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Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms

BACKGROUND: Glucose-dependent insulinotropic peptide (GIP) is one of two incretin hormones that communicate nutrient intake with systemic metabolism. Although GIP was the first incretin hormone to be discovered, the understanding of GIP's biology was quickly outpaced by research focusing on the...

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Autor principal: Campbell, Jonathan E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085569/
https://www.ncbi.nlm.nih.gov/pubmed/33290902
http://dx.doi.org/10.1016/j.molmet.2020.101139
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author Campbell, Jonathan E.
author_facet Campbell, Jonathan E.
author_sort Campbell, Jonathan E.
collection PubMed
description BACKGROUND: Glucose-dependent insulinotropic peptide (GIP) is one of two incretin hormones that communicate nutrient intake with systemic metabolism. Although GIP was the first incretin hormone to be discovered, the understanding of GIP's biology was quickly outpaced by research focusing on the other incretin hormone, glucagon-like peptide 1 (GLP-1). Early work on GIP produced the theory that GIP is obesogenic, limiting interest in developing GIPR agonists to treat type 2 diabetes. A resurgence of GIP research has occurred in the last five years, reinvigorating interest in this peptide. Two independent approaches have emerged for treating obesity, one promoting GIPR agonism and the other antagonism. In this report, evidence supporting both cases is discussed and hypotheses are presented to reconcile this apparent paradox. SCOPE OF THE REVIEW: This review presents evidence to support targeting GIPR to reduce obesity. Most of the focus is on the effect of singly targeting the GIPR using both a gain- and loss-of-function approach, with additional sections that discuss co-targeting of the GIPR and GLP-1R. MAJOR CONCLUSIONS: There is substantial evidence to support that GIPR agonism and antagonism can positively impact body weight. The long-standing theory that GIP drives weight gain is exclusively derived from loss-of-function studies, with no evidence to support that GIPR agonisms increases adiposity or body weight. There is insufficient evidence to reconcile the paradoxical observations that both GIPR agonism and antagonism can reduce body weight; however, two independent hypotheses centered on GIPR antagonism are presented based on new data in an effort to address this question. The first discusses the compensatory relationship between incretin receptors and how antagonism of the GIPR may enhance GLP-1R activity. The second discusses how chronic GIPR agonism may produce desensitization and ultimately loss of GIPR activity that mimics antagonism. Overall, it is clear that a deeper understanding of GIP biology is required to understand how modulating this system impacts metabolic homeostasis.
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spelling pubmed-80855692021-05-11 Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms Campbell, Jonathan E. Mol Metab Review BACKGROUND: Glucose-dependent insulinotropic peptide (GIP) is one of two incretin hormones that communicate nutrient intake with systemic metabolism. Although GIP was the first incretin hormone to be discovered, the understanding of GIP's biology was quickly outpaced by research focusing on the other incretin hormone, glucagon-like peptide 1 (GLP-1). Early work on GIP produced the theory that GIP is obesogenic, limiting interest in developing GIPR agonists to treat type 2 diabetes. A resurgence of GIP research has occurred in the last five years, reinvigorating interest in this peptide. Two independent approaches have emerged for treating obesity, one promoting GIPR agonism and the other antagonism. In this report, evidence supporting both cases is discussed and hypotheses are presented to reconcile this apparent paradox. SCOPE OF THE REVIEW: This review presents evidence to support targeting GIPR to reduce obesity. Most of the focus is on the effect of singly targeting the GIPR using both a gain- and loss-of-function approach, with additional sections that discuss co-targeting of the GIPR and GLP-1R. MAJOR CONCLUSIONS: There is substantial evidence to support that GIPR agonism and antagonism can positively impact body weight. The long-standing theory that GIP drives weight gain is exclusively derived from loss-of-function studies, with no evidence to support that GIPR agonisms increases adiposity or body weight. There is insufficient evidence to reconcile the paradoxical observations that both GIPR agonism and antagonism can reduce body weight; however, two independent hypotheses centered on GIPR antagonism are presented based on new data in an effort to address this question. The first discusses the compensatory relationship between incretin receptors and how antagonism of the GIPR may enhance GLP-1R activity. The second discusses how chronic GIPR agonism may produce desensitization and ultimately loss of GIPR activity that mimics antagonism. Overall, it is clear that a deeper understanding of GIP biology is required to understand how modulating this system impacts metabolic homeostasis. Elsevier 2020-12-05 /pmc/articles/PMC8085569/ /pubmed/33290902 http://dx.doi.org/10.1016/j.molmet.2020.101139 Text en © 2020 The Author https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Review
Campbell, Jonathan E.
Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms
title Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms
title_full Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms
title_fullStr Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms
title_full_unstemmed Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms
title_short Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms
title_sort targeting the gipr for obesity: to agonize or antagonize? potential mechanisms
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085569/
https://www.ncbi.nlm.nih.gov/pubmed/33290902
http://dx.doi.org/10.1016/j.molmet.2020.101139
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