PSUN100 What Determines Leptin Levels: Moving Beyond Fat Mass

BACKGROUND: Leptin is an adipocyte hormone conveying the message of energy availability to the brain. While leptin deficiency is associated with neuroendocrine and metabolic aberrations, general variability over time, and with respect to distinctive metabolic changes are not well understood even in patients with lipodystrophy. We encountered a female patient with normal fat distribution and without a diagnosis of lipodystrophy (LD) who presented to our clinic with severe hypertriglyceridemia (2934 mg/dL) and completely undetectable leptin levels. Upon treatment with fibrates and normalization of her triglyceride levels to 120 mg/dl, her circulating leptin rose to 16 ng/ml. This observation prompted us to investigate the variability of leptin measurements over time as well as the relationship between triglyceride and leptin levels. METHODS: We evaluated the available clinical leptin measurements accessible in our medical records from August 2013 to May 2021. Age, gender, BMI, and triglyceride level data were collected from medical records. We verified if the measurements were obtained in patients with a diagnosis of LD or not (non-LD) and whether the patients with LD are being treated or have been treated with exogenous leptin therapy (Metreleptin). We then examined the percent of variability on repeated leptin levels in the LD versus non-LD groups as well as the relationship of the leptin levels to triglyceride levels. RESULTS: There were 374 leptin levels measured clinically for 156 unique patients (81 LD; 115 F; Age 48.4±14.4; 151 with diabetes). In the non-LD cohort, there was only one patient whose levels were repeated 3 times (the index case described above). In contrast, leptin levels were repeated on average 6.5 times in the LD cohort. We saw 570.6±1654.7% variability in the LD group. The variability was substantially higher in patients being treated with Metreleptin as expected (929.5±1629.8%). The variability in the patients with LD who have never received Metreleptin (n=12) over a mean follow-up of 3.3±1.9 years was 43.1±38.5%. As expected, there was a positive relationship between BMI and leptinemia in the non-LD group (n=27, R= 0.7, p < 0.001). In the LD group, this relationship was not significant (n=39; R= -0.2, p > 0.5). Interestingly, in both cohorts separately and combined (R= -0.3, p <0 .001), there was a negative exponential relationship between circulating triglycerides and leptinemia. CONCLUSIONS: Leptin levels showed 43.1±38.5% variability in an LD cohort when not treated with exogenous leptin therapy. As some new clinical trials and treatment algorithms are basing eligibility on circulating leptin levels in lipodystrophy, quantification of the variability in the same individual over time is essential. More importantly, hypertriglyceridemia and leptin levels appear related in both LD and non-LD cohorts with a curve that suggests a mechanistic relationship. Further work is required to understand this relationship. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.