Severe adipose tissue deficiency (lipoatrophy) causes insulin-resistant diabetes, elevated serum triglyceride and fatty acid levels, and massive triglyceride deposition in the liver. In lipoatrophic A-ZIP/F-1 mice, transplantation of normal adipose tissue greatly improved these parameters, whereas 1 week of leptin infusion had more modest effects. In contrast, leptin infusion was strikingly more effective in the aP2-n sterol response element binding protein 1 lipoatrophic mouse. Here we show that a longer duration of leptin infusion further improves the metabolic status of the A-ZIP/F-1 mice and that genetic background does not make a major contribution to the effect of leptin on glucose and insulin levels. Adipose transplantation using leptin-deficient ob/ob fat had no effect on the phenotype of the A-ZIP/F-1 mice. Moreover, the presence of ob/ob adipose tissue did not enhance the effects of leptin infusion. Serum adiponectin levels were 2% of control levels in the A-ZIP/F-1 mouse and increased only twofold with adipose transplantation and not at all after leptin infusion, suggesting that adiponectin deficiency is not a major contributor to the diabetic phenotype. Taken together, these results suggest that sequestration of triglycerides into fat may not be enough to restore a nondiabetic phenotype and that leptin deficiency plays a major role in causing the metabolic complications of lipoatrophy.