BEGHINI Marianna

Previous University and Subject: University of Pisa, Human Medicine

Thesis since: 02/2020

The Effects of Metreleptin Therapy on Lipid Metabolism in Patients with Lipodystrophy – a Clinical Study in a Rare Disease

Lipodystrophy syndromes are heterogeneous rare diseases characterized by a variable degree of adipose tissue deficiency. In lipodystrophic patients with pronounced loss of adipose tissue, leptin serum levels are low promoting hyperphagia. Excessive calories cannot be stored in the adipose tissue depots and are stored as ectopic fat in liver and muscle. This leads to severe metabolic complications that are a major cause of morbidity and mortality in lipodystrophic patients. In selected patients with lipodystrophy, treatment with recombinant leptin potently ameliorates hepatic steatosis and insulin resistance1 via mechanisms that have not been fully clarified.
With the here proposed study we aim to elucidate two possible effects of leptin treatment on metabolic alterations that characterize patients with lipodystrophy:
• Aim 1: Test the hypothesis that leptin stimulates liver triglycerides export and thereby protects from fatty liver disease:
Prof. Scherer´s group has demonstrated in a series of rodent experiments that leptin potently counteracts hepatic steatosis by increasing VLDL export and reducing de novo lipogenesis in vivo2. We plan to extent these rodent experiments to humans with lipodystrophy, assessing for the first time the effects of recombinant leptin therapy on hepatic TG secretion, hepatic lipid content, de novo lipogenesis, lipid oxidation and lipid composition.
• Aim 2: Test the hypothesis that leptin acutely stimulates IGFBP2 production:
Studies in rodents have identified Insulin-like Growth Factor Binding Protein 2 (IGFBP2) as a possible mediator of the leptin effect on glucose metabolism3. We plan to evaluate changes in circulating IGFBP2 levels in patients with lipodystrophy after acute leptin administration.
Besides enlightening important novel actions of leptin in human metabolism, the results of the proposed study potentially have a significant impact not only for lipodystrophic patients, but also for other more common diseases, such as obesity and type 2 diabetes, that show clear overlapping in their metabolic phenotypes and pathogenesis.

Methods and Skills

Molecular biological techniques (PCR, Western blot); clinical studies; density gradient ultracentrifugation

Publications

Beghini M, Resch FJ, Moslinger D, et al. Project "Backtoclinic I": An overview on the state of care of adult PKU patients in Austria. Mol Genet Metab 133: 257-260, 2021

Beghini M, Brandt S, Korber I, et al. Serum IGF1 and linear growth in children with congenital leptin deficiency before and after leptin substitution. Int J Obes (Lond) 45: 1448-1456, 2021

Matrone A, Ceccarini G, Beghini M, et al. Potential impact of BMI on the aggressiveness of presentation and clinical outcome of differentiated thyroid cancer. J Clin Endocrinol Metab 105 dgz312, 2020