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

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  • Cecilia Ratner
  • Zhenyan He
  • Kaare V Grunddal
  • Louise J Skov
  • Bolette Hartmann
  • Fa Zhang
  • Annette Feuchtinger
  • Anette Bjerregaard
  • Christina Christoffersen
  • Matthias H Tschöp
  • Brian Finan
  • Richard D DiMarchi
  • Gina M Leinninger
  • Kevin W Williams
  • Christoffer Clemmensen
  • Birgitte Holst
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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 synergized 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.

Original languageEnglish
JournalDiabetes
Volume68
Issue number6
Pages (from-to)1329-1340
Number of pages12
ISSN0012-1797
DOIs
Publication statusPublished - Jun 2019

ID: 58287475