Earlier studies suggested that the stimulation of TLR4 seen in obesity/insulin resistance/T2DM results from gut-derived LPS (Lassenius et al. 2011, Jayashree et al. 2014, Velloso et al. 2015); however, it is now evident that FFAs derived from HF diets can also trigger TLR4 signaling in these target tissues (Reyna et al. 2008, Kim et al. 2012) leading to NAFLD and insulin resistance. The gene discussed is TLR4; the disease is metabolic dysfunction-associated steatotic liver disease.