ESPE Abstracts (2018) 89 FC6.4

Identification of the First Obesity-Associated Mutations in Human Mesoderm-Specific Transcript (MEST) Result in Protein Overexpression, Adipocyte Hypertrophy and a Reduction in Adipocyte Mitochondrial Area

Juan Suáreza,b,c, Gabriel Martos-Morenod,e,f,g, Patricia Riverad, Clara Serra-Juhéh,i,j, Julie Chowend,e,f,k, Luis Pérez-Juradoh,i,j,l & Jesús Argented,e,f,g,k

aInstituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain; bUGC Salud Mental, Universidad de Málaga, Málaga, Spain; cHospital Universitario Regional de Málaga, Málaga, Spain; dDepartment of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; eLa Princesa Research Institute, Madrid, Spain; fInstituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Fisiopatologia de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain; gDepartment of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain; hGenetics Unit, Universitat Pompeu Fabra, Barcelona, Spain; iHospital del Mar Research Institute (IMIM), Barcelona, Spain; jInstituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain; kIMDEA Food Institute, Madrid, Spain; lSA Clinical Genetics, Women’s and Children’s Hospital & University of Adelaide, Adelaide, Australia.

Background: Mesoderm-specific transcript (MEST) is an epoxide α/β-hydrolase protein with catalytic activity that is determinant for the development of adipocytes. The MEST gene is an imprinted gene transcribed only from the paternal allele. Although the mechanism by which MEST overexpression augments fat accumulation and storage in adipocytes has not been fully elucidated, frequent subcellular contacts between MEST-positive endoplasmic reticulum, mitochondria and lipid droplets have been shown. This suggests that mitochondrial affectation might be involved. To date, no pathogenic human mutations have been reported in MEST.

Objective: The present study aimed to characterize potential variants in the MEST gene in children with early-onset severe obesity.

Results: We report a total of 14 family members from seven unrelated families presenting with hyperphagia, insulin resistance and body mass index (BMI) greater than 3.5 SDS for age and sex. These patients were shown to present MEST variants as a result of mCpG disruptions in chr7:130131207, chr7:130132310, chr7:130132836 or chr7:130132925 sites. Biopsies of subcutaneous fat were obtained for histology, immunohistochemistry and ultrastructural analysis by transmission electron microscopy (TEM). MEST mutations, without any other obesity-related single-nucleotide polymorphism (SNP) or copy number variations (CNV), were associated with increased immunoreactivity for MEST in adipocytes and hypertrophy of adipocytes. Interestingly, ultrastructural observations of adipocytes by TEM indicated a reduction in the mitochondrial area in patients with MEST mutations and with no other SNP/CNV.

Conclusions: These observations provide important insights into the regulation of adiposity by MEST in humans, and suggest a possible implication of mitochondrial activity in this process. Moreover, affectation of this gene appears to be involved in the development of human obesity.