Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism.
Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism.
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DOI：
10.1038/s41467-020-18751-8
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发表时间：
2020-10-05
影响因子：
16.6
通讯作者：
Lloyd DJ
中科院分区：
文献类型：
--
作者：
Killion EA;Chen M;Falsey JR;Sivits G;Hager T;Atangan L;Helmering J;Lee J;Li H;Wu B;Cheng Y;Véniant MM;Lloyd DJ
在临床前模型中，葡萄糖依赖性促胰岛素多肽（GIP）受体（GIPR）的拮抗或激动作用与胰高血糖素样肽-1受体激动剂联合使用可防止体重增加并导致体重显著减轻。基于支持GIPR拮抗作用的遗传证据，我们先前开发了小鼠抗鼠GIPR抗体（muGIPR-Ab），其保护饮食诱导的肥胖（DIO）小鼠免于体重增加并改善多个代谢参数。这项工作调和了类似的临床前体重的影响，GIPR拮抗剂和激动剂在体内，在这里，我们表明，慢性GIPR激动脱敏GIPR活性在原代脂肪细胞，在体外和脂肪组织在体内分化，和功能像一个GIPR拮抗剂。此外，脂肪细胞中的GIPR活性是muGIPR-Ab防止DIO小鼠体重增加的部分原因，证明了脂肪细胞GIPR在体内肥胖调节中的作用。在临床前模型中，葡萄糖依赖性促胰岛素多肽受体（GIPR）的激动和拮抗作用与胰高血糖素样肽-1受体激动剂联合使用可导致体重减轻。在这里，作者表明，这可以解释为脱敏的GIPR活性的慢性GIPR激动剂在体外和体内。
Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo. Both agonism and antagonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) lead to weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Here the authors show that this may be explained by desensitization of GIPR activity by chronic GIPR agonism in vitro and in vivo.
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影响因子：
158.5
作者：
Kelly, Aaron S.;Auerbach, Pernille;Arslanian, Silva
通讯作者：
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影响因子：
15.9
作者：
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影响因子：
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作者：
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作者：
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通讯作者：
Stahl, Andreas
影响因子：
8.1
作者：
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通讯作者：
Perez-Tilve, Diego