Objective: The adverse effects of metabolic disorders in obesity have been extensively studied; however, the pathologic effects of hyperphosphatemia or phosphate toxicity in obesity have not been studied in similar depth and detail, chiefly because such an association is thought to be uncommon. Studies have established that the incidence of obesity-associated nephropathy is increasing. Because hyperphosphatemia is a major consequence of renal impairment, this study determines the in vivo effects of hyperphosphatemia in obesity. Methods and results: We genetically induced hyperphosphatemia in leptin-deficient obese (oblob) mice by generating oblob and klotho double knockout [ob/ob-klotho(-/-)] mice. As a control, we made oblob mice with hypophosphatemia by generating oblob and 1-alpha hydroxylase double knockout [ob/ob-1 alpha(OH)ase(-/-)] mice. Compared to the wild-type mice, all three obese background mice, namely oblob, ob/ob-klotho(-/-), and ob/ob-1 alpha(OH)ase(-/-) mice developed hypercholesterolemia. In addition, the hyperphosphatemic, ob/ob-klotho(-/-) genetic background induced generalized tissue atrophy and widespread soft-tissue and vascular calcifications, which led to a shorter lifespan; no such changes were observed in the hypophosphatemic, ob/ob-1 alpha(OH)ase(-/-) mice. Significantly, in contrast to the reduced survival of the ob/ob-klotho(-/-) mice, lowering serum phosphate levels in ob/ob-1 alpha(OH)ase(-/-) mice showed no such compromised survival, despite both mice being hypercholesterolemic. Conclusion: These genetic manipulation studies suggest phosphate toxicity is an important risk factor in obesity that can adversely affect survival. (C) 2011 Elsevier Inc. All rights reserved.