Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge
Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge
复制标题
DOI：
10.1186/s13293-019-0233-y
复制
发表时间：
2019-04-15
影响因子：
7.9
通讯作者：
Floyd, Z. Elizabeth
中科院分区：
文献类型：
--
作者：
Ghosh, Sujoy;Taylor, Jessica L.;Floyd, Z. Elizabeth
背景：育龄男性与肥胖相关的代谢综合征风险高于女性，这可能是由于雌激素介导的脂肪组织炎症和脂肪细胞肥大纤维化减少所致。泛素连接酶 Siah2 的消耗减少了肥胖雄性小鼠的白色脂肪组织炎症并改善了葡萄糖代谢。 Siah2 是雌激素的转录靶标，但缺乏有关 Siah2 对女性脂肪组织影响的数据。因此，我们评估了 Siah2 缺陷对育龄雌性白色和棕色脂肪组织的影响。 方法：在喂食低脂或高脂饮食的野生型和 Siah2KO 雌性和雄性小鼠中评估身体成分、脂肪组织形态、棕色脂肪组织基因、蛋白质表达和脂肪细胞大小。在野生型和 Siah2KO 雌性小鼠中评估了葡萄糖和胰岛素耐受性、空腹血糖、胰岛素、脂肪酸和甘油三酯以及性腺周围脂肪中炎症标志物的基因表达。对两种性别的棕色脂肪基因表达进行微阵列分析。通过不配对双尾 t 检验和重复测量方差分析来评估统计分析。结果：在高脂肪喂养的雌性小鼠中，在白色脂肪细胞肥大的情况下，Siah2 缺陷可改善葡萄糖和胰岛素耐受性，其脂肪百分比与雄性小鼠相当。虽然之前的研究表明 Siah2KO 可以降低雄性小鼠的白色脂肪组织炎症反应，但雌性小鼠的反应偏向于白色脂肪组织中 M2 样标记物的上调。相比之下，Siah2 的缺失会导致男性棕色脂肪变白增加，但女性则不会。这对应于女性炎症标记物（F4/80、Ccl2）、产热基因（Pgc1α、Dio2、Ucp-1）和蛋白质（PGC-1α、UCP-1）表达的增加。与预期相反，雌性生热标志物表达增加，同时 ERα 和 ERRgamma 蛋白水平下调。结论：Siah2 缺陷最显着的性别相关影响是高脂肪喂养雌性中棕色脂肪变白减少。在雌性小鼠中，防止棕色脂肪中单房脂肪细胞积聚与产热基因和蛋白质的表达增加相对应，但在雄性小鼠中则不然。这些结果提出了 Siah2 有助于雌激素相关的对男性和女性棕色脂肪功能的影响的可能性。
Background: The obesity-related risk of developing metabolic syndrome is higher in males than in females of reproductive age, likely due to estrogen-mediated reduced adipose tissue inflammation and fibrosis with hypertrophied adipocytes. Depletion of the ubiquitin ligase Siah2 reduced white adipose tissue inflammation and improved glucose metabolism in obese male mice. Siah2 is a transcriptional target of estrogen, but data is lacking about the effect of Siah2 on adipose tissue of females. We therefore evaluated the impact of Siah2 deficiency on white and brown adipose tissue in females of reproductive age.Methods: Body composition, adipose tissue morphology, brown adipose tissue gene, and protein expression and adipocyte sizing were evaluated in wild-type and Siah2KO female and male mice fed a low-fat or high-fat diet. Glucose and insulin tolerance, fasting glucose, insulin, fatty acids and triglycerides, and gene expression of inflammation markers in perigonadal fat were evaluated in wild-type and Siah2KO female mice. Microarray analysis of brown fat gene expression was carried out in both sexes. Statistical analysis was assessed by unpaired two-tailed t test and repeated measures ANOVA.Results: Siah2 deficiency improves glucose and insulin tolerance in the presence of hypertrophied white adipocytes in high-fat-fed female mice with percent fat comparable to male mice. While previous studies showed Siah2KO reduces the white adipose tissue inflammatory response in male mice, the response in females is biased toward the upregulation of M2-like markers in white adipose tissue. In contrast, loss of Siah2 leads to increased whitening of brown fat in males, but not in females. This corresponded to increased expression of markers of inflammation (F4/80, Ccl2) and thermogenic genes (Pgc1alpha, Dio2, Ucp-1) and proteins (PGC-1 alpha, UCP-1) in females. Contrary to expectations, increased expression of thermogenic markers in females was coupled with a downregulation of ERalpha and ERRgamma protein levels.Conclusions: The most striking sex-related effect of Siah2 deficiency is reduced whitening of brown fat in high-fat-fed females. Protection from accumulating unilocular adipocytes in the brown fat corresponds to increased expression of thermogenic genes and proteins in female, but not in male mice. These results raise the possibility that Siah2 contributes to the estrogen-related effects on brown fat function in males and females.