Short-term Effects of Leptin in People With Lipodystrophy

Background Leptin is an adipocyte-derived hormone that can be thought of as a signal from adipose tissue to the rest of the body conveying information about long-term nutritional status. Patients with lipodystrophy have leptin deficiency secondary to lack of adipose tissue, and thus represent a natural model for studying the effects of leptin deficiency and replacement in humans. Leptin replacement in lipodystrophy ameliorates metabolic and endocrine abnormalities, including reducing food intake, improving insulin resistance and diabetes, reducing ectopic lipid, and normalizing reproduction. The reduction in energy intake induced by leptin replacement is likely responsible for part of the improvements observed in glucose and lipid metabolism. The clinical effects of leptin that are independent of changes in energy intake, and the mechanisms underlying these effects, have been poorly explored in humans. Aim The primary aim of this study is to determine the energy intake-independent effects of leptin on energy metabolism in lipodystrophic subjects. The major aspects of energy metabolism to be studied are: 1. Lipid metabolism, including fasting lipids, lipolysis and fatty acid turnover, and ectopic lipid storage. 2. Glucose metabolism, including fasting glucose, endogenous glucose production, and insulin sensitivity 3. Energy expenditure, including total and resting energy expenditure, skeletal muscle work efficiency, and spontaneous physical activity In addition, the effects of leptin on endocrine and autonomic function will be examined, including effects on the thyroid, gonadal, and adrenal axes, as well as blood pressure, body temperature, and heart rate variability. Methods This is a non-randomized, parallel group study. Two groups of patients aged 14 to 70 years with lipodystrophy will be studied: leptin naive and leptin treated. Minors will only be included in the leptin naive arm. All subjects will be stabilized on a weight maintenance diet for 5 days (Period 1). After this, leptin will be withdrawn from leptin treated subjects, and leptin will be initiated in leptin naive subjects for a period of 14 days (Period 2). The same isocaloric diet will be continued throughout both Periods, permitting study of leptin s effects independent of energy intake. All subjects will undergo metabolic testing on admission, at the end of Period 1, and throughout Period 2, to generate a detailed short-term time course of the effects of leptin initiation or withdrawal. At the end of Period 2, leptin will be continued in the leptin naive subjects, and restarted in the leptin treated subjects. Repeat metabolic testing will be performed 6-12 months after leptin initiation in the leptin-naive cohort to generate information on leptin s long-term effects.