Mustelin L, Pietiläinen KH, Rissanen A, Sovijärvi AR, Piirilä P, Naukkarinen J, Peltonen L, Kaprio J, Yki-Järvinen H. Acquired obesity and poor physical fitness impair expression of genes of mitochondrial oxidative phosphorylation in monozygotic twins discordant for obesity. Am J Physiol Endocrinol Metab 295: E148 -E154, 2008. First published May 6, 2008; doi:10.1152/ajpendo.00580.2007.-Defects in expression of genes of oxidative phosphorylation in mitochondria have been suggested to be a key pathophysiological feature in familial insulin resistance. We examined whether such defects can arise from lifestyle-related factors alone. Fourteen obesity-discordant (BMI difference 5.2 Ϯ 1.8 kg/m 2 ) and 10 concordant (1.0 Ϯ 0.7 kg/m 2 ) monozygotic (MZ) twin pairs aged 24 -27 yr were identified among 658 MZ pairs in the population-based FinnTwin16 study. Whole body insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp technique. Transcript profiles of mitochondrial genes were compared using microarray data of fat biopsies from discordant twins. Body composition of twins was determined using DEXA and maximal oxygen uptake (V O2max) and working capacity (Wmax) using a bicycle ergometer exercise test with gas exchange analysis. The obese cotwins had lower insulin sensitivity than their nonobese counterparts (M value 6.1 Ϯ 2.0 vs. 9.2 Ϯ 3.2 mg ⅐ kg LBM Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.01). Transcript levels of genes involved in the oxidative phosphorylation pathway (GO:0006119) in adipose tissue were lower (P Ͻ 0.05) in the obese compared with the nonobese cotwins. The obese cotwins were also less fit, as measured by V O2max (50.6 Ϯ 6.5 vs. 54.2 Ϯ 6.4 ml ⅐ kg LBM Ϫ1 ⅐ min Ϫ1 , for obese vs. nonobese, P Ͻ 0.05), Wmax (3.9 Ϯ 0.5 vs. 4.4 Ϯ 0.7 W/kg LBM, P Ͻ 0.01) and also less active, by the Baecke leisure time physical activity index (2.8 Ϯ 0.5 vs. 3.3 Ϯ 0.6, P Ͻ 0.01). This implies that acquired poor physical fitness is associated with defective expression of the oxidative pathway components in adipose tissue mitochondria. body composition; cardiorespiratory fitness; spiroergometry; gene expression OBESITY IS ASSOCIATED WITH poor physical fitness (15) and insulin resistance (31, 32). Recent studies have suggested that genetic factors account for a substantial fraction (estimates of 50 -90%) of the population variance in BMI (39, 65), insulin action (23-52%) (16,27,35,46,60) and physical activity (32-79%) (24,41,70). These results raise the possibility that shared genetic influences underlie the association between obesity, insulin resistance, and fitness. Recently, it has been suggested that mitochondrial dysfunction might be a key factor in development of insulin resistance (37). Several studies have reported type 2 diabetic patients and "prediabetic" insulinresistant subjects to have impaired structure and function of mitochondria (28,48,53,54,66) and decreased expression of genes encoding key enzymes in oxidative metabolism and mitochondrial function (47, 52). Petersen et al. (54) reported reduced mitochondrial ...