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The rapid rise in obesity and its associated co-morbidities has amplified the importance of understanding exercise-induced metabolic adaptations, particularly within adipose tissue. While previous studies have characterized macro-level tissue responses, the specific molecular and cellular mechanisms remain incompletely defined. Using single-cell RNA sequencing (scRNA-seq) of subcutaneous white adipose tissue (scWAT), our lab identified Zbtb16 as the only gene upregulated across multiple progenitor cell types following exercise. This study investigates the functional significance of Zbtb16 through both in vitro and in vivo models. We demonstrate that Zbtb16 expression increases in male adipose tissue post-exercise, but not in females, indicating a sex-specific response. Overexpression of Zbtb16 in mice via AAV8 leads to a reduction in respiratory exchange ratio (RER) in high-fat-diet-fed males, suggesting enhanced lipid metabolism. Additionally, Zbtb16 expression appears to be modulated via β-adrenergic signaling, as B3-adrenergic receptor blockade suppressed its exercise-induced upregulation. Immune markers typically elevated post-exercise, such as IL6, were also increased with Zbtb16 overexpression, supporting its role in mediating inflammatory adaptations. These findings highlight Zbtb16 as a novel regulator of adipose tissue metabolism and immune signaling in response to physical activity, with implications for future therapeutic strategies targeting metabolic disease.