Globular adiponectin (gAd) is a promising candidate for protein replacement therapy of metabolic syndrome. Recombinant native human gAd is a poorly behaved molecule with low solubility in physiological solutions and relatively poor expression. Therefore, evaluation of gAd as a potential biotherapeutic requires a molecule with improved biochemical properties relative to native. At Xencor we have used our proprietary protein design methods to create gAd variants with improved expression and solubility. Our lead compound XENP3962 has ~100-fold increased expression and > 100-fold increased solubility relative to native gAd. XENP3962 is biologically active in multiple cell based assays; for example, XENP3962 treatment of cultured myotubes promoted AMPK and ACC phosphorylation, AMP Kinase activation, fatty acid oxidation, and glucose uptake. Studies using primary human adipocytes demonstrated a dose-dependent effect of XENP3962 on lipolytic activity and glucose uptake. Additional experiments showed that XENP3962 induces AMPK phosphorylation in mouse macrophage-like cells as well as in both bovine and human aortic endothelial cells. Pilot pharmacological studies in mice showed that XENP3962 was (1) effective at controlling hyperglycemia and (2) demonstrated activity in cardiovascular tissues. In conclusion, we have created gAd variants with significantly improved protein expression and solubility, and our lead compound is biologically active in multiple in vitro and in vivo pharmacology models. With success in engineering and producing large quantities of bioactive gAd, it is now possible to conduct the first rigorous pharmacological assessment of gAd as a potential therapy for metabolic disorders.