Long-Acting Neurotensin Synergizes With Liraglutide to Reverse Obesity Through a Melanocortin-Dependent Pathway

Diabetes. 2019 Jun;68(6):1329-1340. doi: 10.2337/db18-1009. Epub 2019 Apr 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity / drug effects*
  • Animals
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Body Weight / drug effects*
  • Delayed-Action Preparations
  • Drug Synergism
  • Eating / drug effects*
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Hypoglycemic Agents / pharmacology*
  • Liraglutide / pharmacology*
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Melanocortins / metabolism
  • Mice
  • Mice, Knockout
  • Neurotensin / pharmacology*
  • Obesity / metabolism*
  • Polyethylene Glycols


  • Blood Glucose
  • Delayed-Action Preparations
  • Hypoglycemic Agents
  • Melanocortins
  • Neurotensin
  • Polyethylene Glycols
  • Liraglutide