A matter of food and substrain: obesogenic diets induce differential severity of cardiac remodeling in C57Bl/6J and C57Bl/6N substrains

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 (