Aims/hypothesis: Adiponectin is upregulated during adipogenesis and downregulated in insulin-resistant states. The mechanism(s) governing the re-arrangements from adipogenesis to facilitated lipolysis during pregnancy are unknown. Our purpose was to analyse the role of adiponectin relative to the metabolic changes in human pregnancy. Subjects, materials and methods: Lean women (BMI <25 kg/m²) were evaluated longitudinally before conception, and in early (12-14 weeks) and late (34-36 weeks) pregnancy. Insulin sensitivity was measured using the glucose clamp technique. Venous blood and subcutaneous adipose tissue biopsies were obtained at each time point. Results: Adiponectin concentrations were lower in the third trimester than in the pregravid condition (9.9±1.4 vs 13.5±1.8 μg/ml). The hypoadiponectinaemia was reflected by a 2.5-fold decrease in white adipose tissue adiponectin mRNA. These changes were associated with a 25% increase in fat mass (23.7±2.9 vs 18.9±2.9 kg). Insulin infusion decreased high molecular weight adiponectin complexes in pregravid women (9.9±0.6 vs 6.2±0.06) and the suppressive effect of insulin was lost during pregnancy. The pregnancy-mediated changes in adiponectin were strongly correlated with basal insulin levels and insulin sensitivity (p<0.0001). The relationship between adiponectin and insulin sensitivity was related to the decreased insulin regulation of glucose utilisation (r=0.55, p<0.001) but not of endogenous hepatic glucose production. Conclusions/interpretation: These data demonstrate that pregnancy is associated with adiponectin changes in lean women. Hypoadiponectinaemia is reflected by a lower amount of high molecular weight adiponectin and by the ratio of high to low molecular weight multimers. The adiponectin changes relate to decreased insulin sensitivity of glucose disposal rather than alterations of lipid metabolism.