Supplementary Material for: Genetic Variants in the Activation of the Brown-Like Adipocyte Pathway and the Risk for Severe Obesity

<b><i>Background:</i></b> Regular physical activity has an important role in energy expenditure and combats the development of obesity. During exercise, <i>PPARGC1A</i> is overexpressed, stimulating an increase of the expression of <i>FNDC5</i>. This protein is cleaved to release the hormone irisin, which activates a browning process in white adipose tissue through an increase in <i>UCP1</i> expression. As a result, irisin leads to mitochondrial heat production and energy expenditure. <b><i>Objectives:</i></b><i></i>The aim of this study was to investigate whether genetic variants in genes related to browning are associated with severe obesity and obesity-related features. This case-control study comprised 210 individuals with severe obesity (median body mass index [BMI] 45.6 [range 40.5–52.2]) and 191 normal-weight subjects (BMI 22.8 [21.1–23.9]). <b><i>Methods:</i></b> Genomic DNA was extracted from peripheral blood and the genotypes of the <i>PPARGC1A</i>(rs8192678, rs3736265, rs2970847, and rs3755863) and <i>UCP1</i> (rs6536991 and rs12502572) genes were obtained using Taqman® assay. For the <i>FNDC5</i> gene, screening of exons 3–5 as well as their intron-exon boundaries was performed using automatic sequencing. <b><i>Results:</i></b> Our results demonstrated that <i>PPARGC1A</i>rs2970847 and <i>UCP1</i>rs12502572 are associated with severe obesity. Furthermore, these polymorphisms influence anthropometric traits, such as BMI, body weight, and body adiposity index. Our findings also showed a dose-effect relationship between <i>PPARGC1A</i> rs8192678 and fasting plasma glucose. Finally, 5 rare mutations were identified in <i>FNDC5</i>, and 1 of these is a novel missense mutation. <b><i>Conclusion:</i></b> This study shows that genetic variants in the activation of brown-like adipocyte pathway play an important role in the susceptibility to severe obesity.