Summary – Project 1 Defining the factors/pathways that regulate intra- and inter-organ communications in cardiometabolic disease is a pursuit of each Project of this PPG. In collaboration with P2 and P3, P1 will comprehensively investigate molecular mechanisms by which caloric restriction and the common clinical finding of subsequent weight regain (as in “yo-yo” dieting) resolves and exacerbates, respectively, metabolic inflammation in plaques, eWAT, and liver. The goal is to identify maladaptive pathways in obesity and IR and strategies to interrupt them, in order to promote inflammation resolution and tissue homeostasis in atherosclerosis, obesity and NAFLD/NASH. P1 will include studies of clinical samples and integrate ‘omic data with human data sets to estimate the clinical relevance of the outlined models to human cardiometabolic disease, as well as to suggest molecular mechanisms underlying the human data. Given that the phosphorylated form of LXRα occupies the promoters of multiple genes under study in P1-P3, and our report that the inability to phosphorylate LXRα globally attenuated NASH, we are also motivated to determine the cell types and the transcriptional regulation responsible for this notable benefit in the liver. Thus, there are 2 Aims in P1: Aim 1: To determine the mechanisms by which caloric restriction (CR) resolves atherosclerotic plaque and eWAT inflammation, and how these benefits are lost upon weight regain. Aim 2: To determine the effects of CR and LXRα phosphorylation on NASH. Like the other Projects, through the employment of state-of-the-art approaches and shared complementary examinations in human tissues and human transcriptome databases, P1 will contribute to this Program Project’s goal to discover new mechanistic insights that lead to therapeutic approaches to quench the exaggerated macrophage accumulation, inflammation and intra/inter-organ communications that amplify cardiovascular risk.