Effects of decrease in Klotho protein expression on insulin signaling and levels of proteins related to brain energy metabolism

Abstract

Mutations in Klotho have been associated with premature ageing and cognitive dysfunction. Although highly expressed in specific regions of the brain, the actions of Klotho in the central nervous system (CNS) remain largely unknown. Here, we show that animals with a mutated hypomorphic Klotho gene have altered glycaemic regulation, suggesting higher insulin sensitivity. In the CNS, pathways related to insulin intracellular signalling were found to be up-regulated in the hippocampus, with higher activation of protein kinase B and mammalian target of rapamycin and inactivation of the transcription factors forkhead box O (FOXO)-1 and FOXO-3a. In addition, the present study showed that in the hippocampi of wild-type aged mice, where Klotho is naturally downregulated, the levels of some proteins related to energy metabolism and metabolic coupling between neurones and astrocytes, such as monocarboxylate transporter 2 and 4, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 and lactate dehydrogenase enzymes isoforms A and B were altered. These findings suggest that Klotho plays an essential role in regulating proteins and genes related to metabolic coupling in the brain.