Semaglutide restores metabolic and structural homeostasis along the gut-heart-metabolic axis in a cafeteria diet-induced obesity model.

Abstract

Obesity is a growing global health concern that leads to metabolic imbalances and progressive cardiac remodelling. This study investigated whether semaglutide (SMG) can counteract the disruption to the gut-heart-metabolic axis and associated myocardial injury caused by obesity. Twenty-one male Wistar rats were assigned to control, obese (OB), and obese+semaglutide (OB + SMG) groups. The control group was fed a normal diet, while the obese groups were given a cafeteria diet for 16 weeks. In addition, the OB + SMG group received 150 mcg/kg of SMG subcutaneously once a week for the last four weeks. The following were measured alongside HOMA indices: Lipid profile, cardiac enzymes, leptin, insulin, TMAO and LPS levels. Myocardial and intestinal samples were assessed biochemically and histopathological for the levels of MMP-2/MMP-9, TIMP-1, TGF-β, IL-1β, HO-1, occludin, ZO-1 and claudin. Obesity markedly increased body weight, fasting glucose, leptin, insulin resistance, the atherogenic index and cardiac risk, while also increasing LPS, TMAO, TGF-β, IL-1β, MMP-2/MMP-9 activity and decreasing TIMP-1. Semaglutide significantly reversed these abnormalities, improving metabolic indices, restoring the balance between MMPs and TIMPs, and reducing inflammatory mediators. Histological analysis revealed reduced cardiomyocyte degeneration and enhanced intestinal epithelial architecture in the OB + SMG group. Semaglutide notably enhanced the expression of occludin, claudin, and ZO-1, supporting strengthened intestinal barrier integrity, and restored HO-1 expression, indicating improved antioxidant defenses. These findings suggest that semaglutide provides cardioprotection in obesity by restoring gut barrier function, reducing inflammation and normalizing extracellular matrix turnover. By stabilizing the gut-heart-metabolic axis and mitigating structural myocardial injury, semaglutide may interrupt the progression from metabolic dysfunction to cardiomyopathy. This highlights its therapeutic potential in the treatment of obesity-related cardiovascular disease, extending beyond glycemic control.