MON-673 Decreased BCAA Levels in Lipodystrophy Patients Treated With Metreleptin

Abstract Disclosure: M.M. Dyer: None. R.J. Brown: None. M. Lightbourne: None. Branched chain amino acids (BCAA) are elevated in insulin resistance (IR). Mechanisms underlying this association are not clear - some evidence suggests IR causes high BCAA while other data suggest BCAA may cause IR. Conceptually, high BCAA may be caused by increased synthesis or decreased catabolism. Patients with lipodystrophy (LD) lack functional adipose tissue, leading to low leptin and severe IR. Leptin treatment with recombinant leptin (metreleptin) in LD decreases IR. We hypothesized that, due to severe IR, BCAA would be elevated in patients with LD, and would decrease after metreleptin treatment. 17 patients with LD (11 partial, 6 generalized) received metreleptin for 6 months. For five days prior to and during the first 2 weeks of metreleptin, food intake was held constant on a metabolic ward. BCAA (by NMR, umol/L) and insulin sensitivity (as glucose disposal [M] during hyperinsulinemic euglycemic clamp, mg/kgFFM/min) were measured at days -5 relative to metreleptin initiation on ad libitum diet, day 0 immediately prior to metreleptin after 5 days of controlled diet, day 14 after metreleptin on controlled diet, and month 6 of metreleptin on ad libitum diet. During the controlled diet period (Day 0 to Day 14), IR decreased (4.4±2.3 vs 5.9±2.2, p = 0.001). Total BCAA likewise decreased (620±134 vs 577±84, p = 0.04), while changes in individual BCAA did not reach statistical significance. Between day -5 and month 6, when patients consumed ad libitum diet, IR decreased (4.4±2.3 vs 5.9±2.2, p = 0.01). Total BCAA (594±170 vs 478±130, p = 0.007), isoleucine (104±68 vs 68±49, p = 0.01), and leucine (224±58 vs 170±44, p = 0.006) decreased while valine did not change (p = 0.2). BCAA fell after 14 days and 6 months of treatment with metreleptin in patients with LD. The reduction in BCAA was larger after 6 months, which may reflect reductions in dietary BCAA consumption in the context of appetite-suppressing effects of metreleptin. However, the reduction in BCAA after 14 days during controlled diet suggests that improved IR with metreleptin may lead to decreased BCAA even when diet is held constant. This latter finding supports IR as causal for elevations in BCAA. Mechanistically, these data are consistent with increased BCAA catabolism due to a leptin-induced increase in mammalian target of rapamycin complex 1 (mTORC1), an important complex in the catabolism of BCAA. Presentation: Monday, July 14, 2025