Hepatic Sialylation Defects Increase Susceptibility to Obesity and Steatosis in Mice

ABSTRACT Sialic acid is a well‐characterized monosaccharide known to regulate early development and lifelong health, and its aberrant metabolism has been closely linked to multiple pathologies including cancer, cardiovascular disease, and neurological disorders. However, its role in early‐life metabolic programming and adult metabolic homeostasis remains poorly understood. Here, we investigated Cmp‐Neu5Ac synthase (CMAS), a key enzyme in the sialylation pathway, using two complementary mouse models to address this gap. In a mammary‐specific Cmas knockout model, reduced milk sialyllactose levels significantly altered offspring metabolic development. Offspring nursed by CMAS‐deficient dams displayed increased body weight and impaired glucose and insulin tolerance at weaning. When challenged with a high‐fat diet, these offspring developed exaggerated weight gain, enhanced adipose expansion, and more severe hepatic ballooning degeneration, indicating that early‐life sialylation deficiency disrupts metabolic programming and increases susceptibility to metabolic stress in adulthood. To determine whether sialylation is also essential for maintaining hepatic metabolic stability later in life, we generated a liver‐specific Cmas knockout model. Deletion of Cmas markedly reduced serum sialylation and hepatic Neu5Gc‐containing glycopeptides, leading to hepatomegaly, steatosis, and fibrosis, which was accompanied by activated lipogenic axis, impaired mitochondrial respiratory complex activity, increased mitochondrial fission and triggered compensatory AMPK–PGC1α signaling. Notably, CMAS deficiency sensitized hepatocytes to inflammatory stress, as evidenced by exacerbated lipid accumulation, elevated ROS production, and reduced ATP content upon LPS challenge. Together, our results demonstrate that sialylation is indispensable for both developmental metabolic programming and adult hepatic metabolic homeostasis, establishing a critical link between sialylation status and lifelong metabolic health.