Characterization of Blood-Brain Barrier Permeability to PYY_3-36 in the Mouse

Abstract

Peptide YY 3-36 (PYY) has emerged as an important signal in the gut-brain axis, with peripherally administered PYY affecting feeding and brain function. For these effects to be direct, PYY would have to cross the blood-brain barrier (BBB). Here, we determined the permeability of the BBB to PYY radioactively labeled with 131 I (I-PYY). Multiple-time regression analysis showed the unidirectional influx rate (K i ) from blood-to-brain for I-PYY to be 0.49 Ϯ 0.19 l/g-min, a rate similar to that previously measured for leptin. Influx was not inhibited by 1 g/ mouse of unlabeled PYY, suggesting PYY crosses the BBB by transmembrane diffusion. About 0.176% of the i.v.-injected dose of I-PYY was taken up by brain, an amount similar to that for other peptides important in gut-brain communication. Capillary depletion showed that 69% of I-PYY crossed the BBB to enter the parenchymal space of the brain, and high-performance liquid chromatography demonstrated that the radioactivity in this space represented intact I-PYY. After intracerebroventricular injection, I-PYY crossed from brain to blood by the mechanism of bulk flow. We conclude that PYY crosses in both the blood-to-brain and brain-to-blood directions by nonsaturable mechanisms. Passage across the BBB provides a mechanism by which blood-borne PYY can affect appetite and brain function.Peptide YY has emerged as a major component of the gut-brain axis regulation of feeding, body weight, and nutritional status. It is a member of the neuropeptide Y family that includes neuropeptide Y (NPY), pancreatic polypeptide, and two forms of peptide YY, a 36-amino acid form and the 3-to 36-amino acid form (PYY). Each of these forms acts through the NPY receptors (Larhammar, 1996). For example, PYY is an agonist at the Y1/Y2 receptors and promotes feeding, whereas PYY 3-36 is an antagonist at the Y2 receptor and inhibits feeding (Grandt et al., 1994b). PYY is abundant in human blood (Grandt et al., 1994a) and is released from endocrine cells found throughout the small intestine in proportion to the caloric content of a meal (Ekblad and Sundler, 2002). Blood-borne PYY can affect appetite and influence neuronal activity at the arcuate nucleus (Batterham et al., 2002).The arcuate nucleus in the adult is clearly separated from the peripheral circulation and median eminence by the endothelial and ependymal arms of the blood-brain barrier (BBB) (Rethelyi, 1984;Peruzzo et al., 2000). Therefore, PYY would have to negotiate the BBB to reach the receptors in the arcuate nucleus. The BBB controls the exchange of peptides and regulatory proteins between the central nervous system (CNS) and blood (Banks and Kastin, 1985, 1996Kastin et al., 1990;Begley, 1992;Brownlees and Williams, 1993) and has emerged as a major regulator of communication between the central nervous system and the peripheral tissues . One area where this regulation is particularly clear is in the area of feeding hormones. Leptin (Banks et al., 1996), ghrelin (Banks et al., 2002c), melanocyte-stimulating hormone (Wilson ...

Daily, intermittent intravenous infusion of peptide YY(3-36) reduces daily food intake and adiposity in rats

“…It is not clear whether the source of endogenous ligand for these receptors is in the brain or periphery. Systemically administered PYY readily penetrates the blood-brain barrier (30). On the other hand, PYY-like immunoreactivity has been detected in various brain regions linked to control of food intake including hypothalamus and brain stem (8,15,16,27).…”

Interaction of NPY compounds with the rat glucocorticoid-induced receptor (GIR) reveals similarity to the NPY–Y2 receptor

“…Interestingly, rGIR is expressed in the arcuate and NTS, two areas which are known to mediate the anorectic effects of PYY3-36 [2,16]. High blood-brain barrier permeability been reported for PYY [18], which may facilitate its interaction with rGIR in a manner similar to Y 2 receptors.…”

Peptide YY, appetite and food intake

“…Circulating substances have access to the hypothalamic arcuate nucleus (Merchenthaler, 1991) and there appears to be non-saturable transport of PYY 3-36 across the blood-brain barrier (Nonaka et al 2003). Moreover, food intake is inhibited if PYY 3-36 is injected directly into the arcuate nucleus (Batterham et al 2002).…”