Developmental Switch of Leptin Signaling in Arcuate Nucleus Neurons

Abstract

Leptin is well known for its role in the regulation of energy homeostasis in adults, a mechanism that at least partially results from the inhibition of the activity of NPY/AgRP/GABA neurons (NAG) in the arcuate nucleus of the hypothalamus (ARH). During early postnatal development in the rodent, leptin promotes axonal outgrowth from ARH neurons, and preautonomic NAG neurons are particularly responsive to leptin's trophic effects. To begin to understand how leptin could simultaneously promote axonal outgrowth from and inhibit the activity of NAG neurons, we characterized the electrochemical effects of leptin on NAG neurons in mice during early development. Here, we show that NAG neurons do indeed express a functional leptin receptor throughout the early postnatal period in the mouse; however, at postnatal days 13-15, leptin causes membrane depolarization in NAG neurons, rather than the expected hyperpolarization. Leptin action on NAG neurons transitions from stimulatory to inhibitory in the periweaning period, in parallel with the acquisition of functional ATP-sensitive potassium channels. These findings are consistent with the idea that leptin provides an orexigenic drive through the NAG system to help rapidly growing pups meet their energy requirements.

Neonatal ghrelin programs development of hypothalamic feeding circuits

“…As expected, leptin treatment caused a marked increase in pSTAT3 staining in the ARH of control pups on P10 ( Figure 5C). However, the same leptin treatment resulted in significantly fewer numbers of pSTAT3-IR cells in the ARH of P10 neonates chroni- different neurophysiological effects in neonates versus adults, a recent study from Baquero and colleagues reported that during the preweaning period leptin exerts stimulatory electrophysiological effects on NPY/AgRP neurons although it inhibits those same neurons at weaning and in adults (34). Notably, we found that ghrelin influences development of projections to both the neuroendocrine and preautonomic compartments of the PVH.…”

Leptin Controls Parasympathetic Wiring of the Pancreas during Embryonic Life

“…The mechanisms underlying the opposing effects of leptin on hypothalamic and hindbrain axon growth remain to be investigated. However, recent data have suggested that the transition from stimulatory to inhibitory effects of leptin on neuronal activity occurs in parallel with the acquisition of functional ATP-sensitive potassium channels (Baquero et al, 2014), and these data support the hypothesis that leptin activates distinct membrane-linked and intracellular pathways in hindbrain and hypothalamic neurons during development. Prenatal leptin exposure could also result in changes in insulin levels that could then, in turn, indirectly affect the autonomic innervation of the pancreas.…”

Defining Subpopulations of Arcuate Nucleus GABA Neurons in Male, Female, and Prenatally Androgenized Female Mice

“…These findings are similar to those in the rat, where co-localization with glutamic acid decarboxylase, a rate-limiting enzyme for GABA production, identified at least one-quarter of GABA neurons express NPY [48] . There is long-standing functional and anatomical evidence that ARN NPY neurons use GABA neurotransmission in the regulation of circuits mediating food intake behavior [49] , and more recent approaches suggest that co-released GABA actions at postsynaptic targets are essential for normal feeding behavior [3,4,50] . Although the co-expression of GABA in virtually all NPY neurons is well accepted, the present study defines, for the first time, the specific proportion of ARN GABA neurons that co-localize and presumably co-release NPY in the mouse.…”