Epigenetic Mechanisms of Human Hypothalamic Body Weight Regulation

• Applicant: Professor Dr. Peter Kühnen
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2014 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 263507924

Obesity is one of the major health care problems worldwide in industrial as well as in in low and middle-income countries (LMICS) being responsible for approximately 2 millions death per year. Although twin studies point towards a genetic background up to 70%, monogenic forms of obesity are rare and results of large genome-wide association studies including genome-wide analysis explain less than 25 % of intra-individual body weight variability. One potential explanation for this observation, which has been termed “missing heritability” might be related to epigenetic modifications. We have focused our attention on the DNA methylation of the pro-opiomelanocortin (POMC) gene, which plays a pivotal role in the leptin-melanocortin signaling cascade, one of the main pathways regulating satiety and energy expenditure within the hypothalamus. The results of the first funding period have underlined the role for a POMC DNA hypermethylation as an individual risk factor for the development of obesity. There are evidences that the analyzed POMC region fulfills the criteria for a metastable epiallele, being set during early embryonic development and being influenced by a paternal influence and changes in C1 metabolite status of the mother during conception. Due to POMC methylation differences between rodent and human samples, no appropriate animal model is available at the moment and for this reason our conclusions are based on several reproducible observation in different cohorts. To gain further insights into the mechanism we have started to establish during the first funding period a naïve-pluripotent stem cell based model, in which we will now be able to analyze the functional consequences of POMC hypermethylation in-vitro (work package 1). Additionally we want to broaden our view and analyze a few million CpG sites in laser-microdissected human, postmortem MSH and NPY neurons separately of obese and non-obese individuals, using a post-bisulfite adapter tagging (PBAT) technique (work-package 2). Thereby we will be able to identify intra-and inter-individual differentially methylated regions, which might play a role in epigenetic body weight regulation. Both work packages are designed to achieve the major goal of this grant application and to gain further insights how differences within the individual epigenetic signature are affecting body weight regulation and modifying the individual risk to become obese during lifetime.

• DFG Programme: Research Grants