Knockdown of Mct1 in the arcuate nucleus increases food-anticipatory activity in mice

Animals rely on internal time-keeping mechanisms to anticipate regular events such as feeding, allowing preemptive gene expression which enables timely physiological responses. A manifestation of anticipatory mechanisms is also a rise in body temperature and activity before a predictable mealtime. The activity, which resembles food seeking, depends on the communication between peripheral organs and the brain. The liver plays a central role by producing metabolic signals, including beta-hydroxybutyrate, which is released into the blood in anticipation of feeding. This release is controlled by the transporter MCT1, and its hepatic ablation in mice impairs food-anticipatory activity (FAA). However, in parallel, loss of MCT1 in the arcuate nucleus, a brain nucleus that orchestrates feeding behaviour, was implicated in increased food intake, creating a paradox. Here, we demonstrate that MCT1's role in feeding behavior is tissue dependent, and that while hepatic and systemic disruption of <i>Mct1</i> impair FAA, arcuate nucleus <i>Mct1</i> knockdown increases FAA. This underscores the complexity of small molecule signalling in metabolism, of which MCT1 is merely a transporter, and whose actions are ligand, and hence context and tissue dependent.