Influence of ghrelin and growth hormone deficiency on AMP-activated protein kinase and hypothalamic lipid metabolism.

Current evidence demonstrates that the stomach-derived hormone ghrelin, a potent growth hormone (GH) secretagogue, promotes feeding through a mechanism involving the short-term activation of hypothalamic AMP-activated protein kinase (AMPK), which in turn results in decreased hypothalamic levels of malonyl-CoA and increased carnitine palmitoyltransferase 1 (CPT1) activity. Despite this evidence, no data have been reported about the effect of chronic, central ghrelin administration on hypothalamic fatty acid metabolism. In the present study, we examined the differences in hypothalamic fatty acid metabolism in the presence and absence of GH, by using a model for the study of GH-deficiency, namely the spontaneous dwarf rat and the effect of long-term central ghrelin treatment and starvation on hypothalamic fatty acid metabolism in this animal model. Our data showed that GH-deficiency induces reductions in both de novo lipogenesis and beta-oxidation pathways in the hypothalamus. Thus, dwarf rats display reductions in fatty acid synthase (FAS) mRNA expression both in the ventromedial nucleus of the hypothalamus (VMH) and whole hypothalamus, as well as in FAS protein and activity. CPT1 activity was also reduced. In addition, in the present study, we show that chronic ghrelin treatment does not promote AMPK-induced changes in the overall fluxes of hypothalamic fatty acid metabolism in normal rats and that this effect is independent of GH status. By contrast, we demonstrated that both chronic ghrelin and fasting decreased FAS mRNA expression in the VMH of normal rats but not dwarf rats, suggesting GH status dependency. Overall, these results suggest that ghrelin plays a dual time-dependent role in modulating hypothalamic lipid metabolism. Understanding the molecular mechanism underlying the interplay between GH and ghrelin on hypothalamic lipid metabolism will allow new strategies for the design and development of suitable drugs for the treatment of GH-deficiency, obesity and its comorbidities.