Department of Medicine, Section of Endocrinology, Diabetes, Nutrition and Weight Management, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA.
Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, New York, NY 10021, USA.
Endocrinology. 2024 Jul 26;165(9). doi: 10.1210/endocr/bqae100.
Nuclear receptor action is mediated in part by the nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). NCOR1 and SMRT regulate metabolic pathways that govern body mass, insulin sensitivity, and energy expenditure, representing an understudied area in the realm of metabolic health and disease. Previously, we found that NCOR1 and SMRT are essential for maintaining metabolic homeostasis and their knockout (KO) leads to rapid weight loss and hypoglycemia, which is not survivable. Because of a potential defect in glucose absorption, we sought to determine the role of NCOR1 and SMRT specifically in intestinal epithelial cells (IECs). We used a postnatal strategy to disrupt NCOR1 and SMRT throughout IECs in adult mice. These mice were characterized metabolically and underwent metabolic phenotyping, body composition analysis, and glucose tolerance testing. Jejunal IECs were isolated and profiled by bulk RNA sequencing. We found that the postnatal KO of NCOR1 and SMRT from IECs leads to rapid weight loss and hypoglycemia with a significant reduction in survival. This was accompanied by alterations in glucose metabolism and activation of fatty acid oxidation in IECs. Metabolic phenotyping confirmed a reduction in body mass driven by a loss of body fat without altered food intake. This appeared to be mediated by a reduction of key intestinal carbohydrate transporters, including SGLT1, GLUT2, and GLUT5. Intestinal NCOR1 and SMRT act in tandem to regulate glucose levels and body weight. This in part may be mediated by regulation of intestinal carbohydrate transporters.
核受体的作用部分通过核受体共抑制因子 1 (NCOR1) 和视黄酸和甲状腺激素受体沉默介质 (SMRT) 介导。NCOR1 和 SMRT 调节控制体重、胰岛素敏感性和能量消耗的代谢途径，这是代谢健康和疾病领域中研究不足的领域。此前，我们发现 NCOR1 和 SMRT 对于维持代谢平衡是必不可少的，它们的敲除 (KO) 导致体重迅速下降和低血糖，这是无法生存的。由于葡萄糖吸收可能存在缺陷，我们试图确定 NCOR1 和 SMRT 特别是在肠上皮细胞 (IECs) 中的作用。我们使用一种产后策略来破坏成年小鼠 IEC 中的 NCOR1 和 SMRT。这些小鼠进行了代谢特征分析，并进行了代谢表型分析、身体成分分析和葡萄糖耐量测试。空肠 IEC 被分离并进行了批量 RNA 测序。我们发现，IEC 中 NCOR1 和 SMRT 的产后 KO 导致体重迅速下降和低血糖，存活率显著降低。这伴随着葡萄糖代谢的改变和 IEC 中脂肪酸氧化的激活。代谢表型分析证实，体重减轻是由体脂减少而不是食物摄入量改变引起的。这似乎是通过减少关键的肠道碳水化合物转运蛋白介导的，包括 SGLT1、GLUT2 和 GLUT5。肠道 NCOR1 和 SMRT 协同作用调节血糖水平和体重。这在一定程度上可能是通过调节肠道碳水化合物转运蛋白来介导的。
