1. Epigenetic landscape in blood leukocytes following ketosis and weight loss induced by a very low calorie ketogenic diet (VLCKD) in patients with obesity
- Author
-
Alfredo Fernández-Quintela, Andrea G. Izquierdo, David Primo, María P. Portillo, Fermín I. Milagro, A. Jácome, J. Alfredo Martínez, Ana B. Crujeiras, D.A. de Luis, Felipe F. Casanueva, M.A. Martinez-Olmos, and Ignacio Sajoux
- Subjects
Male ,0301 basic medicine ,epigenome-wide association ,Methyltransferase ,Calorie ,dna methylation microarray ,medicine.medical_treatment ,Protein metabolism ,nutritional intervention ,Critical Care and Intensive Care Medicine ,adipose-tissue ,responders ,Epigenesis, Genetic ,chemistry.chemical_compound ,Basal (phylogenetics) ,0302 clinical medicine ,Weight loss ,Leukocytes ,Adiposity ,validation ,adiposity ,Nutritional intervention ,Nutrition and Dietetics ,exercise ,Middle Aged ,Circulating blood cells ,cpg sites ,Obesity, Morbid ,Female ,medicine.symptom ,Diet, Ketogenic ,performance ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Methylation ,03 medical and health sciences ,Internal medicine ,Weight Loss ,medicine ,Humans ,030109 nutrition & dietetics ,business.industry ,biomarkers ,Ketosis ,medicine.disease ,Obesity ,Endocrinology ,chemistry ,ketone-bodies ,responses ,circulating blood cells ,methylation ,business ,Biomarkers ,Ketogenic diet - 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 ¼ 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 ¼ 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 ¼ 10) and at baseline in volunteers (n ¼ 12). Results were further validated by pyrosequencing in representative cohort of patients on a VLCKD (n ¼ 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. This work was supported by the PronoKal Group® and grants from the Fondo de Investigacion Sanitaria as well as PI17/01287, PI20/00628 and PI20/00650 research projects and CIBERobn from the Instituto de Salud Carlos III (ISCIII)-Subdireccion General de Evaluacion y Fomento de la Investigación; Fondo Europeo de Desarrollo Regional (FEDER) Ana B Crujeiras is funded by a research contract “Miguel Servet” (CP17/00088) from the ISCIII, co-financed by the European Regional Development Fund (FEDER) and Xunta de Galicia-GAIN (IN607B2020). The funding source had no involvement in the study design or interpretation of the results
- Published
- 2021