Fasting induces IL-1 resistance and free-fatty acid-mediated up-regulation of IL-1R2 and IL-1RA

Objective: Weight-loss is a near societal obsession and many diet programs use significant calorie restriction including fasting/short term starvation to generate rapid effects. Fasting is also a well-recognized cause of immunosuppression especially within the innate immune system. In this study, we sought to determine if the IL-1 arm of the neuroimmune system was down-regulated by a 24h fast and how fasting might generate this effect. Design: Mice were allowed ad libitum access to food or had food withheld for 24h. Expression of the endogenous IL-1 antagonists, IL-1 receptor type 2 (IL-1R2), and IL-1 receptor antagonist (IL-1RA) was determined as were sickness behaviors before and after IL-1β administration. Results: Fasting markedly increased gene expression of IL-1R2 (83-fold in adipose tissue, 9.5-fold in liver) and IL-1RA (68-fold in liver). Fasted mice were protected from IL-1β-induced weight-loss, hypoglycemia, loss of locomotor, and social anxiety. These protections were coupled to a large positive interaction of fasting and IL-1β on IL-1R2 gene expression in adipose tissue and liver (2.6- and 1.6-fold, respectively). Fasting not only increased IL-1RA and IL-1R2 protein 2.5- and 3.2-fold, respectively, in liver but also increased IL-1R2 1.8-fold in adipose tissue. Fasting, in turn, triggered a 2.4-fold increase in plasma free-fatty acids (FFAs) and a 2.1-fold increase in plasma corticosterone. Inhibition, of glucocorticoid action with mifepristone did not impact fasting-dependent IL-1R2 or IL-1RA gene expression. Administration of the FFA, palmitate, to mice increased liver IL-1R2 and IL-1RA gene expression by 14- and 11-fold, respectively. Conclusion: These findings indicate that fasting augments expression of endogenous IL-1 antagonists inducing IL-1 resistance. Fasting-induced increases in plasma FFAs appears to be a signal that drives immunosuppression during fasting/short term starvation.