Long before the word ‘inflammation’ gained prominence in immunometabolic research, Gökhan S. Hotamışlıgil and his team were investigating the molecular mechanism of a key inflammatory player, tumour necrosis factor (TNF), which drives obesity-induced insulin resistance. In the 1990s, obesity was primarily viewed as a consequence of an imbalance between caloric intake and energy expenditure, and was highly correlated with insulin resistance in both experimental animals and humans. However, a paper published in Nature in 1997 changed the narrative.

The idea that TNF expression in adipose tissue could drive obesity-induced insulin resistance was not entirely new, but the question of causality remained debated. Were elevated cytokines such as TNF merely bystanders in the adipose tissue during obesity, or were they active drivers of systemic metabolic dysfunction? Uysal et al. took a bold leap to answer the question of what happens if TNF is genetically eliminated.