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Profilin-1 (pfn) is a small ubiquitous protein that can bind to: (1) G-actin, (2) phosphatidylinositol 4,5-bisphosphate, and (3) a heterogeneous group of proteins harboring poly-l-proline stretches. Through these interactions, pfn integrates signaling from a diverse array of extracellular cues with actin cytoskeleton dynamics. Cumulating evidence indicates that changes in pfn levels are associated and may play a pathogenic role in such inflammatory diseases as atherosclerosis and glomerulonephritis. We recently demonstrated that high fat diet (HFD) increases pfn expression in the white adipose tissue (WAT), but not in the liver or the muscle. Pfn heterozygote mice (PfnHet) were protected against HFD-induced glucose intolerance, and WAT and systemic inflammation, when compared to pfn wild-type mice. In addition to blunted accumulation of macrophages and reduced "pro-inflammatory" cytokines, the WAT of PfnHet exhibited preserved frequency of regulatory T cells. These findings suggest that pfn levels in WAT-both adipocytes and hematopoietic-derived cells-can modulate immune homeostasis within the WAT and glucose tolerance systemically. Here, we review the interaction of pfn with his diverse array of binding partners and discuss mechanisms that may underlie the effects of pfn dosage on insulin sensitivity and metabolic inflammation.