A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite.
A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite.
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ASRA 是一种富含棕色脂肪的脂肪因子，是一种瘦素受体拮抗剂，可刺激食欲。
DOI：
10.1101/2023.09.12.557454
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Wang,Yong-Xu
中科院分区：
文献类型：
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作者：
Huang,Lei;Liu,Pengpeng;Du,Yong;Pan,Dongning;Lee,Alexandra;Wolfe,ScotA;Wang,Yong-Xu
食物摄入的内分泌控制仍然不完全清楚，下丘脑中瘦素受体（LepR）介导的厌食途径是否受到体液因子的负调节也尚不清楚。在这里，我们确定了一个食欲刺激因子- ASRA -这是一个外围信号的能量不足和orthosterically拮抗LepR信号。Asra编码一种8 kD蛋白，该蛋白在脂肪组织中大量且选择性地表达，在较小程度上在肝脏中表达。ASRA与自噬囊泡相关，其分泌因能量缺乏而增强。在体内，禁食和寒冷刺激Asra表达并增加其在脑脊液中的蛋白浓度。Asra过表达减弱LepR信号传导，导致血糖升高和严重的过度吞噬性肥胖的发展。相反，脂肪特异性或肝脏特异性Asra敲除小鼠显示出瘦素敏感性增加、葡萄糖稳态改善、食物摄入减少、对高脂饮食诱导的肥胖的抵抗以及冷诱发的摄食反应减弱。在机制上，ASRA作为LepR的高亲和力拮抗剂。AlphaFold 2-多聚体预测和突变研究表明，ASRA的核心片段与LepR的免疫球蛋白样结构域结合，类似于瘦素A-B环的“位点3”识别。虽然施用重组野生型ASRA蛋白以LepR信号传导依赖性方式促进食物摄入并增加血糖，但ASRA内破坏LepR结合的点突变导致这些作用的丧失。我们的研究揭示了一个以前未知的食欲调节内分泌机制，并对我们了解瘦素抵抗具有重要意义。
The endocrine control of food intake remains incompletely understood, and whether the leptin receptor (LepR)-mediated anorexigenic pathway in the hypothalamus is negatively regulated by a humoral factor is unknown. Here, we identify an appetite-stimulating factor - ASRA - that represents a peripheral signal of energy deficit and orthosterically antagonizes LepR signaling. Asra encodes an 8 kD protein that is abundantly and selectively expressed in adipose tissue and to a lesser extent, in liver. ASRA associates with autophagy vesicles and its secretion is enhanced by energy deficiency. In vivo, fasting and cold stimulate Asra expression and increase its protein concentration in cerebrospinal fluid. Asra overexpression attenuates LepR signaling, leading to elevated blood glucose and development of severe hyperphagic obesity. Conversely, either adipose- or liver-specific Asra knockout mice display increased leptin sensitivity, improved glucose homeostasis, reduced food intake, resistance to high-fat diet-induced obesity, and blunted cold-evoked feeding response. Mechanistically, ASRA acts as a high affinity antagonist of LepR. AlphaFold2-multimer prediction and mutational studies suggest that a core segment of ASRA binds to the immunoglobin-like domain of LepR, similar to the ‘site 3’ recognition of the A-B loop of leptin. While administration of recombinant wild-type ASRA protein promotes food intake and increases blood glucose in a LepR signaling-dependent manner, point mutation within ASRA that disrupts LepR-binding results in a loss of these effects. Our studies reveal a previously unknown endocrine mechanism in appetite regulation and have important implications for our understanding of leptin resistance.