Reduced leukocyte mitochondrial copy number in metabolic syndrome and metabolically healthy obesity

Abstract

Objective: This study aimed to investigate the associations between peripheral blood leukocyte mitochondrial copy number, metabolic syndrome, and adiposity-related body composition phenotypes in a high prevalence population.

Methods: A single center cross-sectional study was conducted, consisting of 521 middle-aged subjects of Maltese-Caucasian ethnicity. Participants were stratified according to the presence of metabolic syndrome and different metabolic health definitions based on NCEP-ATP III criteria. Relative leukocyte mitochondrial DNA copy number was determined by quantitative polymerase chain reaction and corrected for leukocyte and platelet count. The associations between mitochondrial copy number and metabolic syndrome components was evaluated and adjusted for age and gender.

Results: Significant negative correlations between mtDNA copy number and BMI, waist circumference, triglyceride levels, fasting plasma glucose, HbA1c, HOMA-IR and hsCRP were observed, along with a positive correlation with HDL-C levels. Mitochondrial copy number was lower in individuals with metabolic syndrome. When compared to metabolically healthy normal weight subjects, a reduction in mtDNA copy number was observed in both the metabolically healthy and unhealthy obese categories.

Conclusion: Our data supports the association between reduced leukocyte mtDNA copy number, obesity, and metabolic syndrome. This investigation expands on the spectrum of associations between mtDNA copy number and metabolic phenotypes in different populations and underpins the role of mitochondrial dysfunction in the development and progression of metabolic syndrome and its components.

Keywords: insulin resistance; metabolic health; metabolic syndrome; mitochondrial DNA copy number; obesity.

Figure 1

(A) Correlation matrix between relative mtDNA copy number and key metabolic parameters – BMI, WC, WHR, TC, LDL-C, HDL-C, TG, FPG, HbA1c, HOMA-IR and hsCRP. Color scale depicts Spearman’s rank-order correlation coefficient. ** Correlation is significant at the 0.01 level (2-tailed). * Correlation is significant at the 0.05 level (2-tailed). (B–E) Violin plots depicting mtDNA CN differences between body composition phenotypes and across different definitions of metabolic health and the metabolic syndrome. A significantly lower mtDNA copy number was observed in individuals with metabolic syndrome (Mann-Whitney U test, p < 0.05). A significantly lower copy number was present in both the MHOW/O and MUHOW/O categories, compared to MHNW participants (Kruskal-Wallis test, p <0.001), across different metabolic health definitions. The violin plots reflect data distribution. The centerline in the box plot illustrates the medians; box limits indicate the 25th and 75th percentiles; whiskers extend 1.5 times the interquartile range from the 25th and 75th percentiles. ** significant difference at p < 0.01. NS, not significant; MHNW, Metabolically healthy normal weight; MUHNW, Metabolically unhealthy normal weight; MHOW/O, Metabolically healthy overweight/obese; MUHOW/O, Metabolically unhealthy overweight/obese; CN, Copy Number; NCEP-ATPIII, National Cholesterol Education Program – Adult Treatment Panel III; FPG, Fasting plasma glucose; TC, Total Cholesterol; BMI, Body mass index; BP, Blood pressure; LDL-C, Low density lipoprotein -cholesterol; HDL-C, High density lipoprotein -cholesterol; TG, Triglycerides; UA, Uric acid; WHR, Waist: Hip Ratio.

Figure 2

(A) Scree plot showing eigenvalue against all factors. Three factors have eigenvalues >1, and collectively explain 62.5% of the cumulative variance in the dataset. (B) PCA biplot shows individual observations as datapoints, colored according to presence or absence of metabolic syndrome. Points are plotted on a plane formed by the first two principal components. The original variables are shown as green vectors from the origin. The orientation of the vector with respect to the principal component space represents its contribution to the PC.