This study investigates the role of fatty acids, specifically palmitate, in inducing the activation of the NLRP3-PYCARD inflammasome, which leads to the production of inflammatory cytokines IL-1β and IL-18. The authors found that palmitate, but not oleate, activates the NLRP3-PYCARD inflammasome, leading to the release of these cytokines. This activation involves mitochondrial reactive oxygen species (ROS) and the AMP-activated protein kinase (AMPK) and ULK1 autophagy signaling cascade. Inflammasome activation in hematopoietic cells impairs insulin signaling in target tissues, reducing glucose tolerance and insulin sensitivity. IL-1β affects insulin sensitivity through both TNF-independent and TNF-dependent pathways. The study provides insights into the association between inflammation, diet, and type 2 diabetes (T2D). Key findings include the identification of a novel AMPK-ROS signaling axis that regulates NLRP3-PYCARD inflammasome activation and the role of IL-1β in promoting insulin resistance in response to a high-fat diet (HFD).This study investigates the role of fatty acids, specifically palmitate, in inducing the activation of the NLRP3-PYCARD inflammasome, which leads to the production of inflammatory cytokines IL-1β and IL-18. The authors found that palmitate, but not oleate, activates the NLRP3-PYCARD inflammasome, leading to the release of these cytokines. This activation involves mitochondrial reactive oxygen species (ROS) and the AMP-activated protein kinase (AMPK) and ULK1 autophagy signaling cascade. Inflammasome activation in hematopoietic cells impairs insulin signaling in target tissues, reducing glucose tolerance and insulin sensitivity. IL-1β affects insulin sensitivity through both TNF-independent and TNF-dependent pathways. The study provides insights into the association between inflammation, diet, and type 2 diabetes (T2D). Key findings include the identification of a novel AMPK-ROS signaling axis that regulates NLRP3-PYCARD inflammasome activation and the role of IL-1β in promoting insulin resistance in response to a high-fat diet (HFD).