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Ratner, C.* ; He, Z.* ; Grunddal, K.V.* ; Skov, L.J.* ; Hartmann, B.* ; Zhang, F.* ; Feuchtinger, A. ; Bjerregaard, A.* ; Christoffersen, C.* ; Tschöp, M.H. ; Finan, B.* ; DiMarchi, R.D.* ; Leinninger, G.M.* ; Williams, K.W.* ; Clemmensen, C.* ; Holst, B.*

Long-acting neurotensin synergizes with liraglutide to reverse obesity through a melanocortin-dependent pathway.

Diabetes 68, 1329-1340 (2019)
Publ. Version/Full Text Postprint Research data DOI
Open Access Green
Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a long-acting, pegylated analog of the NT peptide (P-NT) reduces food intake, body weight, and adiposity in diet-induced obese mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the glucagon-like peptide 1 mimetic liraglutide, the two peptides syner-gized to reduce food intake and body weight relative to each monotherapy, without inducing a taste aversion. Further, P-NT and liraglutide coadministration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT–induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination therapy. Overall, our data suggest that P-NT and liraglutide combination therapy could be an enhanced treatment for obesity with improved tolerability compared with liraglutide monotherapy.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Glp-1 Receptor Agonist; Diet-induced Obese; Food-intake; Administered Neurotensin; Glucose-homeostasis; Peptide-1 Receptor; Corrects Obesity; Pomc Neurons; Leptin; Thermogenesis
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Journal Diabetes
Quellenangaben Volume: 68, Issue: 6, Pages: 1329-1340 Article Number: , Supplement: ,
Publisher American Diabetes Association
Publishing Place Alexandria, VA.
Reviewing status Peer reviewed