Sexually Dimorphic Impacts of Early Life <scp>BCAAs</scp> Supplementation on Metabolic Dysfunctions in Adult Mice

BACKGROUND AND AIMS: Early-life environmental exposures, including nutritional supply, can influence health in adulthood. Leucine, isoleucine, and valine are collectively known as branched-chain amino acids (BCAAs). While BCAAs are essential nutrients, their elevated abundances in adults have been tightly associated with metabolic disorders. However, whether excessive intake of BCAAs in early life affects the metabolic dysfunctions in adult life remains unknown. METHODS AND RESULTS: Continuous BCAAs supplementation in drinking water throughout gestation, lactation, and early-juvenile period reduced body weight, decreased fat mass and improved glucose homeostasis in adult male mice challenged with a high-fat diet (HFD) starting at 6 weeks of age. Lactational BCAAs supplementation alone partially recapitulated these beneficial metabolic effects, resulting in decreased body weight and improved insulin tolerance, whereas gestational or early-juvenile exposure showed no significant metabolic impacts in adult males. Analysis of individual BCAA supplementation during lactation period showed that leucine, isoleucine, and valine demonstrated either beneficial or detrimental impacts on obesity, insulin resistance, and fatty liver in adult male mice, respectively. In females, lactational supplementation of individual BCAA produced distinct effects compared with males. CONCLUSIONS: Excessive BCAAs exposure during developmental stages, particularly the lactation period, shows pronounced effects on male adult metabolic dysfunction. Moreover, supplementation with individual BCAA during lactation exerts distinct and sexually dimorphic effects on adult metabolic health. These results highlight the potential of early-life precision nutrition strategies to mitigate metabolic dysfunction later in life.