YIA 03-06 RAMELTEON ATTENUATES CARDIAC INJURY, IMPROVES INSULIN SIGNALING IN WHITE ADIPOSE TISSUE, AND ATTENUATES WHITENING OF BROWN ADIPOSE TISSUE IN RATS WITH METABOLIC SYNDROME.

The pineal hormone melatonin, which regulates the body's circadian rhythm, possesses anti-oxidative and anti-inflammatory effects and thereby improves metabolic disorders. Ramelteon is a potent and highly selective agonist of melatonin receptors and attenuates age-associated hypertension and body weight gain in spontaneously hypertensive rats. However, the effects of ramelteon on cardiovascular and metabolic disorders in metabolic syndrome (MetS) remain unclear. We investigated the effects of ramelteon on cardiac and adipose tissue pathology in a rat model of MetS.We used DahlS.Z-Lepr/Lepr (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of MetS. DS/obese rats were treated with low-dose (0.3 mg/kg/day, p.o.) or high-dose (8 mg/kg/day, drinking water) ramelteon from 9 to 13 weeks of age. Age-matched homozygous lean littermates of DS/obese rats (DahlS.Z-Lepr/Lepr) served as control animals.Treatment with both low-dose and high-dose ramelteon attenuated body weight gain, LV fibrosis and diastolic dysfunction as well as cardiac oxidative stress and inflammation, without affecting hypertension or LV hypertrophy in DS/obese rats. Although ramelteon did not affect visceral (epididymal) white adipose tissue (WAT) mass or adipocyte hypertrophy, it attenuated inflammation, reductions in activities of Akt and AMP-activated protein kinase as well as an increase in p70S6 kinase activity in the WAT. DS/obese rats showed minimal expression of the uncoupling protein 1 (UCP-1) protein in the WAT, which was unaffected by ramelteon treatment. In addition, ramelteon attenuated adipocyte hypertrophy as well as the down-regulation of UCP-1 protein in the interscapular brown adipose tissue (BAT) of DS/obese rats.The present results demonstrate that ramelteon attenuated cardiac injury as well as improved insulin signaling in the WAT in DS/obese rats. Inhibition of whitening of BAT with ramelteon likely contributed to attenuation of body weight gain in this model of MetS.