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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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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Elsevier
2020
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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. |
format | Online Article Text |
id | pubmed-8085569 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT campbelljonathane targetingthegiprforobesitytoagonizeorantagonizepotentialmechanisms |