Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms.
Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms.
复制标题
DOI：
10.1016/j.molmet.2020.101139
复制
发表时间：
2021-04
影响因子：
8.1
通讯作者：
Campbell JE
中科院分区：
文献类型：
--
作者：
Campbell JE
葡萄糖依赖性促胰岛素肽 (GIP) 是两种肠促胰岛素激素之一，可将营养摄入与全身代谢联系起来。尽管 GIP 是第一个被发现的肠促胰岛素激素，但对 GIP 生物学的了解很快就被专注于另一种肠促胰岛素激素、胰高血糖素样肽 1 (GLP-1) 的研究所超越。 GIP 的早期研究产生了 GIP 致肥胖的理论，限制了开发 GIPR 激动剂治疗 2 型糖尿病的兴趣。过去五年，GIP 研究重新兴起，重新激发了人们对这种肽的兴趣。已经出现了两种独立的治疗肥胖的方法，一种促进 GIPR 激动，另一种则拮抗。在本报告中，讨论了支持这两种情况的证据，并提出了假设来调和这一明显的悖论。本综述提供了支持以 GIPR 为目标来减少肥胖的证据。大部分重点是使用功能获得和功能丧失方法单独靶向 GIPR 的效果，其他部分讨论了 GIPR 和 GLP-1R 的联合靶向。有大量证据支持 GIPR 激动和拮抗作用可以对体重产生积极影响。 GIP 导致体重增加的长期理论完全源自功能丧失研究，没有证据支持 GIPR 激动剂会增加肥胖或体重。没有足够的证据来调和 GIPR 激动和拮抗都可以减轻体重这一矛盾的观察结果；然而，为了解决这个问题，基于新数据提出了两个以 GIPR 拮抗作用为中心的独立假设。第一部分讨论了肠促胰岛素受体之间的代偿关系以及 GIPR 的拮抗作用如何增强 GLP-1R 活性。第二部分讨论了慢性 GIPR 激动如何导致脱敏并最终丧失模仿拮抗作用的 GIPR 活性。总的来说，很明显，需要对 GIP 生物学有更深入的了解，才能了解调节该系统如何影响代谢稳态。在临床前模型中，GIPR 的激动和拮抗作用都可以减轻体重，以应对营养过剩。人们正在寻求以 GIPR 激动和拮抗为中心的治疗策略来治疗肥胖。对文献中提出的 GIP 信号调节能量稳态的机制进行了回顾和评估。提出的假设是为了调和 GIP 功能的增加和丧失都会降低体重这一悖论。
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. 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. 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. Both agonism and antagonism of the GIPR can reduce body weight in response to overnutrition in preclinical models. Therapeutic strategies centered on GIPR agonism and antagonism are being pursued for treating obesity. The mechanisms proposed in the literature by which GIP signaling regulates energy homeostasis are reviewed and evaluated. Hypotheses are presented to reconcile the paradox that both gain and loss of GIP function reduces body weight.
登录
查看更多内容
影响因子：
7.7
作者：
Asmar M;Simonsen L;Madsbad S;Stallknecht B;Holst JJ;Bülow J
通讯作者：
Bülow J
影响因子：
7.7
作者：
Asmar, Meena;Asmar, Ali;Bulow, Jens
通讯作者：
Bulow, Jens
影响因子：
8
作者：
Capozzi, Megan E.;Wait, Jacob B.;Campbell, Jonathan E.
通讯作者：
Campbell, Jonathan E.
影响因子：
7.7
作者：
Chia, Chee W.;Carlson, Olga D.;Egan, Josephine M.
通讯作者：
Egan, Josephine M.
影响因子：
8.1
作者：
DiGruccio MR;Mawla AM;Donaldson CJ;Noguchi GM;Vaughan J;Cowing-Zitron C;van der Meulen T;Huising MO
通讯作者：
Huising MO