Leptin and TNF-alpha promoter methylation levels measured by MSP could predict the response to a low-calorie diet

Abstract

Obesity-associated adipose tissue enlargement is characterized by an enhanced proinflammatory status and an elevated secretion of adipokines such as leptin and cytokines such as TNF-alpha. Among the different mechanisms that could underlie the interindividual differences in obesity, epigenetic regulation of gene expression has emerged as a potentially important determinant. Therefore, twenty-seven obese women (age: 32-50 years; baseline Body Mass Index, BMI: 34.4±4.2 Kg/m 2 ) were prescribed an eightweek Low-Calorie-Diet and epigenetic marks were assessed. Baseline and endpoint anthropometric parameters were measured and blood samples were drawn. Genomic DNA and RNA from adipose tissue biopsies were isolated before and after the dietary intervention. Leptin and TNF-alpha promoter methylation were measured by MSP after bisulfite treatment and gene expression was also analyzed.Obese women with a successful weight loss (≥5% of initial body weight, n=21) improved the lipid profile and fat mass percentage (-12%, p<0.05). Both systolic (-5%, p<0.05) and diastolic (-8%, p<0.01) blood pressures significantly decreased. At baseline women with better response to the dietary intervention showed lower promoter methylation levels of leptin (-47%, p<0.05) and TNF-alpha (-39%, p=0.071) than the non-responder group (n=6), while no differences were found between responder and non-responder group in leptin and TNF-alpha gene expression analysis. These data suggest that leptin and TNF-alpha methylation levels could be used as epigenetic biomarkers concerning the response to a Low-CalorieDiet. Indeed, methylation profile could help to predict the susceptibility to weight loss as well as some comorbidities such as hypertension or type 2 diabetes.

Human leptin tissue distribution, but not weight loss-dependent change in expression, is associated with methylation of its promoter

“…In a recent paper Cordero and coworkers 51 described difference at baseline in methylation patterns in responders and non responders to a low calorie diet, but did not investigate the changes over time.…”

Epigenetics in Adipose Tissue, Obesity, Weight Loss, and Diabetes

“…Therefore, it was hypothesized that TNF promoter methylation could be a good biomarker predicting the diet-induced weight loss, which constituted a first step toward personalized nutrition based on epigenetic criteria. In a subsequent study, Cordero et al (48) described that both TNF and LEP methylation levels in the adipose tissue could also be used as epigenetic biomarkers to predict the response to a low-calorie diet. Thus, at baseline, women with a better response to the dietary intervention ($5% of initial body weight) had lower promoter methylation levels in both genes than those in the nonresponder group.…”

“…Also, high-fat or -sugar intake and situations of excessive body weight in rodents are associated with changes in DNA methylation patterns, affecting the promoter region of different genes involved in energy homeostasis and obesity such as LEP (46), NADH dehydrogenase (ubiquinone) 1 b subcomplex subunit 6 (NDUFB6), and FASN (36). On the other hand, epigenetic biomarkers are being identified in humans to predict weight loss and body weight maintenance after weight loss, including LEP and TNF (47,48), aquaporin 9 (AQP9) (49), ATPase class V type 10A (ATP10A), Wilms tumor 1 (WT1), and CD44 molecule (CD44) (50).…”

Epigenetics in Twin Studies

“…As mentioned above, some of these biomarkers have been validated across many studies [34,35,36] and are destined for clinical trials. Outside cancer, notable examples that are yet to be fully validated include predictors of child adiposity [52], progression to overt cardiovascular disease in adults [53] and response to weight loss programs [54,55]. Finally, to capitalize on the reversibility of epigenetic marks, epigenetic therapies have been advocated and a number, based on manipulation of DNA methylation and histone modification, are undergoing clinical trials for cancer [56,57,58].…”