Lifelong high-fat, high-sucrose diet causes sex-specific heart dysfunction in mouse offspring

Abstract

Maternal obesity and high-fat, high-sucrose (HFHS) diets during development increase cardiometabolic risk in offspring, but long-term, sex-specific cardiac effects remain underexplored. This study examined how continuous HFHS exposure impacts cardiac function in male and female mice. Female dams were fed a control standard chow (CON) diet or HFHS diet for 8 weeks before pregnancy, continuing through gestation and lactation. Offspring were maintained on their dam's diet until 29-32 weeks of age. Body composition and cardiac function were assessed using pressure-volume (P-V) loop analysis. HFHS offspring exhibited increased body weight and fat mass, with males showing greater adiposity. Lean mass was higher in males, but relative lean mass decreased in both sexes by 22 weeks in response to the HFHS diet. Cardiac assessments revealed load-dependent and load-independent impairments. HFHS exposure increased end-diastolic and end-systolic volumes, reduced ejection fraction, and lowered end-systolic elastance, indicating systolic dysfunction in both sexes. Diastolic function showed sex-specific alterations; HFHS exposure in males led to slower myocardial relaxation (less negative dP/dt min), while in females it increased end-diastolic elastance (Eed), suggesting greater ventricular stiffness. Ventricular-arterial coupling (Ees/Ea) was reduced in HFHS-exposed animals of both sexes, with females showing more pronounced impairments. Our results highlight sex-specific cardiac dysfunction in HFHS-exposed offspring, with females more susceptible to myocardial stiffness and coupling deficits. This underscores the need for sex-tailored interventions to mitigate long-term cardiovascular risks from early-life HFHS exposure.

Keywords: hemodynamics; maternal diet; obesity; offspring; post-weaning diet; pressure–volume loop.

Figure 1 •

Schematic study design. Timeline of (a) maternal and (b) offspring diet interventions, and body composition assessments and cardiac function analysis using pressure–volume (P–V) loop measurements. CON—control standard chow diet; HFHS—high-fat, high-sucrose diet.

Figure 2 •

Body weight. (a) BW trajectories from weaning, 6, 20, and 27 weeks of age and (b) final BW at 29–32 weeks. Values are expressed as mean ± with the standard error of the mean (SEM). ** p < 0.01; *** p < 0.001; **** p < 0.0001. n = 7–9 in CON male; n = 5 in HFHS male; n = 7–11 in CON female; n = 5–6 in HFHS female. BW—body weight; CON—control standard chow diet; HFHS—high-fat, high-sucrose diet; blue rhombus—CON male; red square—HFHS male; green rhombus—CON female; pink square—HFHS female; blue circle—CON group; red circle—HFHS group.

Figure 3 •

Body composition at 6 and 22 weeks. (a) Fat mass and (b) fat mass/BW. (c) Lean mass and (d) lean mass/BW. Values are expressed as mean ± with the standard error mean (SEM). n = 7–9 in CON male; n = 5 in HFHS male; n = 7–11 in CON female; n = 6 in HFHS female. * p < 0.05; ** p < 0.01; **** p < 0.0001. BW—body weight; CON—control standard chow diet; HFHS—high-fat, high-sucrose diet; blue rhombus—CON male; red square—HFHS male; green rhombus—CON female; pink square—HFHS female.

Figure 4 •

Heart morphology. (a) Absolute HW and (b) LVW. (c) HW/BW and (d) LVW/BW. Values are expressed as mean ± with the standard error mean (SEM). n = 6 in CON male; n = 4 in HFHS male; n = 9 in CON female; n = 5 in HFHS female. * p < 0.05; ** p < 0.01; *** p < 0.001. HW—heart weight; LVW—left ventricle weight; BW—body weight; CON—control standard chow diet; HFHS—high-fat, high-sucrose diet; blue circle—CON group; red circle—HFHS group.

Figure 5 •

Load-independent indices of cardiac performance. (a) Ees, (b) PRSW, (c) Eed, (d) Eed/BW, and (e) Ees/Ea. Values are expressed as mean ± with the standard error mean (SEM). n = 5 in CON male; n = 4 in HFHS male; n = 7 in CON female; n = 5 in HFHS female. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. Ees—end-systolic elastance; PRSW—preload recruitable stroke work; Eed—end-diastolic elastance; BW—body weight; Ees/Ea—ventricular–arterial coupling; CON—control standard chow diet; HFHS—high-fat, high-sucrose diet; blue circle—CON group; red circle—HFHS group.