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Publication
The Chimeric Peptide (GEP44) Reduces Body Weight and Both Energy Intake and
Energy Expenditure in Diet-Induced Obese Rats.
Authors Goldberg M, Blevins JE, Wolden-Hanson T, Elfers CT, Chichura KS, Ashlaw EF, den
Hartigh LJ, Roth CL, Doyle RP
Submitted By Submitted Externally on 4/23/2025
Status Published
Journal International journal of molecular sciences
Year 2025
Date Published 3/1/2025
Volume : Pages 26 : Not Specified
PubMed Reference 40243702
Abstract We recently reported that a chimeric peptide (GEP44) targeting the glucagon-like
peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2- receptors decreased
body weight (BW), energy intake, and core temperature in diet-induced obese
(DIO) male and female mice. In the current study, we tested the hypothesis that
the strong reduction in body weight in response to GEP44 is partially related to
the stimulation of energy expenditure (EE). To test this, rats were maintained
on a high fat diet (HFD) for at least 4 months to elicit DIO prior to undergoing
a sequential 2-day vehicle period, 2-day GEP44 (50 nmol/kg) period, and a
minimum 2-day washout period, and detailed measures of energy homeostasis. GEP44
(50 nmol/kg) reduced EE (indirect calorimetry), respiratory exchange ratio
(RER), core temperature, activity, energy intake, and BW in male and female
rats. As in our previous study in mice, GEP44 reduced BW in male and female
HFD-fed rats by 3.8 ± 0.2% and 2.3 ± 0.4%, respectively. These effects appear to
be mediated by increased lipid oxidation and reductions in energy intake as
GEP44 reduced RER and cumulative energy intake in male and female HFD-fed rats.
The strong reduction in body weight in response to GEP44 is related to a robust
reduction in energy intake, but not to the stimulation of EE. The paradoxical
finding that GEP44 reduced EE might be secondary to a reduction in diet-induced
thermogenesis or might indicate an important mechanism to limit the overall
efficacy of GEP44 to prevent further weight loss.




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