Bridge-Comer Pania E, Plows Jasmine F, Ramzan Farha, Patel Rachna, Ganapathy Thashma P, Stanley Joanna L, Vickers Mark H, Reynolds Clare M
Developmental Programming Research Group, The Liggins Institute, The University of Auckland, Auckland, New Zealand.
Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, United States.
Front Physiol. 2020 Jun 23;11:601. doi: 10.3389/fphys.2020.00601. eCollection 2020.
The global incidence of obesity continues to rise, increasing the prevalence of metabolic diseases such as insulin resistance, dyslipidemia, and type 2 diabetes mellitus. Low-grade chronic inflammation, associated with the obese state, also contributes to the development of these metabolic comorbidities. Interleukin-1-receptor-1 (IL-1R1), a pro-inflammatory mediator, bridges the metabolic and inflammatory systems. In young male mice, deficiency of IL-1R1 (IL-1R1) paired with a high-fat diet (HFD) offered beneficial metabolic effects, however in female mice, the same pairing led to metabolic dysfunction. Therefore, we examined the contribution of maternal HFD in combination with IL1R1 to metabolic health in adult offspring. Female C57BL/6 and IL-1R1 mice were randomly assigned to a control diet (10% kcal from fat) or HFD (45% kcal from fat) 10 days prior to mating and throughout gestation and lactation. Male and female offspring were housed in same-sex pairs post-weaning and maintained on control diets until 16 weeks old. At 15 weeks, an oral glucose tolerance test (OGTT) was performed to assess glucose tolerance. Histological analysis was carried out to assess adipocyte size and gene expression of adipogenic and inflammatory markers were examined. IL-1R1 contributed to increased body weight in male and female adult offspring, irrespective of maternal diet. IL-1R1 and maternal HFD increased adipocyte size in the gonadal fat depot of female, but not male offspring. In female offspring, there was reduced expression of genes involved in adipogenesis and lipid metabolism in response to IL1R1 and maternal HFD. While there was an increase in inflammatory gene expression in response to maternal HFD, this appeared to be reversed in IL1R1 female offspring. In male offspring, there was no significant impact on adipogenic or lipid metabolism pathways. There was an increase in inflammatory gene expression in IL1R1 male offspring from HFD-fed mothers. This study suggests that IL-1R1 plays a complex and important role in the metabolic health of offspring, impacting adipogenesis, lipogenesis, and inflammation in a sex-specific manner.
全球肥胖发病率持续上升，导致胰岛素抵抗、血脂异常和2型糖尿病等代谢性疾病的患病率增加。与肥胖状态相关的低度慢性炎症也促使这些代谢性合并症的发展。白细胞介素-1受体-1（IL-1R1）作为一种促炎介质，连接着代谢系统和炎症系统。在年轻雄性小鼠中，IL-1R1缺陷（IL-1R1 -/-）与高脂饮食（HFD）相结合产生了有益的代谢效应，然而在雌性小鼠中，相同的组合却导致了代谢功能障碍。因此，我们研究了母体高脂饮食与IL-1R1共同作用对成年后代代谢健康的影响。雌性C57BL/6和IL-1R1 -/-小鼠在交配前10天以及整个妊娠和哺乳期被随机分配至对照饮食（脂肪提供10%的千卡热量）或高脂饮食（脂肪提供45%的千卡热量）。雄性和雌性后代在断奶后以同性配对饲养，并维持对照饮食直至16周龄。在15周时，进行口服葡萄糖耐量试验（OGTT）以评估葡萄糖耐量。进行组织学分析以评估脂肪细胞大小，并检测脂肪生成和炎症标志物的基因表达。无论母体饮食如何，IL-1R1均导致成年雄性和雌性后代体重增加。IL-1R1和母体高脂饮食增加了雌性而非雄性后代性腺脂肪库中的脂肪细胞大小。在雌性后代中，响应于IL-1R1和母体高脂饮食，参与脂肪生成和脂质代谢的基因表达降低。虽然响应于母体高脂饮食炎症基因表达增加，但在IL-1R1雌性后代中这种情况似乎得到了逆转。在雄性后代中，对脂肪生成或脂质代谢途径没有显著影响。来自高脂饮食喂养母亲的IL-1R1雄性后代的炎症基因表达增加。这项研究表明，IL-1R1在后代的代谢健康中发挥着复杂而重要的作用，以性别特异性方式影响脂肪生成、脂质生成和炎症。
