Effects of ramelteon on cardiac injury and adipose tissue pathology in rats with metabolic syndrome

Abstract

Melatonin regulates circadian rhythms but also has antioxidative and anti-inflammatory effects that ameliorate metabolic disorders. We investigated the effects of the selective melatonin agonist ramelteon on cardiac and adipose tissue pathology in the DahlS.Z-Lepr /Lepr (DS/obese) rat, a model of metabolic syndrome (MetS). Rats were treated with a low (0.3 mg/kg per day) or high (8 mg/kg per day) dose of ramelteon from 9 to 13 weeks of age. Ramelteon treatment at either dose attenuated body weight gain, left ventricular fibrosis, and diastolic dysfunction, as well as cardiac oxidative stress and inflammation, without affecting hypertension or insulin resistance. Although ramelteon did not affect visceral white adipose tissue (WAT) mass, it attenuated inflammation and downregulated insulin signaling in this tissue. In contrast, ramelteon reduced fat mass, adipocyte hypertrophy, and inflammation, and ameliorated impaired insulin signaling in subcutaneous WAT. In addition, ramelteon attenuated adipocyte hypertrophy, downregulated mitochondrial uncoupling protein 1, and upregulated 11β-hydroxysteroid dehydrogenase type 1 expression in interscapular brown adipose tissue (BAT). In summary, ramelteon treatment attenuated obesity and cardiac injury, improved insulin signaling in visceral and subcutaneous WAT, and inhibited the whitening of BAT in rats with MetS.

Left Ventricular Hypertrophy: Roles of Mitochondria CYP1B1 and Melatonergic Pathways in Co-Ordinating Wider Pathophysiology

“…Melatonin has clinical utility in the management of cardiac hypertrophy and affords protection in an array of different preclinical models, with effects variously attributed, including to an increase in PGC-1b [78], cyclophilin A/CD147 [79], antioxidant effects [80], retinoic acid receptor-related orphan receptor-α (RORα) [81], autophagy and AMPK [82] or a decrease in mTOR [83] and TNF-α [84]. Melatonin receptor regulating pharmaceuticals, such as ramelteon, have also shown utility in the management of LVH, suggesting a protective role for melatonin receptor activation [85].…”

Melatonin in Heart Failure: A Promising Therapeutic Strategy?

“…Multiple molecular and cellular responses including neurohormonal activation, complex metabolic changes and increased production of reactive oxygen species, and oxidative stress contribute to the development of HF in metabolic syndrome [ 96 ]. Melatonin has recently received attention as a potential therapy in obesity and related cardiometabolic abnormalities [ 17 , 34 , 44 , 98 , 99 , 100 ]. Its role in metabolic syndrome is reported in both animal and human studies [ 17 , 34 , 44 , 98 ].…”

“…It also associates with increased oxidative stress and cardiomyopathy [ 104 , 105 ]. Interestingly, a recent study in the DahlS.Z-Lepr (fa) /Lepr (fa) (DS/obese) rat model of metabolic syndrome, shows that melatonin receptor agonist, ramelteon treatment at either low (0.3 mg/kg per day) or high (8 mg/kg per day) dose attenuates body weight gain, left ventricular fibrosis, and diastolic dysfunction, as well as cardiac oxidative stress and inflammation [ 34 ]. Similar beneficial effects on cardiac hypertrophy and fibrosis are also reported in pre-diabetic obese (ob/ob) mice treated with melatonin (100 mg/kg per day in drinking water) for 8 weeks (from 5 weeks of age) [ 99 ].…”

“…Their downstream signaling effector mechanisms include adenylate cyclase, protein kinase C (PKC), phospholipase C, phospholipase A2, potassium channels, guanylyl cyclase and calcium channels and mediate the anti-adrenergic effects of melatonin [ 25 , 28 , 29 ]. In the context of HF, melatonin receptors play a significant role in the prevention of HF following myocardial infarction [ 29 , 30 , 31 , 32 , 33 ], and cardiomyopathy [ 20 , 34 , 35 , 36 ].…”

Surgical ablation of whitened interscapular brown fat ameliorates cardiac pathology in salt‐loaded metabolic syndrome rats

“…7 We also recently detected whitening of interscapular BAT (iBAT) associated with thermogenic dysfunction (downregulation of UCP1) in DS/obese rats. 8 Furthermore, surgical removal of subcutaneous (inguinal) WAT attenuated salt-induced exacerbation of MetS and cardiac and renal pathology in DS/obese rats. 9 The aim of the present study was to investigate the effects of salt loading and surgical removal of whitened iBAT on cardiac and adipose tissue pathology as well as on metabolism in DS/obese rats.…”