ORF44-01 - Metreleptin Reduces Circulating Branched-Chain Amino Acids Independent of Dietary Intake in Lipodystrophy

Branched-chain amino acids (BCAA) are elevated in states of insulin resistance (IR), but whether this reflects dietary intake or altered metabolism remains unclear. Patients with lipodystrophy (LD) have severe IR due to deficient adipose tissue and leptin deficiency. Treatment with recombinant leptin (metreleptin) rapidly improves insulin sensitivity, providing a model to examine changes in BCAA under controlled dietary conditions. We hypothesized that improvements in IR with metreleptin would reduce circulating BCAA independent of dietary BCAA intake.
17 patients with LD (11 partial, 6 generalized) who had not previously received metreleptin were hospitalized on a metabolic ward for 19 days, during which caloric intake and macronutrient composition were held constant. Any uneaten food was weighed. During the first 5 days (Days -5 to -1), patients were not given metreleptin. Metreleptin 5 mg q12 hours was initiated on Day 0, and continued through the end of the hospital stay (Day 14). Serum BCAA (measured by NMR) and insulin sensitivity (measured by HOMA-IR) were assessed after 5 days on the controlled diet before metreleptin initiation (Day 0) and after 14 days of metreleptin on the controlled diet (Day 14). Dietary intake of total and individual BCAA was calculated and averaged over the 5 days prior to each serum BCAA measurement (Days -5 to -1, and Days 9-14). BCAA content for each food consumed was populated from nutrient databases including the Standard Reference (US Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center) and Nutrition Data Systems for Research version 2024 (University of Minnesota, Minneapolis, MN).
Insulin resistance improved after 14 days of metreleptin, although not significantly (HOMA-IR 19.50 ± 17.38 at Day 0, 17.01 ± 17.46 at Day 14, p=0.083). Improved insulin resistance was accompanied by a reduction in total serum BCAA (620 ± 134 vs 577 ± 84 µmol/L, p = 0.04) and isoleucine (p=0.0024). Mean dietary intake of total BCAA did not differ between before vs after metreleptin (19.02 ± 3.0 at Day 0, 20.68 ± 8.1 at Day 14, p=0.39), nor were there significant differences in consumption of individual BCAA. Dietary BCAA intake was not associated with serum BCAA for either total or individual BCAAs (all p>0.7). HOMA-IR correlated with total serum BCAA (r=0.58, p=0.019) and serum isoleucine (r=0.72, p=0.0024), but not with dietary BCAA intake. After adjusting for dietary BCAA intake, both total serum BCAA (p=0.0052) and serum leucine (p=0.0232) decreased after metreleptin.
These findings suggest that short-term reductions in circulating BCAA with metreleptin occur independently of dietary BCAA intake and are linked to improvements in insulin resistance. The data support insulin resistance as a causal determinant of elevated circulating BCAA, consistent with altered BCAA metabolism rather than intake.