Dept. of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; The Center for Computational Medicine, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Dept. of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; Dept. of Military Medicine and Tzameret, Faculty of Medicine, Heberew University of Jerusalem and Medical Corps, Israel Defence Forces, Jerusalem, Israel.
Mol Metab. 2024 Aug;86:101979. doi: 10.1016/j.molmet.2024.101979. Epub 2024 Jun 28.
Bariatric surgery is an effective treatment to obesity, leading to weight loss and improvement in glycemia, that is characterized by hypersecretion of gastrointestinal hormones. However, weight regain and relapse of hyperglycemia are not uncommon. We set to identify mechanisms that can enhance gastrointestinal hormonal secretion following surgery to sustain weight loss.
We investigated the effect of somatostatin (Sst) inhibition on the outcomes of bariatric surgery using a mouse model of sleeve gastrectomy (SG).
Sst knockout (sst-ko) mice fed with a calorie-rich diet gained weight normally and had a mild favorable metabolic phenotype compared to heterozygous sibling controls, including elevated plasma levels of GLP-1. Mathematical modeling of the feedback inhibition between Sst and GLP-1 showed that Sst exerts its maximal effect on GLP-1 under conditions of high hormonal stimulation, such as following SG. Obese sst-ko mice that underwent SG had higher levels of GLP-1 compared with heterozygous SG-operated controls. The SG-sst-ko mice regained less weight than controls and maintained lower glycemia months after surgery. Obese wild-type mice that underwent SG and were treated daily with a Sst receptor inhibitor for two months had higher GLP-1 levels, regained less weight, and improved metabolic profile compared to saline-treated SG-operated controls, and compared to inhibitor or saline-treated sham-operated obese mice.
Our results suggest that inhibition of Sst signaling enhances the long-term favorable metabolic outcomes of bariatric surgery.
减重手术是肥胖症的有效治疗方法，可导致体重减轻和血糖改善，其特征为胃肠激素的过度分泌。然而，体重反弹和高血糖复发并不少见。我们旨在确定可以增强手术后胃肠激素分泌的机制，以维持体重减轻。
我们使用袖状胃切除术（SG）的小鼠模型研究了生长抑素（Sst）抑制对减重手术结果的影响。
高热量饮食喂养的 Sst 敲除（sst-ko）小鼠与杂合子兄弟姐妹对照相比，体重正常增加，具有轻度有利的代谢表型，包括升高的 GLP-1 血浆水平。Sst 和 GLP-1 之间反馈抑制的数学模型表明，Sst 在高激素刺激条件下（如 SG 后）对 GLP-1 发挥最大作用。接受 SG 的肥胖 sst-ko 小鼠与杂合 SG 手术对照相比，GLP-1 水平更高。SG-sst-ko 小鼠比对照组体重减轻更多，手术后数月血糖水平更低。接受 SG 并接受 Sst 受体抑制剂治疗两个月的肥胖野生型小鼠与盐水处理的 SG 手术对照相比，GLP-1 水平更高，体重减轻更多，代谢谱得到改善，与抑制剂或盐水处理的假手术肥胖小鼠相比也是如此。
我们的结果表明，抑制 Sst 信号可增强减重手术的长期有利代谢结果。
