儿童副肿瘤性肥胖的罕见病例表明，散发性肥胖也可能是由适应性免疫细胞介导的机制引起的。由于下丘脑是进食行为和能量消耗的中央调节器，因此我们在一组肥胖和非肥胖人类死后大脑中量化了该区域的淋巴细胞炎症。我们报告说，与非肥胖患者相比，40% 的肥胖患者下丘脑正中隆起/弓状核 (ME/Arc) 和终纹床核中 CD8 阳性细胞毒性 T 细胞增多，但其他下丘脑核团或大脑区域。 CD8 T 细胞在同时患有肥胖症和糖尿病的个体中最为丰富。肥胖患者的 ME/Arc 中细胞毒性 T 细胞诱导损伤的标志物、活化的 caspase 3 和聚 ADP 核糖也升高。为了激发小鼠下丘脑腹内侧区域的 CD8 细胞毒性 T 细胞浸润，我们进行了表达免疫原性绿色荧光蛋白的腺相关病毒或盐水的立体定向注射。 AAV（而不是盐水注射）触发下丘脑 CD8 T 细胞浸润，与小鼠体重快速增加相关，这概括了人类肥胖的发现。这是对人类肥胖神经病理学的首次描述，与小鼠模型中的重建相结合表明，适应性免疫可能导致多达 40% 的人类状况。© 2023。BioMed Central Ltd.，Springer Nature 旗下公司。

Rare cases of paraneoplastic obesity in children suggest sporadic obesity might also arise from an adaptive immune cell-mediated mechanism. Since the hypothalamus is a central regulator of feeding behavior and energy expenditure, we quantified lymphocytic inflammation in this region in a cohort of obese and non-obese human post-mortem brains. We report that CD8-positive cytotoxic T-cells are increased in hypothalamic median eminence/arcuate nucleus (ME/Arc) and bed nucleus of the stria terminalis in 40% of obese compared to non-obese patients, but not in other hypothalamic nuclei or brain regions. CD8 T-cells were most abundant in individuals with concurrent obesity and diabetes. Markers of cytotoxic T-cell induced damage, activated caspase 3 and poly-ADP ribose, were also elevated in the ME/Arc of obese patients. To provoke CD8 cytotoxic T-cell infiltrates in ventromedial region of hypothalamus in mice we performed stereotactic injections of an adeno-associated virus expressing immunogenic green fluorescent protein or saline. AAV but not saline injections triggered hypothalamic CD8 T-cell infiltrates associated with a rapid weight gain in mice recapitulating the findings in human obesity. This is the first description of the neuropathology of human obesity and when combined with its reconstitution in a mouse model suggests adaptive immunity may drive as much as 40% of the human condition.© 2023. BioMed Central Ltd., part of Springer Nature.