Ana B Crujeiras1, Andrea G Izquierdo2, David Primo3, Fermin I Milagro4, Ignacio Sajoux5, Amalia Jácome6, Alfredo Fernandez-Quintela7, María P Portillo7, J Alfredo Martínez4, Miguel A Martinez-Olmos2, Daniel de Luis3, Felipe F Casanueva8. 1. Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), Spain; CIBER Fisiopatologia de La Obesidad y Nutricion (CIBERobn), Spain. Electronic address: anabelencrujeiras@hotmail.com. 2. Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), Spain; CIBER Fisiopatologia de La Obesidad y Nutricion (CIBERobn), Spain. 3. Center of Investigation of Endocrinology and Nutrition, Medicine School and Department of Endocrinology and Investigation, Hospital Clinico Universitario, University of Valladolid, Valladolid, Spain. 4. Department of Nutrition, Food Science and Physiology, Centre for Nutrition Research, University of Navarra (UNAV) and IdiSNA, Navarra Institute for Health Research, 31009, Pamplona, Spain; CIBER Fisiopatologia de La Obesidad y Nutricion (CIBERobn), Spain. 5. Medical Department Pronokal Group, PronokalGroup, Barcelona, Spain. 6. Department of Mathematics, MODES Group, CITIC, Universidade da Coruña, Faculty of Science, A Coruña, Spain. 7. Nutrition and Obesity Group, Department of Nutrition and Food Science, University of the Basque Country (UPV/EHU), Lucio Lascaray Research Institute and Health Research Institute BIOARABA, Vitoria, Spain; CIBER Fisiopatologia de La Obesidad y Nutricion (CIBERobn), Spain. 8. Molecular and Cellular Endocrinology Group. Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS) and Santiago de Compostela University (USC), Spain; CIBER Fisiopatologia de La Obesidad y Nutricion (CIBERobn), Spain.
Abstract
BACKGROUND: The molecular mechanisms underlying the potential health benefits of a ketogenic diet are unknown and could be mediated by epigenetic mechanisms. OBJECTIVE: To identify the changes in the obesity-related methylome that are mediated by the induced weight loss or are dependent on ketosis in subjects with obesity underwent a very-low calorie ketogenic diet (VLCKD). METHODS: Twenty-one patients with obesity (n = 12 women, 47.9 ± 1.02 yr, 33.0 ± 0.2 kg/m2) after 6 months on a VLCKD and 12 normal weight volunteers (n = 6 women, 50.3 ± 6.2 yrs, 22.7 ± 1.5 kg/m2) were studied. Data from the Infinium MethylationEPIC BeadChip methylomes of blood leukocytes were obtained at time points of ketotic phases (basal, maximum ketosis, and out of ketosis) during VLCKD (n = 10) and at baseline in volunteers (n = 12). Results were further validated by pyrosequencing in representative cohort of patients on a VLCKD (n = 18) and correlated with gene expression. RESULTS: After weight reduction by VLCKD, differences were found at 988 CpG sites (786 unique genes). The VLCKD altered methylation levels in patients with obesity had high resemblance with those from normal weight volunteers and was concomitant with a downregulation of DNA methyltransferases (DNMT)1, 3a and 3b. Most of the encoded genes were involved in metabolic processes, protein metabolism, and muscle, organ, and skeletal system development. Novel genes representing the top scoring associated events were identified, including ZNF331, FGFRL1 (VLCKD-induced weight loss) and CBFA2T3, C3orf38, JSRP1, and LRFN4 (VLCKD-induced ketosis). Interestingly, ZNF331 and FGFRL1 were validated in an independent cohort and inversely correlated with gene expression. CONCLUSIONS: The beneficial effects of VLCKD therapy on obesity involve a methylome more suggestive of normal weight that could be mainly mediated by the VLCKD-induced ketosis rather than weight loss.
BACKGROUND: The molecular mechanisms underlying the potential health benefits of a ketogenic diet are unknown and could be mediated by epigenetic mechanisms. OBJECTIVE: To identify the changes in the obesity-related methylome that are mediated by the induced weight loss or are dependent on ketosis in subjects with obesity underwent a very-low calorie ketogenic diet (VLCKD). METHODS: Twenty-one patients with obesity (n = 12 women, 47.9 ± 1.02 yr, 33.0 ± 0.2 kg/m2) after 6 months on a VLCKD and 12 normal weight volunteers (n = 6 women, 50.3 ± 6.2 yrs, 22.7 ± 1.5 kg/m2) were studied. Data from the Infinium MethylationEPIC BeadChip methylomes of blood leukocytes were obtained at time points of ketotic phases (basal, maximum ketosis, and out of ketosis) during VLCKD (n = 10) and at baseline in volunteers (n = 12). Results were further validated by pyrosequencing in representative cohort of patients on a VLCKD (n = 18) and correlated with gene expression. RESULTS: After weight reduction by VLCKD, differences were found at 988 CpG sites (786 unique genes). The VLCKD altered methylation levels in patients with obesity had high resemblance with those from normal weight volunteers and was concomitant with a downregulation of DNA methyltransferases (DNMT)1, 3a and 3b. Most of the encoded genes were involved in metabolic processes, protein metabolism, and muscle, organ, and skeletal system development. Novel genes representing the top scoring associated events were identified, including ZNF331, FGFRL1 (VLCKD-induced weight loss) and CBFA2T3, C3orf38, JSRP1, and LRFN4 (VLCKD-induced ketosis). Interestingly, ZNF331 and FGFRL1 were validated in an independent cohort and inversely correlated with gene expression. CONCLUSIONS: The beneficial effects of VLCKD therapy on obesity involve a methylome more suggestive of normal weight that could be mainly mediated by the VLCKD-induced ketosis rather than weight loss.
Authors: Andrea G Izquierdo; Hatim Boughanem; Angel Diaz-Lagares; Isabel Arranz-Salas; Manel Esteller; Francisco J Tinahones; Felipe F Casanueva; Manuel Macias-Gonzalez; Ana B Crujeiras Journal: Epigenetics Date: 2021-07-26 Impact factor: 4.861