Melatonin enhances leptin expression by rat adipocytes in the presence of insulin

Abstract

Leptin and melatonin play an important role in the regulation of body mass and energy balance. Both hormones show a circadian rhythm, with increasing values at night. In addition, melatonin receptors were recently described in adipocytes, where leptin is synthesized. Here, we investigated the influence of melatonin and its interaction with insulin and dexamethasone on leptin expression. Isolated rat adipocytes were incubated with melatonin (1 nM) alone or in combination with insulin (5 nM) and/or dexamethasone (7 nM) for 6 h. Melatonin or insulin alone did not affect leptin expression, but together they increased it by 120%. Dexamethasone increased leptin mRNA content (105%), and this effect was not enhanced by melatonin. Simultaneous treatment with the three hormones provoked a further increase in leptin release (250%) and leptin mRNA (100%). Melatonin prevented the forskolin-induced inhibition (95%) of leptin expression. In addition, melatonin's ability to stimulate leptin release (in the presence of insulin) was completely blocked by pertussis toxin and luzindole. To gain further insight into the molecular basis of melatonin and insulin synergism, the insulin-signaling pathway was investigated. Melatonin increased the insulin-induced insulin receptor-beta tyrosine phosphorylation, which led to an increased serine phosphorylation of the downstream convergent protein Akt. We concluded that melatonin interacts with insulin and upregulates insulin-stimulated leptin expression. These effects are caused by melatonin binding to the pertussis toxin-sensitive G(i) protein-coupled membrane receptor (MT1 subtype) and the cross talk with insulin, since insulin receptor and its convergent target Akt are coactivated by melatonin.

Night Shift Work and the Risk of Endometrial Cancer

“…In humans, an association between night work and the metabolic syndrome has previously been noted (28). Exogenous melatonin reduces weight gain, particularly among obese women (12), and melatonin may influence appetite (29,30). In addition, women with a BMI > 30 are thought to have an increased risk of endometrial cancer due to an increased level of unopposed estrogens, and melatonin may affect hormone receptor regulation in endometrial tissues.…”

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

“…In epididymal adipocytes, melatonin in the presence of insulin increases leptin secretion and counteracts forskolin-induced inhibition of leptin secretion and mRNA expression through activation of a melatonin receptor. This suggests cross-talk between these hormones to modulate leptin production from adipocytes via MT 1 receptor activation (Alonso-Vale et al, 2005). In human adipocytes, activation of MT 2 melatonin receptors modulates glucose uptake .…”

Neel revisited: the adipocyte, seasonality and type 2 diabetes

“…One might hypothesise that, in the seasonal animal, the suppression of adiponectin and increased leptin secretion are co-ordinated to develop insulin resistance and suppress appetite as food availability diminishes. During long winter nights, melatonin secretion is increased, enhancing adipocyte insulin sensitivity and energy availability whilst the animal is dormant [23,29], leading to an animal that is lean and insulin sensitive once more on re-awakening in spring [23,24]. The seasonally responsive mammal cycles obesity and insulin resistance in response to food availability and photoperiod to generate energy conservation.…”

“…This mechanism is attenuated in the presence of obesity to suggest that fat loading blunts intrinsic cellular clock activity [35]. Bearing in mind that adipocytes express melatonin receptors through which melatonin is able to phosphorylate and co-activate the insulin receptor to enhance insulin sensitivity [29,39], there appears to be complex circadian regulation of adipocyte function, which, when interrupted, may contribute to the insulin resistance phenotype.…”