Mitochondrial epigenetic changes and progression from metabolically healthy obesity to metabolically unhealthy obesity: a cross-sectional study

Abstract Background Obesity is heterogeneous, and more than 40% of metabolically healthy obese (MHO) individuals transition to a metabolically unhealthy obese (MUO) state within 8–10 years. However, the molecular determinants of these two states, and this transition, remain largely unknown. Mitochondria have a key role in metabolic homeostasis, and mitochondrial derangement might induce adipose dysfunction and adipocytokine dysregulation, leading to endocrine and metabolic disorders. In particular, epigenetic changes in mitochondria have been identified in obese individuals with diabetes. We aimed to test the hypotheses that the MHO and MUO states have different mitochondrial epigenetic signatures and that the transition from MHO to MUO is associated with mitochondrial epigenetic changes. Methods In this cross-sectional study, we recruited obese participants (BMI >30 kg/m 2 , aged 26–72 years) in Roanoke, VA, USA. Clinical data (eg, blood pressure) and blood samples were collected. Mitochondrial DNA methylation was assessed by methylation-specific PCR. Metabolic health status (MHO vs MUO) was assessed by several metabolic syndrome criteria: parameters distinguishing MUO from MHO include HDL less than 1·04 mmol/L for men and less than 1·30 mmol/L for women and no treatment; LDL above 2·60 mmol/L; blood pressure above 130/85 mm Hg and no treatment; triglycerides above 1·70 mmol/L; total cholesterol above 5·20 mmol/L; homeostatic model assessment for insulin resistance above 1·95 or 5·13, or 75th percentile; and fasting glucose at least 5·60 mmol/L or 6·10 mmol/L and no treatment. We used ANOVA to determine p values, with values less than 0·05 considered significant. Ethics approval was granted by Institutional Review Boards at Carilion Clinic and at Virginia Tech College, and all participants provided written informed consent. Findings Between April 15, 2014, and Jan 29, 2015, we recruited 73 participants (21 men and 52 women, mean BMI 36·5 kg/m 2 [SD 7·4], mean age 49·4 years [11·9]). Use of panels of different metabolic syndrome criteria led to a wide range of diagnoses. Specifically, 34–55 (47–75%) individuals had MHO and 18–39 (25–53%) had MUO. Stratification of health status by scoring features of metabolic syndrome showed a consistent increase in DNA methylation in the mitochondrial genes MT-CO1 and MT-ND6 , as well as in the mitochondrion-related nuclear gene PPARGC1A , in participants who had a high metabolic syndrome score. For instance, DNA methylation was upregulated by 2·22 times (p=0·0056) in MT-ND6 and by 2·18 times (p=0·0066) in PPARGC1A when the metabolic syndrome score increased from 0 to 4. Interpretation The disparity of diagnosis underscores the need to improve understanding of the molecular determinants of MHO and MUO. To our knowledge, this is the first study showing mitochondrial epigenetic differences between individuals with MHO versus MUO. Mitochondrial epigenetic signature could potentially be used to stratify the risk of metabolic syndrome for obese individuals. Funding US Department of Agriculture National Institute of Food and Agriculture Hatch Project 1007334 and US National Institutes of Health.