Versatile role of NELL2 in brain

Abstract

CommentaryA precise communication between the central nervous system (CNS) and the periphery is fundamental in achieving a fine balance between energy intake and expenditure. When this crosstalk is impaired, obesity, a metabolic state characterized by excess fat accumulation in peripheral tissues, occurs. Obesity is the foundation for several metabolic syndromes, such as type 2 diabetes, stroke, and hypertension, all of which are leading causes of mortality. It is no doubt that multiple regions of the brain participate in the regulation of energy homeostasis. However, the hypothalamus has long been highlighted in metabolism regulation as it forms a coherent whole for direct detection of circulating metabolic signals, integration of metabolic information obtained from periphery and other CNS regions, and production of adequate molecular and behavioral outcomes that preserve whole body energy homeostasis [1][2][3][4].NELL2, a mammalian neural tissue-enriched EGF-Like Like protein 2, is a newly identified secreting molecule from neurons as a neurotransmitter [5,6]. Although NELL2 is broadly distributed throughout the mammalian brain, we previously reported that its expression is brain region-specific and cell type-dependent [5]. Importantly, NELL2 is produced relatively high in the hypothalamus compared to other brain regions [5,7]. In addition, core hypothalamic nuclei known to play a critical role in metabolism regulation, such as the paraventricular nucleus, ventromedial nucleus, and the arcuate nucleus of the hypothalamus (ARC) are also a main site of NELL2 production [5,7]. This anatomical observation allowed us to hypothesize a potential function of NELL2 in whole body metabolism regulation.Recently, we reported "A Role of Central NELL2 in the Regulation of Feeding Behavior in Rats" [7]. In this work, we demonstrated a role for central NELL2 in rodent feeding behavior and energy homeostasis, using an antisense oligonucleotide-dependent gene blocking system for an acute ablation of NELL2 biosynthesis in adult rodent brain in vivo. Importantly, adult rats with acute hypothalamic NELL2 ablation showed a significant reduction in body weight gain under ad libitum, normal chow feeding conditions when compared to controls. This response was attributed to a reduction in food intake behavior. On the other hand, blockade of NELL2 in the hypothalamus did not affect animal's water intake, nor produced sickness behavior. These behavioral studies have demonstrated a role of hypothalamic NELL2 signaling in feeding behavior. Interestingly, short-term food intake followed by overnight fasting was not differ between experimental and control groups, suggesting that NELL2 signaling in the hypothalamus is specific for ad libitum appetite behavior. We also observed in this study that mRNA level of NELL2 expression in the hypothalamus was elevated during fasting, when compared to a fed state. Therefore, it is likely that central NELL2 is responsible for an orexigenic mechanism in rodents.Anatomical verification revealed that NELL2 i...