Abstract Body: Intro: In mice and men, middle age significantly increases the risk of weight gain. In humans, obesity can act as a sole driver of heart failure with preserved ejection fraction (HFpEF). Middle-aged humans, typically aged 50 to 65, can be compared to 14- to 18-month-old mice. We hypothesize that natural obesity in middle-aged mice leads to altered glucose homeostasis and HFpEF.
Methods: Male (M) and female (F) C57BL/6J mice were bred in-house, fed a standard diet (4% kcal fat), and aged to 14-16 months (n=30 M, and n=24 F). Based on the "Mouse Phenome Database", M body weights (BW) over >40-45g, and F BW over >30-35g were considered obese. To assess the effects of natural obesity, glucose tolerance testing (GTT) and echocardiography (echo) were performed. Mice were placed on either a high-fat diet (HFD, 45% kcal fat, D12451) or a control diet (Chow, 10% kcal fat, D12450H) for 4 months, and GTT and echo were repeated.
Results: When compared to 14-16-month-old littermates, 30% of M and 29% of F mice were obese (M 35.62 g ± 3.1 g, n=21, vs 46.14 g ± 4.1, n=9, and F 27.03 g ± 1.8, n=17, vs 37.89 g ± 7.5, n=7, avg. ± sd, lean vs obese per sex p < 0.0001). Natural obesity on standard diet altered glucose tolerance in M mice (M fasting glucose: lean 113.1 mg/dL ± 4.4 versus obese 143.7mg/dL ± 12.2, M GTT tAUC lean 269.8 ± 33.6 vs obese 342 ± 40.11, 2-Way Anova, p < 0.0001) but not in F mice (F fasting glucose: lean 96.2 mg/dL ± 7.8, and obese 101.4 ± 8.6, and GTT tAUC lean 150.2 ± 23.6 vs obese 201.3 ± 33.9, 2-Way Anova, ns). Echo showed that natural obesity in M and F mice led to increased pericardial fat accumulation, a leftwards heart axis shift, preserved systolic function (%EF), and impaired diastolic function (E’/A’). When placed on HFD, BW increased in all M mice, but 25% of F mice developed ulcerative dermatitis and did not gain weight. A 4-month-long HFD impaired glucose tolerance in both sexes and caused a 33% mortality only in M. When normalized to tibia length, increased organ weights (heart, wet lung, dry lung, liver, and kidney) were found in obese M+HFD, but not in F+HFD.
Conclusion: When compared to lean littermates, naturally obese middle-aged M and F mice on a standard diet present with HFpEF, but only M mice show glucose intolerance. HFD for 4 months induced glucose intolerance in F mice. Our data show that obesity in middle-aged mice is the sole driver of HFpEF. Thus, natural obesity in middle-aged mice offers a valuable “single hit” HFpEF model.