Obese adipose tissue (AT) is insulin resistant and inflamed due to changes in the number and activation state of innate and adaptive immune cells. Our single cell RNAseq studies of AT immune cells from lean and obese mice confirm these immunophenotypes. A greater proportion of Veteran than Civilian populations are obese, and while it is well-established that obesity increases risk of many diseases, recent evidence suggests that the cycling of body weight further increases risk of cardiometabolic diseases. We developed a mouse model of weight cycling (WC) and demonstrate that WC mice are more glucose intolerant than equally obese mice that have not cycled. Furthermore, we show that WC amplifies the accumulation of many inflammatory immune populations in AT beyond that of obese controls. Clues as to how WC increases AT inflammation can be gleaned from animals that have lost weight. As expected, weight loss (WL) improves systemic insulin action; however, the immune landscape of AT becomes even more inflammatory. We postulate that residual inflammatory cells in AT after WL become hyperactivated upon subsequent weight regain, and lead to exaggerated inflammation and metabolic dysfunction evident with WC. We and others have reported that the accumulation of AT T cells (ATTs) in obesity is characterized by clonal expansion of CD8+ cells. Strikingly, our preliminary studies show that WL and WC further amplify the number of clonally expanded CD8+ ATTs. Interestingly, the clonally expanded cells have an exhausted phenotype, are not cytotoxic, and display high expression of granzyme K (Gzmk). Although much less in known about Gzmk than other members of the granzyme family, our AT TGzmk cells are remarkably similar to a subset of Gzmk-expressing CD8+ T cells that accumulate in multiple tissues in aged mice. Additionally, a novel function of Gzmk – the ability to induce senescence in fibroblasts – suggests a potential mechanistic link between Gzmk action and dysfunctional tissue aging. Cell senescence is often studied in aging and cancer; however, emerging research suggests a role for adipocyte senescence in obesity and diabetes in mice and humans. Our preliminary data confirm a senescent phenotype of adipocytes in obesity and WC, as well as with Gzmk treatment. However, we do not know the importance of Gzmk or TGzmk cells in driving adipocyte senescence or to the metabolic dysfunction of AT in obesity, WL, and WC. Taken together, these published and preliminary studies lead us to hypothesize that TGzmk cells induce adipocyte senescence in obesity, which is amplified upon weight loss and regain, promoting AT dysfunction and glucose intolerance with WC. Specific Aim 1. To determine the role of Gzmk in adipocyte senescence and AT dysfunction. Specific Aim 2. To determine whether absence of Gzmk-expressing T cells reduces adipocyte senescence. Specific Aim 3. To determine whether TGzmk cells are sufficient to induce adipocyte senescence and AT dysfunction. IMPAC...