Aims: β-Arrestin2 signaling has emerged as a promising therapeutic target for the management of insulin resistance and related complications. Moreover, recent studies have shown that certain G protein-coupled receptor (GPCR) ligands can modulate β-arrestin2 signaling. The current study examined the effects of the β-blocker propranolol and a low dose of the agonist isoproterenol (L-D-ISOPROT) on β-arrestin2 signaling, insulin resistance, and cardiac remodeling in high-fructose, high-fat diet (HFrHFD)-fed mice. In addition, the effects of these agents were compared to those of the clinical antidiabetic agent, metformin. Materials and methods: Insulin resistance was induced by HFrHFD feeding for 16 weeks. Mice were then randomly allocated to groups receiving propranolol, L-D-ISOPROT, metformin, or vehicle (control) for 4 weeks starting on week 13 of HFrHFD feeding. Survival rate, body weight, visceral fat weight, blood glucose, serum insulin, insulin resistance index, hepatic β-arrestin2 signaling, heart weight, left and right ventricular thicknesses, cardiac fibrosis severity, serum endothelin-1, cardiac cardiotrophin-1, and cardiac β-arrestin2 signaling were then compared among groups. Key findings: HFrHFD for 16 weeks significantly increased insulin resistance index, cardiac fibrosis area, and serum endothelin-1, and reduced hepatic β-arrestin2 signaling, cardiac cardiotrophin-1, and cardiac β-arrestin2 signaling without significant changes in survival rate, body weight, visceral fat weight, heart weight, or left and right ventricular thicknesses. All three drugs reduced insulin resistance and cardiac remodeling parameters and enhanced β-arrestin2 signaling with variable efficacies. Significance: Propranolol and L-D-ISOPROT, like metformin, can reduce insulin-resistance and cardiac remodeling in HFrHFD-fed mice, possibly by upregulating β-arrestin2 signaling activity. Therefore, β-arrestin2- signaling modulation might be a promising strategy for insulin-resistance treatment.