Obesity is a chronic organismal stress that disrupts multiple systemic and tissue-specific functions. In this study, we describe the impact of obesity on the activity of the hematopoietic stem cell (HSC) compartment. We show that obesity alters the composition of the HSC compartment and its activity in response to hematopoietic stress. The impact of obesity on HSC function is progressively acquired but persists after weight loss or transplantation into a normal environment. Mechanistically, we establish that the oxidative stress induced by obesity dysregulates the expression of the transcription factor Gfi1 and that increased Gfi1 expression is required for the abnormal HSC function induced by obesity. These results demonstrate that obesity produces durable changes in HSC function and phenotype and that elevation of Gfi1 expression in response to the oxidative environment is a key driver of the altered HSC properties observed in obesity. Altogether, these data provide phenotypic and mechanistic insight into durable hematopoietic dysregulations resulting from obesity.

肥胖症是一种慢性有机体压力，会破坏多种系统和特定于组织的功能。在这项研究中，我们描述了肥胖对造血干细胞（HSC）隔室活动的影响。我们表明，肥胖改变了造血应激反应的HSC隔室的组成及其活动。肥胖对HSC功能的影响是逐渐获得的，但在体重减轻或移植到正常环境后仍然存在。从机理上讲，我们确定肥胖引起的氧化应激会异常调节转录因子Gfi1的表达，并增加Gfi1的表达。肥胖引起的HSC功能异常需要表达。这些结果表明，肥胖症会导致HSC功能和表型产生持久性变化，而Gfi1表达随氧化环境的升高是肥胖症中HSC特性改变的关键驱动因素。总而言之，这些数据为肥胖导致的持久性造血功能异常提供了表型和机制方面的见解。