DNA Methylation at PON3 May Lead to Weight Loss in Humans Following a Hypocaloric Diet.

Obesity has become a major pandemic in the United States and other countries and is a major burden to healthcare costs due to its co-morbidities including cardiovascular disease, type 2 diabetes, and cancer. More effective ways to treat and prevent obesity and its related co-morbidities is a dire need currently being addressed by biomedical and nutritional sciences research.

Weight gain and obesity are driven by a multitude of factors including diet, toxicant exposure, genetic background, and other lifestyle factors. An exciting new line of obesity research is exploring how these factors influence the expression of obesity-related genes by epigenetic mechanisms. In fact, epigenetic marks such as DNA methylation could potentially be used as personalized biomarkers to predict whether specific weight-loss interventions might be effective.

Researchers from the University of Navarra in Spain were interested in how differentially methylated regions (DMRs) of DNA correlate with weight loss after following a calorically restricted diet. The researchers assigned 305 obese or overweight study participants to either a moderately high-protein diet or low-fat diet and followed the study participants for 10 months with the weight loss intervention beginning after a 6-month maintenance period. Data between the two dietary groups were combined because the researchers did not find any difference in the amount of weight loss or responsiveness to either diet.

CpG islands are areas of DNA that are highly susceptible to
methylation. At baseline, 63 differentially methylated CpGs were identified in
peripheral white blood cells of responders vs non-responders of both dietary
interventions. Moreover, a DMR consisting of 13 CpGs was identified at the PON3

Paraoxonase 3 (PON3) is an antioxidant enzyme and although it is the least well studied of PON enzymes, it has a known biological role in preventing lipid oxidation. PON3 is thought to prevent atherosclerosis by inhibiting oxidation of low-density lipoproteins (LDL), which is thought to be one of the primary mechanisms driving atherosclerosis development. However, no difference in LDL oxidation between responders and non-responders was observed, nor was there any difference in PON activity in serum.

The researchers measured PON3 protein concentrations in
serum but did not find a difference between responders and non-responders. A
more significant finding was that PON3 DNA methylation was positively
correlated with the amount of body weight lost in study participants. PON3
DNA methylation was also negatively associated with the amount of PON3 protein
present indicating that methylation of PON3 likely inhibits gene expression—a
common mechanism of regulation by DNA methylation. The authors did acknowledge
a limitation of their study in that they could not directly measure PON3 gene
expression since they did not have access to liver or kidney tissue where PON3
is expressed and synthesized.

Although this study had some limitations including a lack of detail on how PON3 expression might be regulated by weight loss in the liver or whether PON3 activity is driving weight loss by a causal mechanism, it does warrant follow-up experiments to determine the exact role of PON3 in body fat accretion. Paraoxonase enzymes such as PON1, PON2, and PON3 are already being targeted to treat cardiovascular disease. Some dietary components including pomegranate polyphenols and lycopene from tomatoes have been shown to induce PON1 (2). It would be very cool to see studies showing whether other PON enzymes like PON3 are also responsive to dietary bioactive components.

In summary, the authors showed that the methylation status of a DMR at the PON3 gene was associated with study participants’ responsiveness to weight loss after a hypo-caloric diet. This suggests that PON3 might be a useful therapeutic target to reduce body weight and the researchers noted that this is already supported by rodent studies. DNA methylation patterns have already been used to predict biological aging and I think future research will continue to correlate DNA methylation patterns to other chronic diseases with the hopes of using this knowledge in precision medicine.


1.      Salas-Pérez F, et al. (2021). Differentially methylated regions (DMRs) in PON3 gene between responders and non-responders to a weight loss dietary intervention: a new tool for precision management of obesity. Epigenetics. 1–12.

2.      Khateeb J, et. al. (2010). Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway. Atherosclerosis. 208(1):119–125.

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