It has been suggested that interleukin-6 (IL-6) produced by adipocytes in obesity leads to liver insulin resistance, although this hypothesis has never been definitively tested. Accordingly, we did so by generating adipocyte specific IL-6 deficient (AdipoIL-6) mice and studying them in the context of diet-induced and genetic obesity.-/-Mice carrying 2 floxed alleles of IL-6 (C57Bl/6J) were crossed with Cre recombinase overexpressing mice driven by the adiponectin promoter to generate AdipoIL-6 mice. AdipoIL-6 and floxed littermate controls (FL) were fed a standard chow (CHOW) or high fat diet (HFD) for 16 weeks and comprehensively metabolically phenotyped. In addition to a diet-induced obesity (DIO) model, we also examined the role of adipocyte derived IL-6 in a genetic model of obesity and insulin resistance by crossing the AdipoIL-6 mice with leptin deficient () mice.-/-As expected, mice on a HFD and mice displayed marked weight gain and increased fat mass compared with chow fed and (littermate control) animals, respectively. However, deletion of IL-6 from adipocytes in either model had no effect on glucose tolerance or fasting hyperinsulinemia.ob/obAdipocyte specific IL-6 does not contribute to whole body glucose intolerance in obese mice.