Abstract
People frequently experience cycles of weight gain and loss. This weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Obesity itself - and to an even greater extent weight regain - causes adipose tissue inflammation, resulting in metabolic dysfunction. Studies show that even after weight loss, increased numbers of lipid associated macrophages and memory T cells persist in adipose tissue and become more inflammatory upon weight regain. These findings suggest that the immune system retains a "memory" of obesity, which may contribute to the elevated inflammation and metabolic dysfunction associated with weight cycling. Here, we show that blocking the CD70-CD27 axis, critical for formation of immunological memory, decreases the number of memory T cells and reduces T cell clonality within adipose tissue after weight loss and weight cycling. Furthermore, while mice with impaired ability to create obesogenic immune memory have similar metabolic responses as wildtype mice to stable obesity, they are protected from the worsened glucose tolerance associated with weight cycling. Our data are the first to target metabolic consequences of weight cycling through an immunomodulatory mechanism. Thus, we propose a new avenue of therapeutic intervention by which targeting memory T cells can be leveraged to minimize the adverse consequences of weight cycling. These findings are particularly timely given the increasing use of efficacious weight loss drugs, which will likely lead to more instances of human weight cycling.