Mitochondrial DNA Variants in Obesity

Abstract

Heritability estimates for body mass index (BMI) variation are high. For mothers and their offspring higher BMI correlations have been described than for fathers. Variation(s) in the exclusively maternally inherited mitochondrial DNA (mtDNA) might contribute to this parental effect. Thirty-two to 40 mtDNA single nucleotide polymorphisms (SNPs) were available from genome-wide association study SNP arrays (Affymetrix 6.0). For discovery, we analyzed association in a case-control (CC) sample of 1,158 extremely obese children and adolescents and 435 lean adult controls. For independent confirmation, 7,014 population-based adults were analyzed as CC sample of n = 1,697 obese cases (BMI≥30 kg/m2) and n = 2,373 normal weight and lean controls (BMI<25 kg/m2). SNPs were analyzed as single SNPs and haplogroups determined by HaploGrep. Fisher's two-sided exact test was used for association testing. Moreover, the D-loop was re-sequenced (Sanger) in 192 extremely obese children and adolescents and 192 lean adult controls. Association testing of detected variants was performed using Fisher's two-sided exact test. For discovery, nominal association with obesity was found for the frequent allele G of m.8994G/A (rs28358887, p = 0.002) located in ATP6. Haplogroup W was nominally overrepresented in the controls (p = 0.039). These findings could not be confirmed independently. For two of the 252 identified D-loop variants nominal association was detected (m.16292C/T, p = 0.007, m.16189T/C, p = 0.048). Only eight controls carried the m.16292T allele, five of whom belonged to haplogroup W that was initially enriched among these controls. m.16189T/C might create an uninterrupted poly-C tract located near a regulatory element involved in replication of mtDNA. Though follow-up of some D-loop variants still is conceivable, our hypothesis of a contribution of variation in the exclusively maternally inherited mtDNA to the observed larger correlations for BMI between mothers and their offspring could not be substantiated by the findings of the present study.

Mitochondrial Haplogroup T Is Associated with Obesity in Austrian Juveniles and Adults

“…mtDNA T4216C) and were formerly described as sister haplogroups with a common root [ 30 ]. Our results contradict those of Knoll et al [ 8 ], who found no association of mtDNA haplogroups and obesity. However, it should be noted that the cases and control subjects of the Knoll study were either of French or German ancestry [ 31 ]; therefore, differences of geographic origin might account for the different results of the two studies.…”

“…Knoll et al reported a higher frequency of the polymorphism T16189C among extremely obese cases (17% vs. 9%) [ 8 ]. This variant would give rise to an uninterrupted poly-C tract from np 16184 to 16193 and possibly lead to heteroplasmic length variation of different mtDNA molecules within the same person [ 37 ].…”

The Drosophila ETV5 Homologue Ets96B: Molecular Link between Obesity and Bipolar Disorder

“…Lower expression levels of these two genes correlates with insulin resistance [ 60 ]. Furthermore, an association with obesity was found for a frequent allele of the human ATP6 gene [ 61 , 62 ]. Similar to mt : Col and mt : Cyt-b , the Drosophila homolog of ATP6 , mt : ATPase6 , is also upregulated when Ets96B is knocked down in the CNS.…”

OXPHOS xenobiotics alter adipogenic differentiation at concentrations found in human blood

“…Here, we have shown that the mitochondrial OXPHOS system is important for regulation of adipogenesis in hASCs and that its inhibition at the level of mtDNA replication (NRTIs), organelle protein synthesis (antibiotics) or function (TBTC) can either inhibit or promote adipogenesis in vitro . Because important OXPHOS components are mtDNA-encoded and OXPHOS capacity is affected by mtDNA haplogroup ( Gomez-Duran et al, 2010 , 2012 ), genetic variability in mtDNA could affect adipocyte differentiation and related phenotypes such as obesity ( Knoll et al, 2014 ; Nardelli et al, 2013 ; Yang et al, 2011 ).…”