Eur J Pharmacol. 2026 Apr 14:178873. doi: 10.1016/j.ejphar.2026.178873. Online ahead of print.
ABSTRACT
Obesity is associated with low circulating IGF-1 levels, mitochondrial injury, and myocardial anomalies, however, the precise interplay between IGF-1 and obesity cardiomyopathy remains unclear. Our work evaluated the impact of IGF-1 on high fat (HF) diet-evoked alterations in cardiac geometry, function, and mitochondrial integrity. WT and cardiac-specific IGF-1 transgenic mice were offered a low fat (LF, 10% fat calorie) or HF (60% fat calorie) diet for 20 weeks before assessing glucose sensitivity, plasma profiles, myocardial remodeling and function, ROS, mitochondrial integrity, and cell death. Transcriptomic analyses of obese human and murine hearts revealed that obesity cardiomyopathy was characterized by significant metabolic reprogramming, marked by a shift from TCA cycle to glycolysis and disrupted fatty acid homeostasis, alongside identification of ferroptosis as a key regulatory node in myocardial injury. HF led to hyperleptinemia, hypertriglyceridemia, reduced plasma IGF-1, and glucose intolerance, cardiac hypertrophy (higher LV dimensions, wall thickness), interstitial fibrosis, contractile dysfunction (lower fractional shortening, ejection fraction, cell contractile and intracellular Ca2+ derangement), oxidative stress, apoptosis, ferroptosis, and mitochondrial injury (declined PGC1α and UCP-2). Notably, cardiac-specific IGF-1 overexpression mitigated HF-induced myocardial remodeling, dysfunction, mitochondrial injury, and ferroptosis, without affecting systemic glucose metabolism or plasma profiles. Importantly, targeted metabolomics revealed a distinct plasma acylcarnitine signature in obese patients, with C20:0 (arachidylcarnitine) identified as a top discriminative metabolite. Furthermore, reduced myocardial L-carnitine level was observed in HF-fed mice, and L-carnitine supplementation rescued HF-induced cardiac geometric, functional, and mitochondrial anomalies. These data indicate that IGF-1 confers beneficial effect for chronic HF intake-induced damage possibly via preserved mitochondrial integrity, suppressed ferroptosis, and restored arachidylcarnitine levels, highlighting a metabolomic-metabolic axis in obesity-related cardiac dysfunction.
PMID:41990905 | DOI:10.1016/j.ejphar.2026.178873