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

Abstract

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 three 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.

Postnatal Overnutrition Induces Changes in Synaptic Transmission to Leptin Receptor-Expressing Neurons in the Arcuate Nucleus of Female Mice

“…In agreement with former studies that indicated an influence of body weight on synaptic plasticity [ 16 , 18 , 19 , 20 , 21 , 23 ], we observed that postnatal overnutrition further increases the presynaptic excitatory transmission to ARH LepR-expressing cells, beyond the rise already observed with puberty. Suggesting that early weight gain affect other brain nuclei which send projections to ARH LepR-expressing neurons.…”

“…Age-dependent synaptic plasticity has been described in ARH neurons, as well as in neurons of the paraventricular nucleus of the hypothalamus [ 16 , 17 , 21 , 34 , 35 ]. For example, ARH kisspeptin neurons exhibit a lower presynaptic inhibitory tone after puberty onset [ 35 ].…”

“…For example, ARH kisspeptin neurons exhibit a lower presynaptic inhibitory tone after puberty onset [ 35 ]. While, NPY or POMC-expressing neurons exhibit increased inhibitory synaptic transmission with age [ 16 , 17 , 21 ]. Our data are in accordance with the NPY and POMC findings because we observed that ARH LepR-expressing cells also exhibited increased spontaneous inhibitory transmission in the prepubertal to pubertal transition.…”

“…Hypothalamic neurons are constantly exhibiting neuroplasticity in response to homeostatic demands [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. For example, GABAergic inputs to NPY or POMC neurons increase from prepubertal to adult stage, coinciding with the development of feeding circuitry in mice [ 5 , 16 , 21 ]. In adult mice, diet-induced obesity suppresses GABAergic and glutamatergic tone to NPY neurons, whereas fasting increases excitatory transmission to NPY-expressing cells [ 16 , 18 , 19 , 20 , 22 ].…”

Fibroblast Growth Factor-1 Activates Neurons in the Arcuate Nucleus and Dorsal Vagal Complex

“…Brain slices were collected as previously described (30). The forebrain and brainstem were mounted adjacent to each other and sectioned simultaneously with a sapphire knife (Delaware Diamond Knives) yielding roughly three slices from each region (250-mm) per mouse.…”