High-Fat Diet-Induced Obesity Enhances Small Intestinal Glucose and NaCl Absorption Through Selective Transporter Reprogramming

Metabolic dysfunction, a hallmark of diet-induced obesity (DIO), is increasingly attributed to alterations in intestinal nutrient and electrolyte transport. Yet the mechanisms that drive obesity-associated functional alterations of intestinal transporters remain incompletely understood. In this context, the effects of a high-fat diet (HFD) induced obesity on sodium-dependent glucose co-transporter 1 (SGLT1), Na+/H+ exchanger 3 (NHE3), and Cl−/HCO3− exchangers (DRA/PAT1), the primary glucose, sodium, and chloride absorptive pathways in mice small intestinal villus cells, were investigated. SGLT1 activity significantly increased in intact villus cells and brush border membrane vesicles (BBMV) from HFD-fed mice. Kinetic analysis demonstrated reduced Km without a change in Vmax, indicating enhanced transporter affinity. Notably, SGLT1 mRNA and protein expression, including BBM localization, were unchanged. Basolateral Na+/K+-ATPase activity was decreased, excluding enhanced Na+ gradient generation as the mechanism for SGLT1 stimulation. In contrast, DRA/PAT1 activity was significantly increased in HFD-fed mice, and kinetic studies revealed elevated Vmax without a change in Km, indicating increased transport capacity. DRA/PAT1 mRNA, total protein, and BBM expression were all significantly elevated. NHE3 activity and expression remained unchanged. These findings demonstrate that DIO enhances intestinal glucose absorption by increasing SGLT1 affinity and chloride absorption by upregulating DRA/PAT1 transcription. These transporter-specific alterations may amplify nutrient absorption and contribute to metabolic dysregulation in obesity.