In this study, we show for the first time that 4-1BB is expressed on adipocytes and is upregulated by obesity-related factors, and we demonstrate that 4-1BB/4-1BBL-mediated bidirectional signaling in adipocytes/macrophages plays a crucial role in initiating and promoting the obesity-induced adipose inflammatory cascade. This evidence concerns the gene TNFSF9 and obesity due to melanocortin 4 receptor deficiency.