FRI056 Effect of 48 Hour of Metreleptin in Humans with Lipodystrophy During Controlled Feeding

Disclosure: K.M. Bukhari: None. B. Abel: None. R.J. Brown: None. Introduction: The lipodystrophy (LD) syndromes are a rare group of disorders characterized by a generalized or partial loss of adipose tissue resulting in a deficiency of the adipocyte-secreted hormone leptin. Leptin replacement therapy with recombinant human leptin (metreleptin) has favorable effects on the metabolic profile of patients with LD and has been shown to have significant effects on metabolic pathways such as fatty acid oxidation and protein degradation following several months of treatment. However, many of these changes may relate to negative energy balance. Whether these changes can be seen within a few days of initiating metreleptin under energy balance conditions is unknown. Objectives: To explore acute (48 hour) and sub-acute (12 days) metabolomic effects of metreleptin under energy balance conditions in human subjects with leptin deficiency due to LD. Methods: The study included 17 patients with LD (5 generalized LD, 12 partial LD) who were studied on a metabolic ward with food intake held constant to maintain energy balance for 2 weeks. Metreleptin 5 mg q12 hr was administered, and fasting blood samples were collected at baseline (T0), after 2 days of treatment (T2), and after 12 days (T12). Untargeted metabolomic (848 compounds) and lipidomic (984 compounds) analysis was completed with the goal of assessing for any physiologically relevant changes during a period of controlled food intake and prior to any clinically relevant changes in dyslipidemia and diabetes. Statistical analyses between time points were done by paired t-tests. To account for false positives, a false discovery rate (q-value) was calculated for each compound, and only those with P≤0.05 are reported. Results: There was a very consistent reduction in the plasma levels of nearly all lipids detected (except monoacylglycerols) at T2 and T12 compared to T0. This includes plasma levels of phospholipids, ceramides, sphingomyelins, cholesterol esters, diacylglycerols (DAG) and triacylglycerols (TAG). There are significantly lower levels at T12 compared to T2 as well, indicating a continued decrease over time. A number of free fatty acids were significantly lower in the T2 metreleptin treated group compared to T0, with a smaller number that were also lower at T12. These included the medium chain, long chain saturated (palmitate [16:0]), long chain mono- and polyunsaturated (nisinate [24:6n3]). In conjunction with this, the levels of acylcarnitines are lower as well. Other significant changes included evidence of increased aerobic glycolysis with increased demand for pyruvate into the TCA cycle, as well as possible increased branched-chain amino acid catabolism with increased input into the TCA cycle. Conclusion: The effects of metreleptin on metabolism in LD appear to be rapid (48 hours), increase further after 12 days, and are independent from longer term changes in food intake, diabetes, and dyslipidemia. Presentation: Friday, June 16, 2023