Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Mol Metab. 2019 Oct;28:14-25. doi: 10.1016/j.molmet.2019.08.006. Epub 2019 Aug 10.
Glucose-dependent insulinotropic polypeptide (GIP) is secreted from the gut in response to nutrient ingestion and promotes meal-dependent insulin secretion and lipid metabolism. Loss or attenuation of GIP receptor (GIPR) action leads to resistance to diet-induced obesity through incompletely understood mechanisms. The GIPR is expressed in white adipose tissue; however, its putative role in brown adipose tissue (BAT) has not been explored.
We investigated the role of the GIPR in BAT cells in vitro and in BAT-specific (Gipr) knockout mice with selective elimination of the Gipr within the Myf5 expression domain. We analyzed body weight, adiposity, glucose homeostasis, insulin and lipid tolerance, energy expenditure, food intake, body temperature, and iBAT oxygen consumption ex vivo. High-fat diet (HFD)-fed Gipr mice were studied at room temperature (21 °C), 4 °C, and 30 °C ambient temperatures.
The mouse Gipr gene is expressed in BAT, and GIP directly increased Il6 mRNA and IL-6 secretion in BAT cells. Additionally, levels of thermogenic, lipid and inflammation mRNA transcripts were altered in BAT cells transfected with Gipr siRNA. Body weight gain, energy expenditure, and glucose and insulin tolerance were normal in HFD-fed Gipr mice housed at room temperature. However, Gipr mice exhibited higher body temperatures during an acute cold challenge and a lower respiratory exchange ratio and impaired lipid tolerance at 21 °C. In contrast, body weight was lower and iBAT oxygen consumption was higher in HFD-fed mice housed at 4 °C but not at 30 °C.
The BAT GIPR is linked to the control of metabolic gene expression, fuel utilization, and oxygen consumption. However, the selective loss of the GIPR within BAT is insufficient to recapitulate the findings of decreased weight gain and resistance to obesity arising in experimental models with systemic disruption of GIP action.
葡萄糖依赖性胰岛素多肽（GIP）是肠道响应营养摄入而分泌的一种激素，它能促进与进餐相关的胰岛素分泌和脂质代谢。GIP 受体（GIPR）作用的丧失或减弱会导致机体对饮食诱导肥胖产生抗性，但其具体机制尚不完全清楚。GIPR 表达于白色脂肪组织，但它在棕色脂肪组织（BAT）中的潜在作用尚未被探索。
我们在体外和 BAT 特异性（Gipr）敲除小鼠中研究了 GIPR 在 BAT 细胞中的作用，这些小鼠通过在 Myf5 表达域内选择性消除 Gipr 来实现 Gipr 的敲除。我们分析了体重、肥胖程度、葡萄糖稳态、胰岛素和脂质耐受性、能量消耗、摄食量、体温以及离体 BAT 耗氧量。高脂饮食（HFD）喂养的 Gipr 小鼠在室温（21°C）、4°C 和 30°C 环境温度下进行研究。
小鼠 Gipr 基因在 BAT 中表达，GIP 直接增加 BAT 细胞中的 Il6 mRNA 和 IL-6 分泌。此外，用 Gipr siRNA 转染的 BAT 细胞中，产热、脂质和炎症 mRNA 转录物的水平也发生了改变。在室温下饲养的 HFD 喂养 Gipr 小鼠的体重增加、能量消耗以及葡萄糖和胰岛素耐受性均正常。然而，Gipr 小鼠在急性冷应激时表现出更高的体温，在 21°C 时呼吸交换率更低且脂质耐受性受损。相反，在 4°C 下饲养的 HFD 喂养小鼠的体重较低，BAT 耗氧量较高，但在 30°C 下则没有这种情况。
BAT 中的 GIPR 与代谢基因表达、燃料利用和耗氧量的控制有关。然而，在系统破坏 GIP 作用的实验模型中，BAT 中 GIPR 的选择性缺失不足以重现体重增加减少和肥胖抗性的发现。
