Lipodystrophy induces gut microbiota dysbiosis and its related glucose dysmetabolism in mice.

Both excessive white adipose tissue (WAT) in obesity and insufficient WAT in lipodystrophy disrupt metabolic homeostasis. Although a vicious cycle between WAT dysfunction and gut dysbiosis is known to drive insulin resistance in obesity, whether lipodystrophy impairs gut function and contributes to glucose dysregulation remains unclear. Using adipocyte-specific MDM2 knockout (Adipo-MDM2-KO) mice as a model of lipodystrophy, we identified a direct role of WAT in maintaining intestinal and gut microbiota homeostasis. Progressive adipose tissue loss in Adipo-MDM2-KO mice caused multiple intestinal abnormalities, including gut microbiota dysbiosis, altered microbial metabolism, impaired intestinal barrier integrity, defective immunoglobulin A (IgA) responses, and endotoxemia. These defects were largely reversed by transplantation of healthy subcutaneous WAT (sWAT). Moreover, fecal microbiota transplantation from Adipo-MDM2-KO mice into C57BL/6J recipients reproduced intestinal defects and glucose intolerance, whereas microbiota depletion in Adipo-MDM2-KO mice largely rescued intestinal abnormalities and partially restored glucose homeostasis. Furthermore, sWAT-secreted adipokines, including extracellular vesicles, directly modulated the abundance and growth of specific gut bacterial communities. Multi-omics analyses further linked lipodystrophy-induced microbiota and metabolomic alterations to systemic endotoxemia and impaired glucose metabolism. Altogether, our findings reveal a critical WAT-gut-microbiota axis in the regulation of intestinal homeostasis and host glucose metabolism.