Figure 1. Study design.

The leptin initiation cohort was untreated for the first 5 days (period 1), and then metreleptin was given for the following 14 days (period 2). This order was reversed for the leptin withdrawal cohort. During the short-term study, an isocaloric diet was maintained in both cohorts to permit the study of the effects of metreleptin during constant energy and macronutrient intake. During both periods 1 and 2, the patients in both cohorts underwent a DXA scan, a hyperinsulinemic-euglycemic clamp, and an MRS-MRI scan. This was repeated at a 6-month follow-up visit only in patients in the initiation cohort, who were on an ad libitum diet.