Central Nervous System Nutrient-sensing and the Regulation of Energy and Glucose Homeostasis

Hypothalamic lactate metabolism regulates hepatic glucose and lipid homeostasis, however it remains unclear whether hypothalamic lactate also controls energy homeostasis. Furthermore, the precise downstream molecular and signaling pathway(s) involved in hypothalamic lactate-sensing is yet to be fully elucidated. To specifically address these two questions, we tested the hypothesis that hypothalamic lactate metabolism regulates energy homeostasis (Study 1) and assessed whether the activation of N-methyl-D-aspartate (NMDA) receptors in the nucleus of the solitary tract (NTS) of the brainstem is required for hypothalamic lactate, and sufficient per se, to regulate glucose homeostasis (Study 2). In an in vivo rat model, we reported in Study 1 that central lactate lowers food intake and body weight through its metabolism into pyruvate. In Study 2, we identified that hypothalamic lactate metabolism requires the activation of NMDA receptors in the NTS to lower hepatic glucose production. Moreover, we showed that the activation of NTS NMDA receptors per se lowers hepatic glucose production. In summary, these findings advance the understanding of central nutrient-sensing in the regulation of energy and glucose homeostasis, which is critical in bridging the therapeutic gap of obesity and type 2 diabetes.