KHK in leptin receptor-expressing neurons is dispensable for fructose preference and energy homeostasis

Fructose metabolism in the central nervous system not only affects local neuronal function but also plays a critical role in regulating appetite and energy metabolism. However, the precise mechanisms underlying these effects are still not well understood. The leptin receptor (LepR) plays a crucial role in modulating neuronal signaling pathways that control food intake and energy expenditure, integrating peripheral metabolic signals to maintain physiological balance. This study aimed to investigate the potential impact of fructose metabolism in central nervous system on energy metabolism and glucose homeostasis. To this end, we generated a leptin receptor cell-specific Khk knockout mouse model (LepR-Cre;Khk^fl/fl, Khk^ΔLepR) and assessed body weight and blood glucose under normal chow conditions. Fructose preference was evaluated using a two-bottle drinking test. Following prolonged fructose consumption, energy metabolism and fructose metabolism were monitored. Our results showed no significant changes in body weight, blood glucose, or fructose preference in Khk^ΔLepR mice under normal chow conditions. Moreover, after long-term fructose drinking intervention, there were no notable differences in energy expenditure or fructose metabolism. Taken together, these findings suggest that KHK-mediated fructose metabolism in leptin receptor-expressing neurons is not essential for fructose preference or energy homeostasis in mice.