Epigenetic Landscape in Blood Leukocytes Following Ketosis and Weight Loss Induced by a Very Low Calorie Ketogenic Diet (VLCKD) in Patients with Obesity
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Date
2021-05-21Author
Crujeiras, Ana B.
Izquierdo, Andrea G.
Primo, David
Milagro Yoldi, Fermín I.
Sajoux, Ignacio
Jácome, Amalia
Martínez, José Alfredo
Martínez Olmos, Miguel A.
De Luis Román, Daniel Antonio
Casanueva, Felipe F.
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Clinical Nutrition 40(6) : 3959-3972 (2021)
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.