Leptin Decreases Energy Expenditure but Increases Thyroid Hormone in Patients With Lipodystrophy

Leptin is an adipokine that signals energy sufficiency. In rodents, leptin deficiency is associated with decreased body temperature and energy expenditure (EE), which is reversed with leptin replacement. Leptin’s role in EE in humans is unclear; however, one study of 10% weight-reduced healthy subjects suggested that leptin replacement to pre-weight loss levels restored the decline in EE, thyroid hormone, and catecholamines associated with weight loss. Patients with lipodystrophy (LD) are characterized by deficiency of adipose tissue and can serve as models to study effects of leptin deficiency and replacement in humans. We hypothesized that treatment with recombinant leptin (metreleptin) in patients with LD would increase EE, thyroid hormone, and catecholamines. We conducted a non-randomized crossover study of 25 patients with LD who were hospitalized for 19 days on an iso-caloric diet. The initiation cohort consisted of 17 patients with no prior exposure to metreleptin, who were first studied for 5 days without metreleptin (period 1), then were treated with metreleptin for 14 days (period 2). The withdrawal cohort consisted of 8 previously metreleptin-treated patients who were continued on metreleptin for the first 5 days of the study (period 1), then were taken off metreleptin for 14 days (period 2). At the end of each period, we measured 24-hour EE (TEE) and resting EE (REE) using indirect calorimetry and free T3, T4, epinephrine, norepinephrine and dopamine after an 8–12 hour fast. In the leptin initiation cohort, TEE and REE decreased from 2402±383 kcal/day and 1805±332 kcal/day to 2272±396 kcal/day (p=0.003) and 1688±318 kcal/day (p=0.03), respectively. Free T3 increased from median (IQR) 248 (200, 270) pg/mL to 295 (259, 315) (p=0.006). No changes in catecholamines were observed in the initiation cohort. In the withdrawal cohort, free T3 decreased from 295 (267, 331) pg/mL to 265 (237, 323) (p=0.008), free T4 decreased from 1.2 ±0.2 ng/dL to 1.0±0.2 (p=0.002), and norepinephrine decreased from 191±70 pg/mL to 112±47 (p=0.03) after metreleptin withdrawal. No changes in EE, epinephrine or dopamine were observed in the withdrawal cohort. Contrary to previous studies in rodents and healthy humans, we found that introduction of metreleptin reduced EE in patients with LD. Consistent with rodent and prior human data, patients with LD had increased thyroid hormone on metreleptin, which would be expected to increase EE. The discrepancy in EE compared to other models may be due to metreleptin-induced correction of severe metabolic derangements in LD, including reduction in energy-requiring processes such as de novo lipogenesis and gluconeogenesis. These changes may offset increases in leptin-induced mediators of increased EE, such as thyroid hormone.