Adult NG2-Glia Are Required for Median Eminence-Mediated Leptin Sensing and Body Weight Control

Abstract

While leptin is a well-known regulator of body fat mass, it remains unclear how circulating leptin is sensed centrally to maintain energy homeostasis. Here we show that genetic and pharmacological ablation of adult NG2-glia (also known as oligodendrocyte precursors), but not microglia, leads to primary leptin resistance and obesity in mice. We reveal that NG2-glia contact the dendritic processes of arcuate nucleus leptin receptor (LepR) neurons in the median eminence (ME) and that these processes degenerate upon NG2-glia elimination, which explains the consequential attenuation of these neurons' molecular and electrical responses to leptin. Our data therefore indicate that LepR dendrites in the ME represent the principal conduits of leptin's anorexigenic action and that NG2-glia are essential for their maintenance. Given that ME-directed X-irradiation confirmed the pharmacological and genetically mediated ablation effects on body weight, our findings provide a rationale for the known obesity risk associated with cranial radiation therapy.

Development of the hypothalamus: conservation, modification and innovation

“…Interestingly, postnatally born hypothalamic neurons in rodents appear to be localized throughout the parenchyma rather than just near the ventricular zone (Kokoeva et al, 2007). It is therefore possible that quiescent neural progenitors reside in the parenchyma as well (Djogo et al, 2016), and might represent a stem cell or progenitor pool that is distinct from tanycytes.…”

NG2 Glia: Novel Roles beyond Re-/Myelination

“…In line with this view, confocal and electron microscopy studies showed that NG2 glia establish physical contacts with functionally relevant neuronal domains, including dendrites [41,42], somata [14,41,43,44], nodes of Ranvier [45,46] and synapses [47,48] (Figure 1C). About 30-50% of the nodes are contacted by both NG2 glia and astrocyte processes in the optic nerve, corpus callosum, and spinal cord of young adult rodents.…”

“…In line with this view, confocal and electron microscopy studies showed that NG2 glia establish physical contacts with functionally relevant neuronal domains, including dendrites [41,42], somata Figure 1. Schematic representation of the mechanisms assuring NG2 glia maintenance and of their physical interactions with neurons and other central nervous system (CNS) cell types (A) NG2 glia are distributed in a grid-like manner and occupy non-overlapping domains.…”

“…A third recent study [42] used three different methods (i.e., X-irradiation, AraC infusion into the third ventricle and a novel mouse line where Esco2, a protein necessary for cell cycle progression, could be deleted in NG2 glia, inducing cell death in cycling NG2 cells; see also [12]) to ablate NG2 glia in the adult mouse median eminence. Here, NG2 glia ablation caused the degeneration of the dendrites of hypothalamic neurons expressing the leptin receptor.…”

“…Further efforts are needed to overcome the limitations of the experimental strategies employed so far, and to identify the molecular and cellular processes subserving NG2 glia participation in CNS homeostasis, ontogeny, and disease. Namely, the in vivo NG2 glia ablation approaches showed important intrinsic caveats, e.g., the achievement of a partial and transient cell ablation due to the fast repopulation of NG2 glia; region-specific differences in the ablation efficiency due to different cell cycle dynamics and repopulation efficiency of NG2 glia in distinct CNS areas [87]; selective/predominant ablation of specific NG2 glia subsets (i.e., those that are more prone to enter cell cycle; [42,88]); possible interference/superimposition of the reactions of other CNS cell types responding to NG2 glia loss [88]. Such limitations restrict the time window/extent/types of phenotypes that could be attributed to NG2 glia loss, and may also hamper investigation into the underlying molecular mechanisms.…”