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Study · Animal study (in vivo) · mouse · 2026

5 results

Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism.

Lewis JE, Montaner M, Nuzzaci D, James-Okoro PP, Harada N, Inagaki N, Dodson WS, Knerr PJ, Douros JD, Gribble FM, Reimann F

Nature metabolism24 Jul 2026Cited by 1 (Europe PMC)

PMID42498824 (opens in a new tab)PMCIDPMC13489937 (opens in a new tab)DOI10.1038/s42255-026-01575-z (opens in a new tab)PepBankPUB-42498824
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Summary

The development of dual agonists for the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has been a landmark moment in the treatment of type 2 diabetes and obesity. However, for reasons that are incompletely understood, in preclinical and clinical studies, adding either a GIPR agonist or GIPR antagonist to GLP-1R agonism causes additional weight loss1. Here we show that distinct brain regions mediate the appetite-suppressing effects of GIPR agonists and the synergistic weight loss effects conferred by GIPR antagonists. We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (GiprAP-KO and Giprhypo-KO, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide. GiprAP-KO mice exhibit partial protection against diet-induced obesity, reduced responsiveness to the appetite-suppressing effects of acyl-GIP and a reduced ability of acyl-GIP to prevent avoidance triggered by peptide YY. Weight loss effects of liraglutide are comparable in GiprAP-KO and control mice, and the co-administration of a GIPR antagonist peptide causes similar additional weight loss in both groups. Giprhypo-KO mice, by contrast, exhibit normal appetite suppression by acyl-GIP but enhanced weight loss on liraglutide compared with control mice. Giprhypo-KO also abolishes the synergistic effect of a GIPR antagonist when combined with liraglutide-an effect that is not mediated by nucleus tractus solitarius preproglucagon neurons. GIPR antagonism and Giprhypo-KO also sensitise to cagrilintide-induced weight loss. Overall, our results suggest that the AP is responsible for the appetite-suppressing effects of GIPR agonism but that GIP receptors in the hypothalamus underlie the ability of GIPR antagonism to enhance the weight loss effects of GLP-1R and amylin receptor agonists.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study5

2 results from studies that gave the peptide. No result from this study comes from people.

  1. 01AnimalAnimal study (in vivo)Efficacy outcome

    In mice with Gipr knocked out in the area postrema, liraglutide produced weight loss comparable to that in control mice.

    In plain wordsIn mice lacking the GIP receptor in one brain area, liraglutide caused about the same weight loss as in normal mice.

    Peptide
    Liraglutide
    Outcome
    No significant changeWeight loss with liraglutide in Gipr AP-KO versus control mice
    Study

    mousen: not reported in source

    Gipr knockout mice (area postrema or hypothalamus)
    Comparator
    Control mice
    Outcome group
    Body weight · Metabolic and weight
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Weight loss effects of liraglutide are comparable in GiprAP-KO and control mice
    1 context sentence
    Summary · context
    We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (GiprAP-KO and Giprhypo-KO, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide.
  2. 02AnimalAnimal study (in vivo)Efficacy outcome

    In mice with Gipr knocked out in the hypothalamus, liraglutide produced enhanced weight loss compared with control mice.

    In plain wordsIn mice lacking the GIP receptor in the hypothalamus, liraglutide caused more weight loss than in normal mice.

    Peptide
    Liraglutide
    Outcome
    IncreaseWeight loss with liraglutide in Gipr hypo-KO versus control mice
    Study

    mousen: not reported in source

    Gipr knockout mice (area postrema or hypothalamus)
    Comparator
    Control mice
    Outcome group
    Body weight · Metabolic and weight
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Giprhypo-KO mice, by contrast, exhibit normal appetite suppression by acyl-GIP but enhanced weight loss on liraglutide compared with control mice.
    1 context sentence
    Summary · context
    We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (GiprAP-KO and Giprhypo-KO, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide.

Studies that did not test the peptide alone3

In this study, the peptide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking the peptide.

  1. 03AnimalNot a test of Cagrilintide aloneAnimal study (in vivo)Efficacy outcome

    In mice, GIPR antagonism and hypothalamic Gipr knockout each increased the weight loss that cagrilintide caused.

    In plain wordsIn mice, blocking GIP receptors, or removing them from the hypothalamus, made the weight loss from cagrilintide stronger.

    Peptide
    Cagrilintide
    Outcome
    IncreaseCagrilintide-induced weight loss
    Study

    mousen: not reported in source

    Hypothalamic Gipr knockout mice (Gipr hypo-KO)
    Outcome group
    Body weight · Metabolic and weight

    Source sentences

    Summary
    GIPR antagonism and Giprhypo-KO also sensitise to cagrilintide-induced weight loss.
    1 context sentence
    Summary · context
    We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (GiprAP-KO and Giprhypo-KO, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide.

    In this study, Cagrilintide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Cagrilintide.

  2. 04AnimalNot a test of Liraglutide aloneAnimal study (in vivo)Efficacy outcome

    In mice with Gipr knocked out in the area postrema, co-administration of a GIPR antagonist peptide with liraglutide caused similar additional weight loss as in control mice.

    In plain wordsIn mice lacking the GIP receptor in one brain area, adding a GIP receptor blocker to liraglutide gave the same extra weight loss.

    Peptide
    Liraglutide
    Outcome
    No significant changeAdded weight loss from GIPR antagonist peptide plus liraglutide in Gipr AP-KO versus control mice
    Study

    mousen: not reported in source

    Gipr knockout mice (area postrema or hypothalamus)
    Comparator
    Control mice
    Outcome group
    Body weight · Metabolic and weight

    Source sentences

    Summary
    the co-administration of a GIPR antagonist peptide causes similar additional weight loss in both groups.
    1 context sentence
    Summary · context
    We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (GiprAP-KO and Giprhypo-KO, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide.

    In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.

  3. 05AnimalNot a test of Liraglutide aloneAnimal study (in vivo)Efficacy outcome

    In mice with Gipr knocked out in the hypothalamus, the synergistic weight loss effect of a GIPR antagonist combined with liraglutide was abolished.

    In plain wordsIn mice lacking the GIP receptor in the hypothalamus, the extra weight loss from adding a GIP receptor blocker to liraglutide disappeared.

    Peptide
    Liraglutide
    Outcome
    DecreaseSynergy of GIPR antagonist with liraglutide in Gipr hypo-KO mice
    Study

    mousen: not reported in source

    Gipr knockout mice (area postrema or hypothalamus)
    Outcome group
    Body weight · Metabolic and weight

    Source sentences

    Summary
    Giprhypo-KO also abolishes the synergistic effect of a GIPR antagonist when combined with liraglutide
    1 context sentence
    Summary · context
    We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (GiprAP-KO and Giprhypo-KO, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide.

    In this study, Liraglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Liraglutide.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Versions 3 to 38Current

    28 Oct 2026, 02:04 UTC

    The same notice was added 36 times, first on 9 Oct 2026, 18:17 UTC. The status did not change between them.

    Study results updated

  2. Version 2

    9 Oct 2026, 03:04 UTC

    Study data updated · source update from Europe PMC

  3. Version 1

    9 Oct 2026, 03:04 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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