Interrupting T-Cell Memory Ameliorates Exaggerated Metabolic Response to Weight Cycling.

Weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Both obesity itself and weight cycling cause adipose tissue inflammation and 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 on weight regain. This suggests that the immune system retains an obesogenic memory, which may contribute to the elevated inflammation and metabolic dysfunction associated with weight cycling. We show that blocking the CD70-CD27 axis, critical for the formation of immunologic memory, decreases the number of memory T cells and T-cell clonality within adipose tissue after weight loss and weight cycling. Furthermore, although CD70-/- mice have metabolic responses to stable obesity similar to those of wild-type mice, they are protected from the worsened glucose tolerance associated with weight cycling. Our data are the first to support mitigating the metabolic consequences of weight cycling through an immunomodulatory mechanism. We propose a new avenue of therapeutic intervention targeting memory T cells to minimize the adverse consequences of weight cycling. These findings are timely, given the increasing use of weight-loss drugs, which may lead to more instances of human weight cycling. ARTICLE HIGHLIGHTS: We aimed to address a critical gap in understanding how persistent immune changes with weight cycling contribute to worsened metabolic health. We wanted to determine whether disrupting immune memory formation could prevent the accumulation and reactivation of memory T cells in adipose tissue and thereby protect against the metabolic dysfunction associated with weight cycling. In targeting the CD70-CD27 axis, thereby inhibiting T-cell memory formation, we were able to mitigate the exacerbated glucose intolerance observed in wild-type weight-cycled mice. This study highlights the potential to address the negative metabolic effects of weight cycling through an immunomodulatory approach, offering a novel therapeutic target by disrupting obesogenic immune memory.