Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, Japan.
Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Japan.
Biochem Biophys Res Commun. 2019 Jun 11;513(4):974-982. doi: 10.1016/j.bbrc.2019.04.036. Epub 2019 Apr 17.
AIMS/INTRODUCTION: Caloric restriction (CR) promotes longevity and exerts anti-aging effects by increasing Sirtuin production and activation. Gastric inhibitory polypeptide (GIP), a gastrointestinal peptide hormone, exerts various effects on pancreatic β-cells and extra-pancreatic tissues. GIP promotes glucose-dependent augmentation of insulin secretion and uptake of nutrients into the adipose tissue.
Gipr and Gipr mice were used for lifespan analysis, behavior experiments and gene expression of adipose tissue and muscles. 3T3-L1 differentiated adipocytes were used for Sirt1 and Nampt expression followed by treatment with GIP and α-lipoic acid.
We observed that GIP receptor-knockout (Gipr) mice fed normal diet showed an extended lifespan, increased exploratory and decreased anxiety-based behaviors, which are characteristic behavioral changes under CR. Moreover, Gipr mice showed increased Sirt1 and Nampt expression in the adipose tissue. GIP suppressed α-lipoic acid-induced Sirt1 expression and activity in differentiated adipocytes.
Although maintenance of CR is difficult, food intake and muscle endurance of Gipr mice were similar to those of wild-type mice. Inhibition of GIP signaling may be a novel strategy to extend the lifespan of diabetic patients.
目的/引言：热量限制（CR）通过增加 Sirtuin 的产生和激活来促进长寿和发挥抗衰老作用。胃抑制肽（GIP），一种胃肠肽激素，对胰腺β细胞和胰腺外组织发挥多种作用。GIP 促进葡萄糖依赖性胰岛素分泌增加和营养物质摄取到脂肪组织中。
使用 Gipr 和 Gipr 小鼠进行寿命分析、行为实验以及脂肪组织和肌肉的基因表达分析。使用 3T3-L1 分化的脂肪细胞进行 Sirt1 和 Nampt 的表达，然后用 GIP 和 α-硫辛酸进行处理。
我们观察到，正常饮食喂养的 GIP 受体敲除（Gipr）小鼠表现出寿命延长、探索性增强和焦虑相关行为减少，这是 CR 下的典型行为变化。此外，Gipr 小鼠的脂肪组织中 Sirt1 和 Nampt 的表达增加。GIP 抑制了分化脂肪细胞中 α-硫辛酸诱导的 Sirt1 表达和活性。
尽管维持 CR 很困难，但 Gipr 小鼠的食物摄入量和肌肉耐力与野生型小鼠相似。抑制 GIP 信号可能是延长糖尿病患者寿命的一种新策略。
