Adiponectin and its receptors play an important role in energy homeostasis and insulin resistance, but their regulation remains to be fully elucidated. We hypothesized that high fat diet would decrease adiponectin but increase adiponectin receptors (AdipoR1 and AdipoR2) expression in diet-induced obesity (DIO)-prone C57Bl/6J and DIO-resistant A/J mice. We found that circulating adiponectin and adiponectin expression in WAT are higher at baseline in C57Bl/6J mice, compared to A/J mice. Circulating Adiponectin increases at 10 weeks but decreases at 18 weeks in response to advancing age and high fat feeding. However, adiponectin levels corrected for visceral fat mass and adiponectin mRNA expression in WAT are affected by high fat feeding only; both being decreased after 10 weeks in C57Bl/6J mice. Muscle AdipoR1 expression in both C57Bl/6J and A/J mice and liver adipoR1 expression in C57Bl/6J mice increases at 18 weeks of age. High fat feeding increases both AdipoR1 and AdipoR2 expression in liver in both strains of mice and increases muscle AdipoR1 expression in C57Bl/6J mice after 18 weeks. Thus, advanced age and high fat feeding, both of which are factors that predispose humans to obesity and insulin resistance, are associated with decreasing adiponectin and increasing AdipoR1 and/or AdipoR2 levels.