The Adipose Tissue-Derived Secretome (ADS) in Obesity Uniquely Regulates the Na-Glucose Transporter SGLT1 in Intestinal Epithelial Cells

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_m) 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.