A critical role for the novel CREB coactivator CRTC2 (CREB-regulated transcription coactivator, a.k.a TORC2 (transducer of regulated CREB activity)) in maintaining glucose homeostasis was previously demonstrated in liver, where hormonal and energy-sensing signals mediate their effects on gluconeogenic gene transcription via regulation of CRTC2 phosphorylation. Here, we report CRTC2 expression in neurons of several hypothalamic areas of the mouse, showing alterations in CRTC2’s subcellular localisation and thus activity in response to fasting. Important questions arise: Which metabolic signals regulate hypothalamic CRTC2 activity? Which hypothalamic genes does CRTC2 regulate? What is the physiological role of CRTC2 in the hypothalamus? Using a range of in vitro, in vivo and imaging studies, we identified glucose as on of the metabolic stimuli regulating hypothalamic CRTC2 activity. More specifically, glucose levels regulate hypothalamic CRTC2 subcellular localisation via AMP Kinase-mediated phosphorylation of CRTC2, thereby controlling CRTC2’s occupancy of the insulin receptor substrate 2 (IRS2) promoter. We thus uncover CRTC2 as a novel hypothalamic AMPK target and highlight a role for CRTC2 in linking hypothalamic metabolic sensing pathways with CRE-gene regulation.