Objective

Fibroblast growth factor 21 (FGF21) has been shown to rapidly lower body weight in the Siberian hamster, a preclinical model of adiposity. This induced negative energy balance mediated by FGF21 is associated with both lowered caloric intake and increased energy expenditure. Previous research demonstrated that adipose tissue (AT) is one of the primary sites of FGF21 action and may be responsible for its ability to increase the whole-body metabolic rate. The present study sought to determine the relative importance of white (subcutaneous AT [sWAT] and visceral AT [vWAT]), and brown (interscapular brown AT [iBAT]) in governing FGF21-mediated metabolic improvements using the tissue-specific uptake of glucose and lipids as a proxy for metabolic activity.

Methods

We used positron emission tomography-computed tomography (PET-CT) imaging in combination with both glucose (¹⁸F-fluorodeoxyglucose) and lipid (¹⁸F-4-thiapalmitate) tracers to assess the effect of FGF21 on the tissue-specific uptake of these metabolites and compared responses to a control group pair-fed to match the food intake of the FGF21-treated group. In vivo imaging was combined with ex vivo tissue-specific functional, biochemical, and molecular analyses of the nutrient uptake and signaling pathways.

Results

Consistent with previous findings, FGF21 reduced body weight via reduced caloric intake and increased energy expenditure in the Siberian hamster. PET-CT studies demonstrated that FGF21 increased the uptake of glucose in BAT and WAT independently of reduced food intake and body weight as demonstrated by imaging of the pair-fed group. Furthermore, FGF21 increased glucose uptake in the primary adipocytes, confirming that these in vivo effects may be due to a direct action of FGF21 at the level of the adipocytes. Mechanistically, the effects of FGF21 are associated with activation of the ERK signaling pathway and upregulation of GLUT4 protein content in all fat depots. In response to treatment with FGF21, we observed an increase in the markers of lipolysis and lipogenesis in both the subcutaneous and visceral WAT depots. In contrast, FGF21 was only able to directly increase the uptake of lipid into BAT.

Conclusions

These data identify brown and white fat depots as primary peripheral sites of action of FGF21 in promoting glucose uptake and also indicate that FGF21 selectively stimulates lipid uptake in brown fat, which may fuel thermogenesis.

中文翻译：

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西伯利亚仓鼠成纤维细胞生长因子 21 代谢作用的全身和脂肪组织特异性机制。

客观的

成纤维细胞生长因子 21 (FGF21) 已被证明可以迅速降低西伯利亚仓鼠的体重，这是一种肥胖的临床前模型。这种由 FGF21 介导的诱导负能量平衡与热量摄入降低和能量消耗增加有关。先前的研究表明，脂肪组织 (AT) 是 FGF21 作用的主要部位之一，可能是其提高全身代谢率能力的原因。本研究试图确定白色（皮下 AT [sWAT] 和内脏 AT [vWAT]）和棕色（肩胛间褐色 AT [iBAT]）在使用组织特异性葡萄糖摄取调节 FGF21 介导的代谢改善方面的相对重要性和脂质作为代谢活动的代表。

方法

我们使用正电子发射断层扫描计算机断层扫描 (PET-CT) 成像结合葡萄糖（¹⁸ F-氟脱氧葡萄糖）和脂质（¹⁸ F-4-硫棕榈酸酯）示踪剂来评估 FGF21 对这些组织特异性摄取的影响代谢物并比较对配对喂养的对照组的反应，以匹配 FGF21 治疗组的食物摄入量。体内成像与营养摄取和信号通路的离体组织特异性功能、生化和分子分析相结合。

结果

与之前的研究结果一致，FGF21 通过减少热量摄入和增加西伯利亚仓鼠的能量消耗来减轻体重。PET-CT 研究表明，FGF21 增加了 BAT 和 WAT 中葡萄糖的摄取，与减少的食物摄入量和体重无关，如配对喂养组的成像所示。此外，FGF21 增加了初级脂肪细胞的葡萄糖摄取，证实这些体内效应可能是由于 FGF21 在脂肪细胞水平上的直接作用。从机制上讲，FGF21 的作用与 ERK 信号通路的激活和所有脂肪库中 GLUT4 蛋白含量的上调有关。为响应 FGF21 治疗，我们观察到皮下和内脏 WAT 库中脂肪分解和脂肪生成的标志物增加。相比之下，

结论

这些数据确定棕色和白色脂肪库是 FGF21 促进葡萄糖摄取的主要外周作用位点，还表明 FGF21 选择性刺激棕色脂肪中的脂质摄取，这可能会促进产热。