Institute of Experimental and Clinical Research, Pharmacology and Therapeutics, Cliniques Universitaires St Luc and Université catholique de Louvain, Brussels, Belgium.
2IP-IREC Imaging Platform (RRID:SCR_023378), Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.
Physiol Genomics. 2024 Oct 1;56(10):649-660. doi: 10.1152/physiolgenomics.00044.2024. Epub 2024 Jul 15.
The prevalence of metabolic syndrome in cardiac diseases such as heart failure with preserved ejection fraction (HFpEF) prompts the scientific community to investigate its adverse effects on cardiac function and remodeling. However, the selection of a preclinical model of obesity-induced cardiac remodeling has proven more challenging with inconsistencies often found in very similar mouse models. Here, we investigated the implication of genetic background as well as diet composition to identify a suitable model of diet-induced cardiac alterations. C57Bl/6J and C57Bl/6N male mice were subjected to distinct obesogenic diets consisting of high-fat and moderate sucrose content (HF-S) or high-sucrose and moderate lipid content (F-HS) versus matching control diets. Five-month dietary intervention with obesogenic diets induced weight gain, adipocyte hypertrophy, and increased visceral and subcutaneous fat mass in both substrains. Obese mice showed similar impairment of glucose disposition and insulin tolerance, with both strains developing insulin resistance within 2 mo. However, echocardiographic follow-up and histological analysis confirmed that the HF-S diet increased cardiac hypertrophy, interstitial fibrosis, and left atrial area in the C57Bl/6J strain only. In contrast, the C57Bl/6N strain exhibited cardiac eccentric remodeling under control diets, possibly owing to a genetic mutation in the myosin light chain kinase 3 () gene, specific to this substrain, which was not further enhanced under obesogenic diets. Altogether, the present results highlight the importance of carefully selecting the suitable mouse strain and diets to model diet-induced cardiac remodeling. In this regard, C57Bl/6J mice develop significant cardiac remodeling in response to HF-S and seem to be a suitable model for cardiometabolic disease. Metabolic syndrome is highly prevalent in cardiac pathologies. Underlying mechanisms have not been thoroughly investigated, owing to the lack of reliable preclinical model of diet-induced cardiac remodeling. Our work demonstrates that genetic variants in inbred strains influence the response to metabolic stress and identifies C57Bl/6J mice as a suitable model for cardiometabolic disease in response to high-fat diet. These findings reinforce the need to carefully select the mouse strain in relation to the imposed pathophysiologic stress.
代谢综合征在心力衰竭伴射血分数保留（HFpEF）等心脏疾病中的患病率促使科学界研究其对心脏功能和重构的不良影响。然而，肥胖诱导的心脏重构的临床前模型的选择更加具有挑战性，因为非常相似的小鼠模型中经常存在不一致之处。在这里，我们研究了遗传背景和饮食成分的选择对确定合适的饮食诱导心脏改变模型的影响。C57Bl/6J 和 C57Bl/6N 雄性小鼠分别接受高脂肪和中等蔗糖含量（HF-S）或高蔗糖和中等脂肪含量（F-HS）的肥胖饮食与匹配的对照饮食的不同处理。肥胖饮食干预 5 个月导致两种亚系体重增加、脂肪细胞肥大以及内脏和皮下脂肪量增加。肥胖小鼠表现出类似的葡萄糖处置和胰岛素耐量受损，两种品系在 2 个月内均发展为胰岛素抵抗。然而，超声心动图随访和组织学分析证实，HF-S 饮食仅在 C57Bl/6J 品系中增加了心脏肥大、间质纤维化和左心房面积。相比之下，C57Bl/6N 品系在对照饮食下表现出心脏偏心性重构，这可能是由于该亚系特有的肌球蛋白轻链激酶 3（）基因突变，而这种突变在肥胖饮食下没有进一步增强。总之，本研究结果强调了仔细选择合适的小鼠品系和饮食来模拟饮食诱导的心脏重构的重要性。在这方面，C57Bl/6J 小鼠对 HF-S 反应显著，心脏重构明显，似乎是代谢性心脏疾病的合适模型。代谢综合征在心脏疾病中高度流行。由于缺乏可靠的饮食诱导心脏重构的临床前模型，因此其潜在机制尚未得到彻底研究。我们的工作表明，近交系中的遗传变异会影响对代谢应激的反应，并确定 C57Bl/6J 小鼠是高脂肪饮食诱导的代谢性心脏疾病的合适模型。这些发现强化了根据所施加的病理生理应激来仔细选择小鼠品系的必要性。
