시상하부 에너지 대사 조절에서 FAM19A5와 TTF-1의 역할에 관한 연구

Abstract

Energy imbalance is a serious issue in modern society and is associated with various metabolic disorders such as obesity and diabetes. Hypothalamus, as a center of regulating energy homeostasis, plays an important role in whole-body energy balance and is targeted in various research on metabolic disorders. In the arcuate nucleus (ARC) of the hypothalamus, agouti-related protein (AgRP) neuronal activation strongly promotes the feeding behavior that affects the positive energy balance and activation of pro-opiomelanocortin (POMC) neurons induces the negative energy balance through enhancing energy expenditure. Therefore, balance of positive and negative energy is a crucial role in energy homeostasis. Here, I reported a role of FAM19A5, as a novel neuro-chemokine, in TNF-α-induced negative energy balance such as sickness responses (chapter 1), and the mechanism regulating positive energy balance through the expression of AgRP and POMC by TTF-1 (chapter 2). In chapter 1, I demonstrated that FAM19A5 induced negative energy balance by activation of POMC neurons in hypothalamic inflammation. TNF-α-induced hypothalamic inflammation affected FAM19A5 mRNA expression and inhibition of FAM19A5 in hypothalamic inflammation condition reduced sickness response by inhibiting gene expression of inflammatory cytokines. Moreover, FAM19A5 induced POMC neuronal activation that is related to illness-induced anorexia. In summary, FAM19A5 induced negative energy balance in the hypothalamus, and hypothalamic inflammation-induced negative energy balance was restored by inhibition of FAM19A5, as a result, maintaining energy balance. In chapter 2, I verified that interaction of TTF-1 and Sirt1 controls energy homeostasis by regulating AgRP and POMC gene expression according to energy states. Interaction of Sirt1 with TTF-1 resulted in deacetylation of TTF-1. Furthermore, TTF-1 deacetylation enhanced AgRP mRNA expression and reduced POMC mRNA expression by promoting nuclear translocation. In summary, AgRP and POMC gene expression was regulated by TTF-1 and Sirt1 interaction, and TTF-1 deacetylation. Together, these results suggest that FAM19A5 and TTF-1 in the hypothalamus play a pivotal role in energy homeostasis.