Leptin suppresses development of GLP-1 Inputs to the Paraventricular Nucleus of the Hypothalamus

The nucleus of the solitary tract is critical for the central integration of signals from visceral organs and contains preproglucagon (PPG) neurons, which express leptin receptors and send direct projections to the paraventricular nucleus of the hypothalamus (PVH). Here, we visualized neuronal projections of PPG neurons in leptin-deficient Lep ob/ob mice and found that projections from PPG neurons are elevated compared with controls, and PPG projections were normalized by targeted rescue of leptin receptors in LepRb TB/TB mice, which lack functional neuronal leptin receptors. Moreover, Lep ob/ob and LepRb TB/TB mice displayed increased levels of neuronal activation in the PVH following vagal stimulation, and whole-cell patch recordings of GLP-1 receptor-expressing PVH neurons revealed enhanced excitatory neurotransmission, suggesting that leptin acts cell autonomously to suppress representation of excitatory afferents from PPG neurons, thereby diminishing the impact of visceral sensory information on GLP-1 receptor neurons in the PVH.