Dietary galactose enhances systemic lipid oxidation but decreases intestinal fatty acid oxidation in post-weaning female mice

Replacing part of dietary glucose with galactose in the early post-weaning diet of mice, mimicking extended breastfeeding, improves both short- and long-term physiological and metabolic health parameters. As the primary organ for nutrient absorption, the small intestine was hypothesized to play a key role in these effects. Young, weaned mice underwent a three-week dietary intervention comparing isocaloric diets with a monosaccharide fraction of galactose+glucose versus glucose. Physiological parameters were assessed in both sexes, while metabolic analyses, transcriptomics, and immunohistochemistry of the proximal small intestine were conducted in fed female mice. Dietary galactose increased whole-body 24-hour fatty acid oxidation (FAO), both absolute and relative to carbohydrate oxidation, without changes in body weight or energy expenditure. Contrasting, the small intestine showed lower expression of transcripts involved in FAO, along with reduced enterocytic lipid droplets. Carbohydrate metabolism remained unaffected, while reduced expression of NADPH-dependent and -independent antioxidant enzymes and the pentose phosphate pathway suggested a shift in local metabolism. Despite these intestinal changes, the liver showed no alterations in lipid catabolism, implicating other organs in the observed systemic FAO increase. In addition, Ppargc1a, central regulator of mitochondrial biogenesis was upregulated, which is in line with the known role of galactose in upregulating mitochondrial oxidative phosphorylation. In conclusion, replacing half of post-weaning dietary glucose with galactose, mimicking prolonged lactose intake, profoundly affects substrate metabolism at both systemic and intestinal levels. We propose that reduced intestinal FAO redirects fatty acid oxidation to extra-intestinal, extra-hepatic tissues, driving the observed systemic metabolic benefits.