Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats

Abstract

Melatonin can contribute to glucose homeostasis either by decreasing gluconeogenesis or by counteracting insulin resistance in distinct models of obesity. However, the precise mechanism through which melatonin controls glucose homeostasis is not completely understood. Male Wistar rats were administered an intracerebroventricular (icv) injection of melatonin and one of following: an icv injection of a phosphatidylinositol 3-kinase (PI3K) inhibitor, an icv injection of a melatonin receptor (MT) antagonist, or an intraperitoneal (ip) injection of a muscarinic receptor antagonist. Anesthetized rats were subjected to pyruvate tolerance test to estimate in vivo glucose clearance after pyruvate load and in situ liver perfusion to assess hepatic gluconeogenesis. The hypothalamus was removed to determine Akt phosphorylation. Melatonin injections in the central nervous system suppressed hepatic gluconeogenesis and increased hypothalamic Akt phosphorylation. These effects of melatonin were suppressed either by icv injections of PI3K inhibitors and MT antagonists and by ip injection of a muscarinic receptor antagonist. We conclude that melatonin activates hypothalamus-liver communication that may contribute to circadian adjustments of gluconeogenesis. These data further suggest a physiopathological relationship between the circadian disruptions in metabolism and reduced levels of melatonin found in type 2 diabetes patients. melatonin; gluconeogenesis; melatonin receptors; liver MELATONIN (5-methoxy-N-acetyltryptamine) is produced and secreted by the pineal gland in a circadian fashion, with peak levels during the dark phase of the light-dark cycle. The canonical function of melatonin is to transmit environmental information (i.e., the length of the dark period) to the living organism, thereby synchronizing the circadian clock in the hypothalamic suprachiasmatic nucleus (22). In vivo and in vitro experiments have demonstrated that melatonin also plays a role in energy homeostasis by regulating body mass and adiposity and leptin expression by adipocytes (1, 40). Glucose homeostasis is also altered by the absence of melatonin in such a way that pinealectomized rats display glucose intolerance and desynchronized circadian pattern of gluconeogenesis, hallmarked by increased nighttime glucose levels (17,18,23). Moreover, chronic melatonin administration has been shown to improve glucose homeostasis not only in pinealectomized rats but also in rats rendered insulin resistant by diet manipulation (16,33,34).Although it has been demonstrated that melatonin stimulates glucose uptake in adipocytes and skeletal muscle cells in vitro (10, 19), the precise mechanism by which this hormone reduces whole body glucose intolerance has not been determined precisely. In mammals, the effects of melatonin are mediated in part by specific high-affinity G protein-coupled receptors known as melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) (31). We have demonstrated previously that melatonin acts locally in the hypothalamus to activate the p...

Long-term melatonin administration improves glucose homeostasis and insulin resistance state in high-fat-diet fed rats

“…Many studies have shown that melatonin has favorable effects on glucose homeostasis since it might increase glucose tolerance and improve insulin sensitivity in various animal models [32][33][34]. Melatonin administration has been shown to acutely decrease plasma insulin level and increase insulin sensitivity in rats [35].…”

Inhibitory G proteins and their receptors: emerging therapeutic targets for obesity and diabetes

“…This is because MT1/MT2 receptor signaling also reduces dyslipidemia, reduces hepatic glucose output, decreases adiposity and improves metabolic function. 41, 101, 102 Low melatonin levels have also been independently associated with T2DM risk. 103 Thus, stimulating melatonin signaling has been proposed as a treatment for metabolic syndrome.…”

“…103 Melatonin was shown to function by reducing hepatic gluconeogenesis and phosphorylation and activation of Akt in the hypothalamus. 101 Most of the recent research into the links between the melatonin receptors and diabetes is focused on MT2. Independent genome-wide association studies in European populations identified single nucleotide polymorphisms near MTNR1B that were associated with fasting plasma glucose, reduced beta cell function, and significantly increased T2DM risk: rs1387153 and rs10830963.…”

Epigenetic mechanisms of melatonin action in human SH-SY5Y neuroblastoma cells

“…Melatonin has been shown to modulate the PI3K/Akt signaling pathway, which plays a central role in controlling cell growth, proliferation, survival, and differentiation (Faria et al, 2013;Lee et al, 2006;Proietti et al, 2011). Pharmacological doses of melatonin have been reported to induce Akt phosphorylation in mouse hippocampus, cultured primary astrocytes, and the ischemic rat brain (Kilic et al, 2005;Kong et al, 2008;Lee et al, 2006).…”