肥胖合并 2 型糖尿病患者行 Roux-en-Y 胃旁路术后对循环中卵泡抑素、激活素 A 和外周 ActRIIB 信号的影响。
Effects of Roux-en-Y gastric bypass on circulating follistatin, activin A, and peripheral ActRIIB signaling in humans with obesity and type 2 diabetes.
机构信息
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.
出版信息
Int J Obes (Lond). 2021 Feb;45(2):316-325. doi: 10.1038/s41366-020-00664-7. Epub 2020 Sep 1.
BACKGROUND
Roux-en-Y gastric bypass (RYGB) surgery is a therapeutic intervention for morbid obesity and type 2 diabetes (T2D) that improves metabolic regulation. Follistatin (Fst) could be implicated in improved glycemia as it is highly regulated by RYGB. However, it is unknown if metabolic status, such as T2D, alters the Fst response to RYGB. In addition, the effect of RYGB on the Fst target, activin A, is unknown in individuals with obesity and T2D, but is needed to interpret the functional effects of altering Fst. Finally, whether Fst-regulated intracellular signaling contributes to beneficial effects of RYGB is undetermined.
METHODS
Circulating Fst and activin A were measured before, 1 week, and 1 year after RYGB surgery in a total of 20 individuals with obesity, 10 with normoglycemia (NGT) and 10 with preoperative T2D. Intracellular signaling downstream of the Activin receptor type IIB (ActRIIB) signaling pathway was analyzed in skeletal muscle and adipose tissue.
RESULTS
The doubling in circulating Fst observed in subjects with NGT 1-week and 1-year post surgery was absent in T2D. After 1 week, RYGB reduced activin A by 27% (p < 0.001) and 20% (p < 0.01) in subjects with NGT and T2D, respectively; a reduction that tended to be maintained in the subjects with T2D at 1-year post-RYGB (-15%; p = 0.0592). RYGB had no effects on skeletal muscle ActRIIB signaling. In contrast, adipose tissue phosphorylation of SMAD2, p70S6K, S6RP, and 4E-BP1 was highly regulated, particularly 1-year post-RYGB (p < 0.05).
CONCLUSIONS
In subjects with preoperative T2D, RYGB did not increase circulating Fst contrasting subjects with NGT, while the reduction in activin A was maintained. ActRIIB signaling was upregulated in adipose tissue, but not skeletal muscle, following RYGB in both individuals with NGT and T2D. Our results suggest a role of adipose tissue ActRIIB signaling for the beneficial effects of RYGB surgery.
背景
Roux-en-Y 胃旁路（RYGB）手术是治疗肥胖症和 2 型糖尿病（T2D）的一种方法，可改善代谢调节。卵泡抑素（Fst）可能与改善血糖有关，因为它受 RYGB 的高度调节。然而，尚不清楚代谢状态（如 T2D）是否会改变 Fst 对 RYGB 的反应。此外，肥胖和 T2D 个体的 RYGB 对 Fst 靶标激活素 A 的影响尚不清楚，但需要解释改变 Fst 的功能影响。最后，Fst 调节的细胞内信号是否有助于 RYGB 的有益效果尚不确定。
方法
共 20 名肥胖患者、10 名血糖正常（NGT）患者和 10 名术前 T2D 患者在 RYGB 手术后 1 周和 1 年分别测量循环 Fst 和激活素 A。分析骨骼肌和脂肪组织中激活素受体 IIB（ActRIIB）信号通路的下游细胞内信号。
结果
NGT 患者术后 1 周和 1 年 Fst 循环增加一倍，但 T2D 患者则没有。术后 1 周，RYGB 使 NGT 和 T2D 患者的激活素 A 分别降低 27%（p<0.001）和 20%（p<0.01）；在 T2D 患者中，这种降低在 RYGB 术后 1 年时趋于维持（-15%；p=0.0592）。RYGB 对骨骼肌 ActRIIB 信号没有影响。相反，脂肪组织中 SMAD2、p70S6K、S6RP 和 4E-BP1 的磷酸化高度调节，特别是 RYGB 术后 1 年（p<0.05）。
结论
在术前 T2D 患者中，RYGB 并未增加循环 Fst，与 NGT 患者形成对比，而激活素 A 的减少则得以维持。在 NGT 和 T2D 患者中，RYGB 后脂肪组织中的 ActRIIB 信号均被上调，但骨骼肌组织没有。我们的结果表明，脂肪组织 ActRIIB 信号可能对 RYGB 手术的有益效果具有重要作用。
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