Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome

Jelte Wieting; Kirsten Jahn; Vanessa Buchholz; Ralf Lichtinghagen; Stephanie Deest-Gaubatz; Stefan Bleich; Christian K Eberlein; Maximilian Deest; Helge Frieling

doi:10.1016/j.psyneuen.2022.105857

Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome

Psychoneuroendocrinology. 2022 Sep:143:105857. doi: 10.1016/j.psyneuen.2022.105857. Epub 2022 Jul 3.

Authors

Jelte Wieting¹, Kirsten Jahn², Vanessa Buchholz², Ralf Lichtinghagen³, Stephanie Deest-Gaubatz², Stefan Bleich², Christian K Eberlein², Maximilian Deest², Helge Frieling²

Affiliations

¹ Hannover Medical School, Department for Psychiatry, Social Psychiatry and Psychotherapy, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: wieting.jelte@mh-hannover.de.
² Hannover Medical School, Department for Psychiatry, Social Psychiatry and Psychotherapy, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
³ Hannover Medical School, Department for Clinical Chemistry, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

PMID: 35803048
DOI: 10.1016/j.psyneuen.2022.105857

Abstract

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11-13. PWS individuals typically show insatiable appetite with subsequent obesity representing the major mortality factor unless food intake is inhibited. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, a region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level. The present study investigates serum leptin levels (S-leptin) and DNA methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS. S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter DNA methylation was assessed by bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated significantly with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS. The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to sex-, age- and BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror those seen in non-syndromic obesity.

Keywords: Hyperphagia; LEP; LEPR; Leptin; Methylation; Prader-Willi syndrome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Child, Preschool
DNA Methylation / genetics
Humans
Hyperphagia / genetics
Leptin / genetics
Obesity / genetics
Prader-Willi Syndrome* / drug therapy
Prader-Willi Syndrome* / genetics

Substances

Leptin