Nature metabolismApr 29, 2025

Combined activation of brain GIP and GLP-1 receptors helps reduce weight in obese mice

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 20, 2026

Abstract

A peptide-antibody conjugate that blocks while activating is essential for maximal weight loss in obese mice.

CNS GIPR and GLP-1R are both necessary for achieving the full weight loss benefits of the GIPR-Ab/GLP-1 treatment.
Dulaglutide leads to greater weight loss in mice lacking CNS GIPR compared to those with it.
The combination of dulaglutide and GIPR-Ab results in reduced weight loss in CNS GIPR knockout mice.
Mice treated with GIPR-Ab/GLP-1 and CNS GIPR knockout mice show similar changes in gene expression related to fat tissue and liver function.
Activation of specific brain regions related to appetite regulation occurs with the GIPR-Ab/GLP-1 treatment.

Simplified

Glucose-dependent insulinotropic polypeptide receptor () and glucagon-like peptide 1 receptor () are expressed in the central nervous system (CNS) and regulate food intake. Here, we demonstrate that a peptide-antibody conjugate that blocks GIPR while simultaneously activating GLP-1R (GIPR-Ab/GLP-1) requires both CNS GIPR and CNS GLP-1R for maximal weight loss in obese, primarily male, mice. Moreover, dulaglutide produces greater weight loss in CNS GIPR knockout (KO) mice, and the weight loss achieved with dulaglutide + GIPR-Ab is attenuated in CNS GIPR KO mice. Wild-type mice treated with GIPR-Ab/GLP-1 and CNS GIPR KO mice exhibit similar changes in gene expression related to tissue remodelling, lipid metabolism and inflammation in white adipose tissue and liver. Moreover, GIPR-Ab/GLP-1 is detected in circumventricular organs in the brain and activates c-FOS in downstream neural substrates involved in appetite regulation. Hence, both CNS GIPR and GLP-1R signalling are required for the full weight loss effect of a GIPR-Ab/GLP-1 peptide-antibody conjugate.

Key numbers

31.9%

Weight Loss Percentage

Average weight loss observed by day 18 in treated mice.

19.4%

Body Weight Change in Female Mice

Percentage weight loss in female mice treated with .

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Funding

Competing interests

Competing interests: All authors, with the exception of D.J.D. and R.H., are or were employees or contractors of Amgen and have received Amgen stock. Most of the work has been included in patent no. PCT/US2016/068138: ‘Method of treating or ameliorating metabolic disorders using binding proteins for gastric inhibitory peptide receptor (GIPR) in combination with GLP-1 agonists.’ D.J.D. has served as a consultant or speaker within the past 12 months to Amgen, AstraZeneca, Insulet, Kallyope, Novo Nordisk and Pfizer. D.J.D. holds non-exercised options in Kallyope.

PubMed

Combined activation of brain GIP and GLP-1 receptors helps reduce weight in obese mice

Abstract

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Competing interests

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Abstract

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