Adipose Tissue Memory and Why Patients Regain Weight after Weight Loss: Understanding the Immunologic Basis for...

Weight loss remains one of the primary strategies for reducing cardiometabolic risk, particularly with the advent of glucagon-like peptide-1 receptor agonists, which have been demonstrated to induce significant weight loss. Recent evidence suggests, however, that weight loss does not completely normalize the underlying biology of obesity. When weight loss medications are discontinued, patients may regain lost weight along with an increase in cardiometabolic disease risk, indicating that these medications may contribute to transiently altering the phenotype of obesity, but do not produce long-term remission. Adipose tissue is increasingly recognized as an active organ regulating systemic inflammation and metabolic homeostasis. In obesity, adipose tissue becomes inflamed through the activation of innate and adaptive immune pathways. This response has a lasting effect on the immune system. T cells in adipose tissue develop memory-like qualities via epigenetic and transcriptional reprogramming and can persist after weight loss, ready for rapid activation upon renewed metabolic stress. These immunologic memory effects drive repeated weight gain, progressive metabolic dysfunction, and ongoing cardiovascular risk. An immune process is working alongside the endocrine and metabolic adjustments that facilitate energy conservation and fat regain. The repetitive cycles of weight loss and regain further amplify these responses, leading to greater inflammation. Memory T-cell populations are maintained primarily through the CD70-CD27 axis; therefore, targeting this axis may be an effective approach to developing therapies that modify immune memory and achieve long-term cardiometabolic remission when combined with weight loss.