The role of tanycytic TSPO in the regulation of lipid and energy metabolism through autophagy

Abstract

In the central nervous system (CNS), the hypothalamus is a critical region of the brain that regulates appetite or energy balance by integrating metabolic signals such as nutrients or hormones. Although the action of hypothalamic neural circuits in control of feeding behavior or energy homeostasis widely has been elucidated, recent emerging evidence demonstrates that glial cells, non-neuronal cells, also have important functions to maintain energy balance. Especially, hypothalamic macroglial cells named tanycytes, which line the 3rd ventricle (3V), are components of the hypothalamic network that regulates a diverse array of metabolic functions for energy homeostasis. It has been suggested that tanycytes can sense nutrients such as glucose, amino acids, and lipids, and those nutritional signals may be transmitted to hypothalamic neurons participating in the appetite regulation. However, the mechanisms for the tanycytes-mediated regulation of energy metabolism remain poorly understood. The translocator protein (TSPO, 18kDa), previously discovered as a peripheral benzodiazepine receptor (PBR), is a protein mainly located in an outer-mitochondrial membrane. Recently, TSPO located at the periphery has emerged as a candidate regulator for cellular bioenergetics whereas the understanding of the role of TSPO in the brain related to energy metabolism remains elusive. In this study, I report that TSPO is highly enriched in tanycytes and regulates homeostatic responses to nutrient excess as a potential target for effective intervention in obesity. Administration of a TSPO ligand, PK11195, into the 3V, and tanycyte-specific deletion of Tspo reduced food intake and elevated energy expenditure, leading to negative energy balance in a high-fat diet challenge. Ablation of tanycytic Tspo elicited AMPK-dependent lipophagy, breaking down lipid droplets into free fatty acids, thereby elevating ATP in a lipid stimulus. Activated AMPK in inhibition of TSPO was due to elevation of cytosolic calcium caused by blocking the uptake of mitochondrial calcium. These findings suggest that tanycytic TSPO affects systemic energy balance through macroautophagy/autophagy regulated lipid metabolism, and highlight the physiological significance of TSPO in hypothalamic lipid sensing and bioenergetics in response to overnutrition.