per peptide). FINDINGS: One-way ANOVA with post-hoc Dunnett's test was used in which each comparison was with the PYY3-36 or saline group. Plasma concentrations of the modified analogue, PYY-AP3H, were significantly higher than PYY3-36 up to 24 h post injection (p=0·0008 at 4 h, p=0·0028 at 24 h). The results confirm that modification of the native peptide, by addition of an α-helix stabilising sequence and histidine residues, lengthens the pharmacokinetic profile. Furthermore, PYY-AP3H significantly reduced food intake for up to 24 h compared with saline (p<0·0001) and native PYY3-36 (p<0·0001). INTERPRETATION: The rationally designed analogue, PYY-AP3H, has potential as a once-a-day subcutaneously administered preparation for the treatment of obesity. FUNDING: UK Medical Research Council, Biotechnology and Biological Sciences Research Council, National Institute for Health Research (NIHR), an Integrative Mammalian Biology (IMB) Capacity Building award, an FP7-HEALTH-2009-241592 EuroCHIP grant, NIHR Imperial Biomedical Research Centre Funding Scheme.

The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism.

Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo(11)C-acetate and PET-CT scanning to show that colonic acetate crosses the blood-brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through (13)C high-resolution magic-angle-spinning that (13)C acetate from fermentation of (13)C-labelled carbohydrate in the colon increases hypothalamic (13)C acetate above baseline levels. Hypothalamic (13)C acetate regionally increases the (13)C labelling of the glutamate-glutamine and GABA neuroglial cycles, with hypothalamic (13)C lactate reaching higher levels than the 'remaining brain'. These observations suggest that acetate has a direct role in central appetite regulation.

Intracerebroventricular administration of vasoactive intestinal peptide inhibits food intake.

Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide expressed throughout the peripheral and central nervous systems. VIP and the VIP receptor VPAC(2)R are expressed in hypothalamic nuclei involved in the regulation of energy homeostasis. VIP has been shown to be involved in the regulation of energy balance in a number of non-mammalian vertebrates. We therefore examined the effects of intracerebroventricular (ICV) administration of VIP on food intake, energy expenditure and activity in adult male Wistar rats. VIP administration caused a potent short lived decrease in food intake and an increase in activity and energy expenditure. The pathways potentially involved in the anorexigenic effects of VIP were investigated by measuring the release of neuropeptides involved in the regulation of food intake from hypothalamic explants treated with VIP. VIP significantly stimulated the release of the anorexigenic peptide alpha-melanocyte stimulating hormone (αMSH). These studies suggest that VIP may have an endogenous role in the hypothalamic control of energy homeostasis.