SUN-LB019 Myeloid Krüppel-like Factor 2 is a Critical Regulator of Metabolic Inflammation

Substantial evidence implicates crosstalk between metabolic tissues and the immune system, both centrally and peripherally, in the inception and progression of obesity. Nodal factors that orchestrate systemic “metaflammation” remain very incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. Macrophages with KLF2 deletion enrich transcriptional networks associated with metabolic syndrome. In mice and humans, consumption of a fatty diet is associated with downregulation of KLF2 in myeloid cells. Mice with myeloid specific deletion of KLF2 (K2KO) exhibited basal metabolic disturbances including increased feeding contributing to rapid weight gain. Stimulating K2KO mice with metaflammatory stress (high fat diet) caused genotype-dependent increases in insulin resistance and non-alcoholic steatohepatitis. Mechanistically, loss of myeloid KLF2 increased metaflammation in peripheral (white adipose, liver) and central (hypothalamus) metabolic tissues, demonstrating the widespread regulation that KLF2 poses on metabolic homeostasis. This regulation occurs, in part, through KLF2’s attenuation of inflammasome activation, a major pathogenic mechanism of metabolic disease. Critically, overexpression of KLF2 in the myeloid compartment protected mice from long-term HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a decisive regulator of central and peripheral metabolic inflammation in homeostasis and disease. Funding: This work was funded by the American Heart Association and National Institutes of Health from the NHLBI and NIGMS. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.