Degradation Paradigm of the Gut Hormone, Pancreatic Polypeptide, by Hepatic and Renal Peptidases.
Pancreatic polypeptide (PP) is a gut hormone that acts on Y4 receptors to reduce appetite. Obese humans display a reduced postprandial increase in PP and remain fully sensitive to the anorectic effects of exogenous PP. The utility of PP as an anti-obesity treatment is limited by its short circulating half-life. Insight into the mechanisms by which PP is degraded could aid in the design of long-acting PP analogs. We investigated the role of peptidases in PP degradation to determine whether inhibition of these enzymes enhanced PP plasma levels and bioactivity in vivo. Dipeptidyl peptidase IV (DPPIV) and neprilysin (NEP) were two peptidase found to cleave PP. Limiting the effect of both peptidases improved the in vivo anorectic effect of PP and PP-based analogs. These findings suggest that inhibiting the degradation of PP using specific inhibitors and/or the design of analogs resistant to cleavage by DPPIV and NEP might be useful in the development of PP as an anti-obesity pharmacotherapy.
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London SW7 2AZ, United Kingdom.
Joyceline
J
Cuenco
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London SW7 2AZ, United Kingdom.
James
J
Minnion
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London SW7 2AZ, United Kingdom.
Tricia
T
Tan
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London SW7 2AZ, United Kingdom.
Rebecca
R
Scott
Department of Endocrinology, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne 42100, France.
Natacha
N
Germain
Department of Endocrinology, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne 42100, France.
Yiin
Y
Ling
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London SW7 2AZ, United Kingdom.
Rong
R
Chen
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London SW7 2AZ, United Kingdom.
Mohammad
M
Ghatei
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London SW7 2AZ, United Kingdom.
Stephen
S
Bloom
D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005768:Gastrointestinal Hormones / Q000097:blood / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015260:Neprilysin / Q000378:metabolism; D010191:Pancreatic Polypeptide / Q000097:blood / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D059748:Proteolysis; D051381:Rats
D005768:Gastrointestinal Hormones; D010191:Pancreatic Polypeptide; D010447:Peptide Hydrolases; D018819:Dipeptidyl Peptidase 4; D015260:Neprilysin