- Adipose tissue inflammation and dysfunction are considered central in the pathogenesis of obesity-related dys-metabolism, but their role in the rapid metabolic recovery upon obesity reversal is less well-defined. We hypothesized that changes in adipose tissue endocrine and paracrine mechanisms may support the rapid improvement of obesity-induced impairment in cellular lipid handling. C57Bl-6J mice were fed ad-libitum either normal chow (NC) or high-fat diet (HFF) for 10 weeks. A dietary obesity reversal group was fed HFF for 8 weeks, then switched to NC for 2 weeks (HFF?NC). Whole-body glucose homeostasis rapidly nearly-normalized in the HFF?NC mice (fasting glucose and insulin fully-normalized, glucose and insulin tolerance tests reversed 82% to the NC group levels). During 2 weeks of dietary reversal, the liver was significantly cleared from ectopic fat, and functionally- glucose production from pyruvate, alanine or fructose was normalized. In contrast, adipose tissue inflammation (macrophage infiltration and polarization) largely remained as in HFF, though obesity-induced adipose tissue macrophage lipid accumulation decreased by ~50%, and adipose tissue MAP-kinase hyper-activation was reversed. Ex-vivo, mild changes in adipose tissue adipocytokine secretion profile were noted. These corresponded to partial or full reversal of the excess cellular lipid droplet accumulation induced by HFF adipose tissue conditioned-media in hepatoma or macrophage cells, respectively. We propose that rapid metabolic normalization early following nutritional obesity reversal largely precedes resolution of adipose tissue inflammation. Nevertheless, we demonstrate a hitherto unrecognized contribution of adipose tissue to the rapid improvement in lipid handling by the liver and by macrophages.