Rajcsanyi Luisa S, Hoffmann Anne, Ghosh Adhideb, Matrisch-Dinkler Birgit, Zheng Yiran, Peters Triinu, Sun Wenfei, Dong Hua, Noé Falko, Wolfrum Christian, Herpertz-Dahlmann Beate, Seitz Jochen, de Zwaan Martina, Herzog Wolfgang, Ehrlich Stefan, Zipfel Stephan, Giel Katrin, Egberts Karin, Burghardt Roland, Föcker Manuel, Tsai Linus T, Müller Timo D, Blüher Matthias, Hebebrand Johannes, Hirtz Raphael, Hinney Anke
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany.
Front Genet. 2023 Apr 10;14:1128133. doi: 10.3389/fgene.2023.1128133. eCollection 2023.
Increased thermogenesis in brown adipose tissue might have an obesity-reducing effect in humans. In transgenic mice, depletion of genes involved in creatine metabolism results in disrupted thermogenic capacity and altered effects of high-fat feeding on body weight. Data analyses of a sex-stratified genome-wide association study (GWAS) for body mass index (BMI) within the genomic regions of genes of this pathway (, , and ) revealed one sex-dimorphic BMI-associated SNP in (rs1136165). The effect size was larger in females than in males. A mutation screen of the coding regions of these three candidate genes in a screening group (192 children and adolescents with severe obesity, 192 female patients with anorexia nervosa, and 192 healthy-lean controls) identified five variants in each, and , and nine variants in the coding sequence of . Non-synonymous variants identified in and were genotyped in an independent confirmation study group (781 families with severe obesity (trios), 320 children and adolescents with severe obesity, and 253 healthy-lean controls). tools predicted mainly benign yet protein-destabilizing potentials. A transmission disequilibrium test in trios with severe obesity indicated an obesity-protective effect of the infrequent allele at rs149544188 located in . Subsequent correlation analyses in 1,479 individuals of the Leipzig Obesity BioBank revealed distinct correlations of with the other two genes in omental visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT). Furthermore, between-subject comparisons of gene expression levels showed generally higher expressions of all three genes of interest in VAT than in SAT. Future analyses are needed to assess the functional implications of these findings.
棕色脂肪组织中增加的产热可能对人类具有减轻肥胖的作用。在转基因小鼠中，参与肌酸代谢的基因缺失会导致产热能力受损以及高脂喂养对体重的影响改变。对该途径（、和）基因的基因组区域内体重指数（BMI）进行性别分层的全基因组关联研究（GWAS）数据分析显示，在（rs1136165）中有一个与BMI相关的性别二态性单核苷酸多态性。女性的效应大小大于男性。在一个筛查组（192名重度肥胖儿童和青少年、192名神经性厌食症女性患者和192名健康瘦对照）中对这三个候选基因的编码区进行突变筛查，每个基因分别鉴定出五个变体，和，以及在的编码序列中有九个变体。在和中鉴定出的非同义变体在一个独立的验证研究组（781个重度肥胖家庭（三联体）、320名重度肥胖儿童和青少年以及253名健康瘦对照）中进行基因分型。工具预测主要为良性但具有蛋白质不稳定的潜力。对重度肥胖三联体进行的传递不平衡检验表明，位于rs149544188的罕见等位基因具有肥胖保护作用。随后在莱比锡肥胖生物银行的1479名个体中进行的相关性分析显示，在网膜内脏脂肪组织（VAT）和腹部皮下脂肪组织（SAT）中，与其他两个基因存在明显的相关性。此外，基因表达水平的受试者间比较显示，所有三个感兴趣的基因在VAT中的表达通常高于SAT。需要进一步的分析来评估这些发现的功能意义。
