未经证实:减肥可改善肥胖相关的糖尿病风险。然而,大多数人恢复体重,这恶化了患糖尿病和心血管疾病的风险。我们以前报道,雄性小鼠即使在体重减轻后仍保留与肥胖相关的免疫学变化,这表明免疫细胞可能会记住肥胖的状态。因此,我们假设体重增加和减少的周期,也被称为重量循环,可以诱导脂肪巨噬细胞的先天记忆。
未经证实:在先天性免疫记忆的培养模型中,用棕榈酸或脂肪组织条件培养基对骨髓来源的巨噬细胞进行致敏。小鼠还在14-27周内进行低脂肪或高脂肪饮食以诱导体重增加,减肥,和重量循环。
未经证实:用来自肥胖小鼠的棕榈酸或脂肪组织条件培养基启动细胞增加了最大糖酵解和氧化磷酸化,并增加了LPS诱导的TNFα和IL-6的产生。棕榈酸的作用依赖于TLR4,并受到甲基转移酶抑制和AMPK激活的损害。虽然体重减轻改善了小鼠的葡萄糖耐量,如通过细胞因子产生所测量的,脂肪巨噬细胞对LPS离体刺激的激活更大.在重量循环模型中,脂肪巨噬细胞代谢升高并分泌更高水平的基础TNFα,这表明,减肥也可以引发巨噬细胞的高度激活,以恢复体重。
未经批准:一起,这些数据表明,肥胖后的体重减轻可以使脂肪巨噬细胞在体重恢复后增强炎症。这种先天免疫记忆反应可能导致体重循环后葡萄糖耐量恶化。
Weight loss improves obesity-associated diabetes risk. However, most individuals regain weight, which worsens the risk of developing diabetes and cardiovascular disease. We previously reported that male mice retain obesity-associated immunological changes even after weight loss, suggesting that immune cells may remember the state of obesity. Therefore, we hypothesized that cycles of weight gain and loss, otherwise known as weight cycling, can induce innate memory in adipose macrophages.
Bone marrow derived macrophages were primed with palmitic acid or adipose tissue conditioned media in a culture model of innate immune memory. Mice also put on low fat or high fat diets over 14-27 weeks to induce weight gain, weight loss, and weight cycling.
Priming cells with palmitic acid or adipose tissue conditioned media from obese mice increased maximal glycolysis and oxidative phosphorylation and increased LPS-induced TNFα and IL-6 production. Palmitic acid effects were dependent on TLR4 and impaired by methyltransferase inhibition and AMPK activation. While weight loss improved glucose tolerance in mice, adipose macrophages were primed for greater activation to subsequent stimulation by LPS ex vivo as measured by cytokine production. In the model of weight cycling, adipose macrophages had elevated metabolism and secreted higher levels of basal TNFα, suggesting that weight loss can also prime macrophages for heighted activation to weight regain.
Together, these data suggest that weight loss following obesity can prime adipose macrophages for enhanced inflammation upon weight regain. This innate immune memory response may contribute to worsened glucose tolerance following weight cycling.