Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology , Daegu, Republic of Korea.
Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology , Daegu, Republic of Korea.
Autophagy. 2020 Jul;16(7):1200-1220. doi: 10.1080/15548627.2019.1659616. Epub 2019 Aug 30.
Hypothalamic glial cells named tanycytes, which line the 3 ventricle (3V), are components of the hypothalamic network that regulates a diverse array of metabolic functions for energy homeostasis. Herein, we report that TSPO (translocator protein), an outer mitochondrial protein, is highly enriched in tanycytes and regulates homeostatic responses to nutrient excess as a potential target for an effective intervention in obesity. Administration of a TSPO ligand, PK11195, into the 3V, and tanycyte-specific deletion of reduced food intake and elevated energy expenditure, leading to negative energy balance in a high-fat diet challenge. Ablation of tanycytic elicited AMPK-dependent lipophagy, breaking down lipid droplets into free fatty acids, thereby elevating ATP in a lipid stimulus. Our 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.
3V: 3 ventricle; ACAC: acetyl-Coenzyme A carboxylase; AGRP: agouti related neuropeptide; AIF1/IBA1: allograft inflammatory factor 1; AMPK: AMP-activated protein kinase; ARC: arcuate nucleus; Atg: autophagy related; Bafilo: bafilomycin A; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2, beta; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CNS: central nervous system; COX4I1: cytochrome c oxidase subunit 4I1; FFA: free fatty acid; GFAP: glial fibrillary acidic protein; HFD: high-fat diet; ICV: intracerebroventricular; LAMP2: lysosomal-associated membrane protein 2; LD: lipid droplet; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MBH: mediobasal hypothalamus; ME: median eminence; MEF: mouse embryonic fibroblast; NCD: normal chow diet; NEFM/NFM: neurofilament medium; NPY: neuropeptide Y; OL: oleic acid; POMC: pro-opiomelanocortin-alpha; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; : retina and anterior neural fold homeobox; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; RER: respiratory exchange ratio; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TG: triglyceride; TSPO: translocator protein; ULK1: unc-51 like kinase 1; VCO: carbon dioxide production; VMH: ventromedial hypothalamus; VO: oxygen consumption.
命名为室管膜细胞的下丘脑神经胶质细胞，位于第三脑室（3V），是调节各种代谢功能以维持能量平衡的下丘脑网络的组成部分。在此，我们报告 TSPO（转位蛋白），一种外线粒体蛋白，在室管膜细胞中高度丰富，并作为肥胖有效干预的潜在靶点，调节对营养过剩的稳态反应。将 TSPO 配体 PK11195 注入 3V，以及特异性敲除 ，可减少食物摄入并增加能量消耗，导致高脂肪饮食挑战中的负能量平衡。室管膜细胞特异性敲除 会引发 AMPK 依赖性脂溶作用，将脂滴分解成游离脂肪酸，从而在脂质刺激下提高 ATP。我们的研究结果表明，室管膜细胞 TSPO 通过巨自噬/自噬调节的脂质代谢影响全身能量平衡，并强调 TSPO 在脂肪感应和下丘脑生物能学中的生理意义，以响应营养过剩。
3V：第三脑室；ACAC：乙酰辅酶 A 羧化酶；AGRP：刺鼠相关神经肽；AIF1/IBA1：同种异体炎症因子 1；AMPK：AMP 激活的蛋白激酶；ARC：弓状核；Atg：自噬相关；Bafilo：巴非洛霉素 A；CAMKK2：钙/钙调蛋白依赖性蛋白激酶激酶 2，β；CCCP：羰基氰化物 m-氯苯腙；CNS：中枢神经系统；COX4I1：细胞色素 c 氧化酶亚基 4I1；FFA：游离脂肪酸；GFAP：神经胶质纤维酸性蛋白；HFD：高脂肪饮食；ICV：脑室内；LAMP2：溶酶体相关膜蛋白 2；LD：脂滴；MAP1LC3B/LC3B：微管相关蛋白 1 轻链 3β；MBH：中基底下丘脑；ME：中脑；MEF：小鼠胚胎成纤维细胞；NCD：正常饲料饮食；NEFM/NFM：神经丝中等；NPY：神经肽 Y；OL：油酸；POMC：前阿黑皮素原-α；PRKN/Parkin：parkin RBR E3 泛素蛋白连接酶；：视网膜和前神经折叠同源盒；RBFOX3/NeuN：RNA 结合蛋白，fox-1 同源物（秀丽隐杆线虫）3；RER：呼吸交换率；siRNA：小干扰 RNA；SQSTM1：自噬体 1；TG：甘油三酯；TSPO：转位蛋白；ULK1：UNC-51 样激酶 1；VCO：二氧化碳产生；VMH：腹内侧下丘脑；VO：耗氧量。
