Early overnutrition alters synaptic signaling and induces leptin resistance in arcuate proopiomelanocortin neurons.

Early overnutrition disrupts leptin sensitivity and the development of hypothalamic pathways involved in the regulation of metabolism and feeding behavior. While previous studies have largely focused on the development of neuronal projections, few studies have examined the impact of early nutrition on hypothalamic synaptic physiology. In this study we characterized the synaptic development of proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH), their sensitivity to leptin, and the impact of early overnutrition on the development of these neurons. Electrophysiology recordings were performed in mouse ARH brain slices containing POMC-EGFP neurons from postnatal age (P) 7-9 through adulthood. We determined that pre- and postsynaptic components of inhibitory inputs increased throughout the first 3 weeks of the postnatal period, which coincided with a decreased membrane potential in POMC neurons. We then examined whether chronic postnatal overnutrition (CPO) altered these synaptic connections. CPO mice exhibited increased body weight and circulating leptin levels, as described previously. POMC neurons in CPO mice had an increase in post-synaptic inhibitory currents compared to controls at 2 weeks of age, but this effect reversed by the third week. In control mice we observed heterogenous effects of leptin on POMC neurons in early life that transitioned to predominantly stimulatory actions in adulthood. However, postnatal overfeeding resulted in POMC neurons becoming leptin-resistant which persisted into adulthood. These studies suggest that postnatal overfeeding alters the postsynaptic development of POMC neurons and induces long-lasting leptin resistance in ARH-POMC neurons.