The effect of an intracerebroventricular injection of metformin or AICAR on the plasma concentrations of melatonin in the ewe: potential involvement of AMPK?

Abstract

BackgroundIt is now widely accepted that AMP-activated protein kinase (AMPK) is a critical regulator of energy homeostasis. Recently, it has been shown to regulate circadian clocks. In seasonal breeding species such as sheep, the circadian clock controls the secretion of an endogenous rhythm of melatonin and, as a consequence, is probably involved in the generation of seasonal rhythms of reproduction. Considering this, we identified the presence of the subunits of AMPK in different hypothalamic nuclei involved in the pre- and post-pineal pathways that control seasonality of reproduction in the ewe and we investigated if the intracerebroventricular (i.c.v.) injection of two activators of AMPK, metformin and AICAR, affected the circadian rhythm of melatonin in ewes that were housed in constant darkness. In parallel the secretion of insulin was monitored as a peripheral metabolic marker. We also investigated the effects of i.c.v. AICAR on the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), a downstream target of AMPK, in brain structures along the photoneuroendocrine pathway to the pineal gland.ResultsAll the subunits of AMPK that we studied were identified in all brain areas that were dissected but with some differences in their level of expression among structures. Metformin and AICAR both reduced (p < 0.001 and p < 0.01 respectively) the amplitude of the circadian rhythm of melatonin secretion independently of insulin secretion. The i.c.v. injection of AICAR only tended (p = 0.1) to increase the levels of phosphorylated AMPK in the paraventricular nucleus but significantly increased the levels of phosphorylated ACC in the paraventricular nucleus (p < 0.001) and in the pineal gland (p < 0.05).ConclusionsTaken together, these results suggest a potential role for AMPK on the secretion of melatonin probably acting trough the paraventricular nucleus and/or directly in the pineal gland. We conclude that AMPK may act as a metabolic cue to modulate the rhythm of melatonin secretion.

Melatonin and the theories of aging: a critical appraisal of melatonin's role in antiaging mechanisms

“…AMP‐activated protein kinase may be of interest under an additional aspect of aging, as it was shown to be required for high amplitudes of circadian rhythms including that of melatonin , that is, functions known to decline during aging.…”

Cardiolipin Profile Changes are Associated to the Early Synaptic Mitochondrial Dysfunction in Alzheimer's Disease

“…AMPK total and phosphorylated AMPK levels in nonTg and 3xTg-AD mice brains were evaluated by western blots analysis [31]. Western blots were performed in the mitochondria-free cytosolic fractions obtained as described above and supplemented with phosphatase inhibitors cocktail (Roche).…”

Melatonin Prevents Mitochondrial Damage Induced by Doxorubicin in Mouse Fibroblasts Through Ampk-Ppar Gamma-Dependent Mechanisms

“…In our study, melatonin given with doxorubicin increased the PPAR-gamma and AMPK levels, which suggests that there is a link between these 2 proteins [ 38 ]. Also, AMPK is related to circadian rythm [ 39 ]. To the best of our knowledge, our study is the first to suggest a trimodal relationship between AMPK-PPAR-gamma and melatonin.…”