Semaglutide Reverses CMR Features of Obesity-Induced Metabolic Heart Disease Independent of Reduced Food Intake in Mice

Background: Semaglutide (SEMA), a glucagon-like peptide-1 receptor agonist (GLP-1RA), causes significant weight loss,¹ in part driven by appetite reduction, and improves outcomes in obesity-related cardiovascular disease.² However, SEMA’s effects on cardiovascular function remain incompletely understood. We have shown that mice fed a high-fat, high-sucrose (HFHS) diet for 18 weeks develop obesity-induced metabolic heart disease characterized by excessive lipid accumulation, reduced myocardial perfusion reserve (MPR), and impaired cardiac strain.^3,4 Here, we investigated whether SEMA improves these features and whether its effects are independent of reduced dietary intake.

Methods: C57BL/6J mice were studied and Fig 1A shows the experimental design. One control group was fed a standard diet (SD). Three groups were fed a HFHS diet for 18 weeks to induce features of cardiometabolic heart disease. The three groups included: SEMA-treated (SEMA) HFHS mice, pair-fed (PF) HFHS mice, and HFHS controls. To isolate the effects of SEMA from those due to reductions in dietary intake, PF mice received food matched to the average daily intake of SEMA-treated animals (Fig. 1C). CMR was performed on a 9.4T small animal MRI (Bruker). The CMR protocol included black-blood cine imaging, a multi-echo gradient echo (GRE) sequence to measure epicardial adipose tissue (EAT) fatty acid composition (FAC) and myocardial proton density fat fraction (PDFF),⁴ arterial spin labeling (ASL) for rest and adenosine stress MPR,⁵ and DENSE for systolic strain and diastolic strain rate.⁶ Pre-treatment imaging was performed after 18 weeks of HFHS diet and was followed by 28 days of daily subcutaneous SEMA (9 nmol/kg/day, uptitrated over 5 days) or vehicle (PBS) injections. Multi-echo GRE and cine imaging were repeated after 5 days (n=8-9/group), and cine, multi-echo GRE, ASL, and DENSE were repeated after 28 days (n=14-16/group).

Results: After 5 days, EAT volume index decreased significantly in both PF and SEMA groups, but only SEMA reduced the EAT saturated fatty acid (SFA) index (1.01 ± 0.07 vs. 0.88 ± 0.10; p < 0.05), a marker of proinflammatory EAT.⁴ After 28 days, SEMA reduced myocardial lipid (PDFF = 14.77 ± 6.97 vs 11.04 ± 3.28%; p< 0.05), and improved circumferential strain (-0.136 ± 0.012 vs. -0.154 ± 0.013; p < 0.0001) and diastolic strain rate (3.29 ± 0.56 vs. 4.08 ± 0.60 s⁻¹; p < 0.01), whereas PF did not. Importantly, SEMA significantly increased MPR (1.55 ± 0.17 vs. 1.87 ± 0.27; p < 0.01), while PF had no effect.

Conclusion: CMR showed that SEMA treatment reversed impairments in EAT composition, myocardial lipid accumulation, systolic strain, diastolic function, and MPR, independently of reduced food intake. These findings contribute to our understanding of the physiological mechanisms by which SEMA improves cardiovascular function in obesity-induced metabolic heart disease and highlight the role of CMR in this context.

Supported by AHA 25PRE1362174, NIH R01HL162872, NIH S10OD025024, and NIH T32GM007267.

Figure 1: A) Timeline of mouse experiments. B) Measurements of animal body weights over the treatment period. C) Measurements of daily food intake. Data presented as mean ± SEM. Abbreviations as in text.
Figure 2: A) EAT volume normalized to body weight before and after 5 days of treatment. B) Example SFA maps overlaid on regions of EAT in short-axis images from the same animal before and after SEMA treatment. C) EAT SFA index in mice before and after 5 days of treatment. D) Myocardial PDFF before and after 28-day treatment. Statistical analysis was performed using two-way repeated measures ANOVA with Tukey’s post hoc tests. Data are presented as mean ± SD. *p < 0.05, **p < 0.01, ****p < 0.0001. Abbreviations as in text.
Figure 3: A) Example circumferential strain maps from the same animal before and after SEMA treatment. B) Circumferential strain (Ecc) and C) peak early diastolic strain rate (PEDSR) before and after 28-day SEMA treatment from DENSE imaging. D) Example rest and stress perfusion maps from the same animal before and after SEMA treatment. E) Myocardial perfusion reserve before and after 28-day SEMA treatment. Statistical analysis was performed using two-way repeated measures ANOVA with Tukey’s post hoc tests. Data are presented as mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Abbreviations as in text.