에너지 항상성 조절에 대한 시상하부 미세아교세포의 역할에 대한 연구

Abstract

Microglia perform an essential role in maintaining brain homeostasis. In addition, microglia metabolic flexibility recognizes changes in the brain environment and performs functions that are suitable for the changing environment through contact with neurons. Microglia contact with neurons, which is mediated by various soluble factors containing ATP as well as contact-dependent mechanisms, is critical for neuronal activation and synaptic development in a healthy brain. In particular, the contact of the ATP of neurons and the P2Y12 receptor of microglia is involved in neuronal inhibition caused by generated adenosine through activated purinergic signaling. However, it is unclear whether the decreased ATP in the hypothalamic arcuate nucleus (ARC) according to energy starvation affects the contact of microglia with AgRP neurons. Moreover, it is unclear whether the activation of AgRP neurons is regulated by adenosine generated by contact with microglia. Interestingly, I observed that microglia contact with AgRP neurons was decreased during overnight fasting and that the contact with AgRP neurons increased when microglia P2Y12 receptor activation was increased. In addition, the increased contact of microglia with AgRP neurons during overnight fasting induces an increase of purinergic signaling mediators such as CD39, vesicular nucleotide transporter (vNUT) and adenosine 1 receptor (A1R) in the hypothalamic ARC. Thus, hypothalamic AgRP neuronal activation is affected by the microglia contact through P2Y12 receptor activation according to the energy state as well as the purinergic signaling in the microglia and AgRP neurons through microglia contact with AgRP neurons.|Morphology change of the microglia by P2Y12 receptor performs surveillance and phagocytosis functions in the various brain conditions, and these roles are involved in maintaining brain homeostasis. The P2Y12 receptor activation is affected by the generated adenosine 5’-triphosphate (ATP) in the mitochondria of the neurons, and this activation is involved in the regulation of the microglia process. In particular, change in hypothalamic microglial morphology through the P2Y12 receptor plays a crucial role in the energy homeostasis mechanism of the microglia that is important in regulation of neuronal functions by releasing cytokines and chemokines. However, it is unclear whether the morphological change of microglia through the P2Y12 receptor is affected by energy starvation. Therefore, in this study, I investigated the morphological change of hypothalamic microglia by overnight fasting. In the hypothalamic arcuate nucleus (ARC), process length and P2Y12 receptor activation in microglia were decreased by overnight fasting. Administration of P2Y12 agonist and antagonist affected the morphological parameters such as process length and branching of the hypothalamic microglia. Interestingly, the P2Y12 agonist and antagonist also affected neuronal activation in the hypothalamic ARC. These observations suggest that the P2Y12 receptor of hypothalamic microglia is a crucial mediator of microglial morphology and neuronal activation.