TNF / TNFR1 is a Key Regulator of Prolonged Fasting‐Induced Decrease in Adipose Tissue

ABSTRACT Nutrient availability influences white adipose tissue (WAT) inflammation, leading to decreased or increased adiposity. Tumor necrosis factor (TNF) is elevated in WAT under both conditions, being involved in lipolysis and regulation of interleukin 18 (IL‐18) secretion, which may regulate lipolytic processes. However, the role of these cytokines in adiposity reduction due to low energy availability remains unclear. Wild‐type (WT) mice fasted for 24 h showed decreased adiposity, whereas TNFR1 knockout mice (TNFR1 −/− ) were unresponsive to fat pad loss, even after 48‐h fasting. TNFR1 −/− mice were also resistant to β 3‐adrenergic receptor agonist CL316,243‐induced fat mobilization, which was linked with reduced expression of lipases, β 3‐adrenergic receptors, and cytokines in WAT. Also, mice treated with the TNF‐α inhibitor infliximab and fasted for 48 h showed resistance to adiposity loss, suggesting that prolonged fasting‐induced TNF signaling may modulate adipose tissue reduction. Conversely, IL‐18 does not seem to influence fat pad loss induced by 24‐h fasting as IL‐18 knockout mice (IL‐18 −/− ) express TNF in WAT and respond to prolonged fasting similarly to WT animals. To assess the potential translational relevance of our findings to human obesity, we analyzed 53 samples from patients with obesity who underwent bariatric surgery. Interestingly, TNFR1 and IL‐18 expressions in sWAT correlate with the expression of lipases and adipokines in the subcutaneous site despite no correlation with body weight or fat mass 1 year after surgery. In summary, this study suggests that the TNF/TNFR1 axis is crucial for metabolic adaptation and is a prerequisite for prolonged fasting‐induced lipolysis in male mice.