PYY/Y2R 缺陷型雄性小鼠不能免受 Roux-en-Y 胃旁路术引起的骨丢失的影响。
The PYY/Y2R-deficient male mouse is not protected from bone loss due to Roux-en-Y gastric bypass.
机构信息
Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, United States of America.
Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, United States of America.
出版信息
Bone. 2023 Feb;167:116608. doi: 10.1016/j.bone.2022.116608. Epub 2022 Nov 8.
BACKGROUND
Peptide YY (PYY) is an anorexigenic gut hormone that also has anti-osteogenic effects, inhibiting osteoblastic activity and inducing catabolic effects. It has been postulated that increases in PYY after Roux-en-Y gastric bypass (RYGB) contribute to declines in bone mineral density (BMD) and increases in bone turnover. The aim of this study is to determine the role of the PYY Y2-receptor in mediating bone loss post-RYGB in mice.
METHODS
We compared adult male wildtype (WT) and PYY Y2 receptor-deficient (KO) C57BL/6 mice that received RYGB (WT: n = 8; KO: n = 9), with sham-operated mice (Sham; WT: n = 9; KO: n = 10) and mice that were food-restricted to match the weights of the RYGB-treated group (Weight-Matched, WM; WT: n = 7; KO: n = 5). RYGB or sham surgery was performed at 15-16 weeks of age, and mice sacrificed 21 weeks later. We characterized bone microarchitecture with micro-computed tomography (μCT) at the distal femur (trabecular) and femoral midshaft (cortical). Differences in body weight, bone microarchitecture and biochemical bone markers (parathyroid hormone, PTH; C-telopeptide, CTX; and type 1 procollagen, P1NP) were compared using 2-factor ANOVA with Tukey's adjustments for multiple comparisons.
RESULTS
Body weights were similar in the WT-RYGB, WT-WM, KO-RYGB, and KO-WM: 41-44 g; these groups weighed significantly less than the Sham surgery groups: 55-57 g. Trabecular BMD was 31-43 % lower in RYGB mice than either Sham or WM in WT and KO groups. This deficiency in trabecular bone was accompanied by a lower trabecular number (19 %-23 %), thickness (22 %-30 %) and increased trabecular spacing (25 %-34 %) in WT and KO groups (p < 0.001 for all comparisons vs. RYGB). RYGB led to lower cortical thickness, cortical tissue mineral density, and cortical bone area fraction as compared to Sham and WM in WT and KO groups (p ≤ 0.004 for all). There were no interactions between genotype and bone microarchitecture, with patterns of response to RYGB similar in both WT and KO groups. CTX and P1NP were significantly higher in RYGB mice than WM in WT and KO groups. PTH did not differ among groups.
CONCLUSIONS
RYGB induced greater trabecular and cortical deficits and high bone turnover than observed in weight-matched mice, with a similar pattern in the WT and Y2RKO mice. Thus, skeletal effects of RYGB are independent of weight loss, and furthermore, PYY signaling through Y2R is not a key mediator of bone loss post-RYGB.
背景
肽 YY（PYY）是一种抑制食欲的肠道激素，具有抗成骨作用，抑制成骨细胞活性并诱导分解代谢作用。有人假设 Roux-en-Y 胃旁路术（RYGB）后 PYY 的增加有助于骨密度（BMD）下降和骨转换增加。本研究旨在确定 PYY Y2 受体在介导 RYGB 后小鼠骨丢失中的作用。
方法
我们比较了接受 RYGB（WT：n=8；KO：n=9）的成年雄性野生型（WT）和 PYY Y2 受体缺陷型（KO）C57BL/6 小鼠，与假手术（Sham；WT：n=9；KO：n=10）和接受与 RYGB 治疗组体重匹配的饮食限制（Weight-Matched，WM；WT：n=7；KO：n=5）的小鼠。RYGB 或假手术于 15-16 周龄进行，21 周后处死小鼠。我们使用微计算机断层扫描（μCT）在远端股骨（小梁）和股骨中段（皮质）对骨微结构进行特征描述。使用双因素方差分析和 Tukey 多重比较调整比较体重、骨微结构和生化骨标志物（甲状旁腺激素、CTX；I 型前胶原、P1NP）的差异。
结果
WT-RYGB、WT-WM、KO-RYGB 和 KO-WM 组的体重相似，为 41-44g；这些组的体重明显低于 Sham 手术组，为 55-57g。WT 和 KO 组的 RYGB 小鼠的小梁骨密度比 Sham 或 WM 组低 31-43%。在 WT 和 KO 组中，这种小梁骨的缺乏伴随着小梁数量（19%-23%）、厚度（22%-30%）和小梁间距增加（25%-34%）（与 RYGB 相比，所有比较均<0.001）。与 Sham 和 WM 相比，WT 和 KO 组的 RYGB 导致皮质厚度、皮质组织矿物质密度和皮质骨面积分数降低（所有比较均≤0.004）。基因型与骨微结构之间没有相互作用，WT 和 KO 组对 RYGB 的反应模式相似。CTX 和 P1NP 在 RYGB 小鼠中明显高于 WM 组，而 PTH 无差异。
结论
与体重匹配的小鼠相比，RYGB 诱导的小梁和皮质缺损和高骨转换更多，WT 和 Y2RKO 小鼠的模式相似。因此，RYGB 的骨骼效应独立于体重减轻，此外，PYY 通过 Y2R 发出的信号不是 RYGB 后骨丢失的关键介质。
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