Adipocyte OX40L promotes adipose T cell activation and insulin resistance in obesity

T cells contribute critically to obesity-induced adipose inflammation and insulin resistance, yet the co-stimulatory signals that govern their activation in adipose tissue remain unclear. Here, we systematically profile co-stimulatory molecules in adipocytes and adipose tissue macrophages and identify OX40 ligand (OX40L) as the most robustly upregulated in obesity. OX40L is also elevated in adipocytes from obese humans. Although macrophage-specific OX40L deletion has no metabolic impact, global OX40 deficiency or adipocyte-specific OX40L deletion reduces Th1 cell accumulation in visceral adipose tissue, attenuates inflammation and improves insulin sensitivity without affecting adiposity. These benefits are reversed by Th1 cell transfer. Therapeutic blockade of OX40L with a neutralizing antibody mimics the protective effects of genetic deletion. Our findings identify adipocyte-derived OX40L as a critical mediator of obesity-associated immune dysfunction and establish it as a targetable checkpoint for tissue-specific immunotherapy in metabolic disease.