BACKGROUNDS Social interaction with others is essential to life. Although social isolation and loneliness have been implicated as increased risks of cardiometabolic and cardiovascular diseases and all-cause mortality, the cellular and molecular mechanisms by which social connection maintains cardiometabolic and cardiovascular health remain largely unresolved. METHODS To investigate how social connection protects against cardiometabolic and cardiovascular diseases, atherosclerosis-prone, high-fat diet-fed Apoe-/- mouse siblings were randomly assigned to either individual or grouped housing for 12 weeks. Histological, flow cytometric, biochemical, gene, and protein analyses were performed to assess atherosclerotic lesions, systemic metabolism, inflammation, and stress response. The effects of oxytocin on hepatocytes and subsequent cardiometabolic and cardiovascular function were investigated by in vivo and in vitro approaches. RESULTS Apoe-/- mice housed individually developed larger vulnerable atherosclerotic lesions by disrupted lipid metabolism compared with those of mice in regular group housing, irrespective of body weight, eating behavior, feeding conditions, sympathetic nervous activity, glucocorticoid response, or systemic inflammation. Mechanistically, the chronic isolation reduced the hypothalamic production of oxytocin, which controls bile acid production and LPL (lipoprotein lipase) activity through the peripheral OXTR (oxytocin receptor) in hepatocytes, whose downstream targets include Cyp7a1, Angptl4, and Angptl8. While hepatocyte-specific OXTR-null mice and mice receiving adeno-associated virus targeting OXTR on hepatocytes led to severe dyslipidemia and aggravated atherosclerosis, oral oxytocin supplementation to socially isolated mice, but not to hepatocyte-specific OXTR conditional knockout mice, improved lipid profiles and retarded atherosclerosis development. CONCLUSIONS These results identify a novel brain-liver axis that links sociality to hepatic lipid metabolism, thus proposing a potential therapeutic strategy for loneliness-associated atherosclerosis progression.

中文翻译：

---

社会纽带保留催产素介导的脑肝轴以延缓动脉粥样硬化。


背景 与他人的社交互动对生活至关重要。尽管社会孤立和孤独与心脏代谢和心血管疾病以及全因死亡率的风险增加有关，但社会联系维持心脏代谢和心血管健康的细胞和分子机制在很大程度上仍未得到解决。方法 为了研究社会联系如何预防心脏代谢和心血管疾病，将易发生动脉粥样硬化、高脂肪饮食喂养的 Apoe-/- 小鼠兄弟姐妹随机分配到个体或群体饲养 12 周。进行组织学、流式细胞术、生化、基因和蛋白质分析，以评估动脉粥样硬化病变、全身代谢、炎症和应激反应。通过体内和体外方法研究催产素对肝细胞以及随后的心脏代谢和心血管功能的影响。结果 与常规群体饲养的小鼠相比，单独饲养的 Apoe-/-小鼠由于脂质代谢中断而发展出更大易受攻击的动脉粥样硬化病变，无论体重、进食行为、摄食条件、交感神经活动、糖皮质激素反应或全身炎症如何。从机制上讲，慢性分离减少了下丘脑催产素的产生，催产素通过肝细胞中的外周 OXTR（催产素受体）控制胆汁酸的产生和 LPL（脂蛋白脂肪酶）活性，其下游靶标包括 Cyp7a1、Angptl 4 和 Angptl8。 虽然肝细胞特异性 OXTR 缺失小鼠和接受靶向肝细胞 OXTR 的腺相关病毒的小鼠导致严重的血脂异常和动脉粥样硬化加重，但口服催产素补充剂对社会隔离小鼠，而不是肝细胞特异性 OXTR 条件性敲除小鼠，改善了血脂谱并延缓了动脉粥样硬化的发展。结论 这些结果确定了一个新的脑-肝轴，该轴将社会性与肝脏脂质代谢联系起来，从而为孤独相关的动脉粥样硬化进展提出了一种潜在的治疗策略。