Wellington Vivian Naa Amua, Singh Soudamani
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25703, USA.
Cells. 2025 Aug 12;14(16):1241. doi: 10.3390/cells14161241.
Obesity is a complex chronic inflammatory condition that results from excess fat accumulation. It increases the risk of developing numerous co-morbidities such as Type 2 diabetes mellitus, cardiovascular disease, hypertension, and stroke. The adipose tissue is itself a vital endocrine organ that secretes numerous adipokines, cytokines, and exosomes, which are collectively known as the adipose-derived secretome (ADS). This ADS has been shown to influence and modulate many physiological processes. During obesity, the composition of ADS is altered, which may contribute to the development of obesity-associated diseases. Type-2 diabetes mellitus is one of the most common complications of obesity due to alterations in glucose homeostasis. Glucose absorption occurs via Na-glucose co-transport via SGLT1 at the brush border membrane (BBM) of small intestinal villus cells. This process of transepithelial glucose uptake is the primary method of glucose absorption from diet. However, how ADS mediates the function of SGLT1 is not yet known. This study aims to determine the mechanism of regulation of SGLT1 by ADS in intestinal epithelial cells. We show that ADS from OZR (but not LZR) stimulates SGLT1 in IEC-18 cells. OZR-ADS treatment diminished Na/K-ATPase activity in IEC-18 cells. Kinetic studies indicated that the mechanism of stimulation for SGLT1 during OZR-ADS treatment was secondary to an increase in the affinity (1/K) of the co-transporter for glucose without a change in co-transporter number. Western blot studies revealed that SGLT1 protein expression was unaltered in the two groups, confirming our kinetic studies. Immunoprecipitation demonstrated that an increase in the affinity of the SGLT1 protein was mediated by altered phosphorylation. In conclusion, during obesity, the adipose tissue secretome stimulates SGLT1 in intestinal epithelial cells, leading to an increase in affinity for glucose. The affinity change is due to alterations in SGLT1 phosphorylation. Together, these results may provide important insight into the mechanisms underlying altered glucose homeostasis in obesity and how this may lead to the development of Type 2 diabetes mellitus.
肥胖是一种由脂肪过度堆积导致的复杂慢性炎症性疾病。它会增加患多种合并症的风险，如2型糖尿病、心血管疾病、高血压和中风。脂肪组织本身是一个重要的内分泌器官，可分泌多种脂肪因子、细胞因子和外泌体，这些统称为脂肪组织分泌组（ADS）。已证明这种ADS会影响和调节许多生理过程。在肥胖期间，ADS的组成会发生改变，这可能导致肥胖相关疾病的发生。2型糖尿病是肥胖最常见的并发症之一，原因是葡萄糖稳态发生了改变。葡萄糖通过小肠绒毛细胞刷状缘膜（BBM）上的SGLT1进行钠-葡萄糖共转运而被吸收。这种跨上皮葡萄糖摄取过程是从饮食中吸收葡萄糖的主要方式。然而，ADS如何介导SGLT1的功能尚不清楚。本研究旨在确定肠道上皮细胞中ADS对SGLT1的调节机制。我们发现，来自OZR（而非LZR）的ADS可刺激IEC-18细胞中的SGLT1。OZR-ADS处理降低了IEC-18细胞中的钠钾ATP酶活性。动力学研究表明，OZR-ADS处理期间SGLT1的刺激机制是由于共转运蛋白对葡萄糖的亲和力（1/K）增加，而共转运蛋白数量没有变化。蛋白质印迹研究显示，两组中SGLT1蛋白表达未改变，证实了我们的动力学研究。免疫沉淀表明，SGLT1蛋白亲和力的增加是由磷酸化改变介导的。总之，在肥胖期间，脂肪组织分泌组刺激肠道上皮细胞中的SGLT1，导致对葡萄糖的亲和力增加。亲和力变化是由于SGLT1磷酸化的改变。这些结果共同为肥胖中葡萄糖稳态改变的潜在机制以及这如何导致2型糖尿病的发生提供了重要见解。
