Department of Medicine/Division of Cardiology and Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
Department of Medicine/Division of Cardiology and Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
Cell Metab. 2019 Apr 2;29(4):932-949.e4. doi: 10.1016/j.cmet.2018.12.013. Epub 2019 Jan 10.
We studied sex differences in over 50 cardio-metabolic traits in a panel of 100 diverse inbred strains of mice. The results clearly showed that the effects of sex on both clinical phenotypes and gene expression depend on the genetic background. In support of this, genetic loci associated with the traits frequently showed sex specificity. For example, Lyplal1, a gene implicated in human obesity, was shown to underlie a sex-specific locus for diet-induced obesity. Global gene expression analyses of tissues across the panel implicated adipose tissue "beiging" and mitochondrial functions in the sex differences. Isolated mitochondria showed gene-by-sex interactions in oxidative functions, such that some strains (C57BL/6J) showed similar function between sexes, whereas others (DBA/2J and A/J) showed increased function in females. Reduced adipose mitochondrial function in males as compared to females was associated with increased susceptibility to obesity and insulin resistance. Gonadectomy studies indicated that gonadal hormones acting in a tissue-specific manner were responsible in part for the sex differences.
我们在一个由 100 种不同近交系小鼠组成的小组中研究了 50 多种心脏代谢特征的性别差异。结果清楚地表明，性别对临床表型和基因表达的影响取决于遗传背景。支持这一观点的是，与这些特征相关的遗传位点通常表现出性别特异性。例如，Lyplal1 是一个与人类肥胖相关的基因，它是饮食诱导肥胖的性别特异性基因座的基础。对整个小组的组织进行的全基因组表达分析表明，脂肪组织的“褐变”和线粒体功能与性别差异有关。分离的线粒体在氧化功能方面表现出基因与性别之间的相互作用，例如某些品系（C57BL/6J）在两性之间表现出相似的功能，而其他品系（DBA/2J 和 A/J）则表现出雌性功能增强。与女性相比，男性脂肪组织中线粒体功能的减少与肥胖和胰岛素抵抗的易感性增加有关。去势研究表明，以组织特异性方式发挥作用的性腺激素部分导致了性别差异。
