ABSTRACT Obesity coincides with pro-inflammatory phenotypes in adipose tissues and the insulin resistance that precedes type 2 diabetes. Despite a wealth of evidence, causal relationships between obesity-induced inflammation and insulin resistance remain unknown. In the last grant cycle, we explored how inflammation uncouples obesity from insulin resistance. We showed blocking interferon gamma (IFN) activation of the transcription factor STAT1 limits pro-inflammatory programs that would otherwise restrict white adipose tissue (WAT) expansion and decrease insulin sensitivity. We also demonstrated complete elimination of IFN activity mediates many adverse effects of high fat diet, including weight gain, diminished mitochondrial function, and insulin resistance. Multiple studies, including our own, observed higher STAT1 expression in WAT of diabetic mice and humans, suggesting that IFN activity may still represent a pathogenic consequence of chronic obesity. The goal of the current cycle is to fill vital remaining gaps in our mechanistic understanding of the fundamental ways IFN transmits signals to transcriptional regulation of metabolism and insulin sensitivity in fat cells. To achieve our goal, we will demonstrate that the IFN receptor in WAT initiates the metabolic decrement of overnutrition (Aim 1) and establish the downstream transcriptional outcomes of IFN that repress cellular energy balance in the fat cell (Aim 2). Lastly, we will determine whether obesity-associated inflammation restricts a novel pathway that supports lipogenic responses necessary to sustain WAT expansion (Aim 3). Ultimately, such knowledge will teach us how to leverage the immune system to treat obesity and its co-morbidities.