Metabolic dysfunctions are often linked to reproductive abnormalities. Adiponectin (ADP), a peripheral hormone secreted by white adipose tissue, is important in energy homeostasis and appetite regulation. GnRH neurons are integral components of the reproductive axis, controlling synthesis, and release of gonadotropins. This report examined whether ADP can directly act on GnRH neurons. Double-label immunofluorescence on brain sections from adult female revealed that a subpopulation of GnRH neurons express ADP receptor (AdipoR)2. GnRH/AdipoR2+ cells were distributed throughout the forebrain. To determine the influence of ADP on GnRH neuronal activity and the signal transduction pathway of AdipoR2, GnRH neurons maintained in explants were assayed using whole-cell patch clamping and calcium imaging. This mouse model system circumvents the dispersed distribution of GnRH neurons within the forebrain, making analysis of large numbers of GnRH cells possible. Single-cell PCR analysis and immunocytochemistry confirmed the presence of AdipoR2 in GnRH neurons in explants. Functional analysis revealed 20% of the total GnRH population responded to ADP, exhibiting hyperpolarization or decreased calcium oscillations. Perturbation studies revealed that ADP activates AMP kinase via the protein kinase Cζ/liver kinase B1 pathway. The modulation of GnRH neuronal activity by ADP demonstrated in this report directly links energy balance to neurons controlling reproduction.