W170 - TMEM176B is a Target to Control Pathogenic Inflammasome Activation in Obesity

Inflammation is thought to play a pathogenic role in obesity and related morbidities. However, targeting inflammatory players has not shown a significant benefit in the clinics. Thus, identification of novel druggable targets and anti-inflammatory strategies is needed. We speculated that the cation channel TMEM176B, a physiological inhibitor of the NLRP3 inflammasome, may protect the host against obesity and insulin resistance. Here we show that high fat diet (HFD) down-regulates TMEM176B expression in white adipose tissue (WAT). In WAT from HFD-fed Tmem176b^-/- mice, inflammasome activation was enhanced versus WT animals. HFD also led to increased weight gain and insulin resistance in Tmem176b^-/- mice. This metabolic phenotype was partially reversed by blocking IL-1β or deletion of Casp1. Having shown that TMEM176B is a potential target in obesity, we then wished to pharmacologically modulate this channel. We show that a salicylic acid nitroalkene (SANA), known to control diet-induced obesity, triggered TMEM176B-dependent ion transport. Accordingly, SANA inhibited inflammasome activation in vitro and in HFD-fed animals. Finally, genotypic studies show that TMEM176B single nucleotide polymorphisms are associated with obesity and type 2 diabetes in a cohort of 288 obese individuals. Thus, TMEM176B is a druggable target to control inflammasome activation in obesity and insulin resistance.