Effects of Klotho protein on insulin signaling and energy metabolism of the brain.

Author(s)

Caio Henrique Yokoyama Mazucanti

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2018-01-15

Examining board members

Cristoforo Scavone; Alícia Juliana Kowaltowski; Tania Marcourakis; Carolina Demarchi Munhoz; Andréa da Silva Torrão

• Advisor: Cristoforo Scavone

Abstract

Mutations in the <font face = \"symbol\">b-glucuronidase protein Klotho have been associated with premature aging and cognitive dysfunction. Although highly expressed in specific regions of the brain, Klotho actions in the central nervous system are still largely unknown. Here we show that animals with a mutated hypomorphic Klotho gene have altered glycemia regulation, suggestive of a higher insulin sensitivity. In the central nervous system, pathways related to insulin intracellular signaling were shown to be up-regulated in the hippocampus, with higher AKT and mTOR activation, and inactivation of transcription factor FOXO. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels. Conversely, APA and NMDA antagonism suppress neuronal Klotho expression. We also provide evidence that soluble Klotho enhances astrocytic aerobic glycolysis by hindering pyruvate metabolism through the mitochondria, and stimulating its processing by lactate dehydrogenase. Pharmacological inhibition of FGFR1, ERK phosphorylation, and monocarboxylic acid transporters prevents Klotho-induced lactate release from astrocytes. AKT inhibition by Klotho treatment induces transcriptional activity of FOXO transcription factors and promote antioxidant defense in astrocytes by inducing catalase expression. Similarly, Klotho treatment has anti-inflammatory properties, as shown by its ability to hinder NF-<font face = \"symbol\">kB activation in astrocytes after LPS stimulation. In neurons, Klotho treatment induces PFKFB3 ubiquitination and degradation through the proteasome. Lastly, in the hippocampus, we show that Klotho is less present in hippocampi of aged mice. Genes and proteins related to energy metabolism and metabolic coupling between neurons and astrocytes show an altered expression pattern with aging, suggesting that this could be a crucial characteristic that explains cognitive decline commonly seen during the aging process. Taken together these data suggest Klotho as a potential new player in the metabolic coupling between neurons and astrocytes. (AU)

• FAPESP's process: 13/10787-8 - Klotho effects on insulin signaling and energetic metabolism in the central nervous system
• Grantee: Caio Henrique Yokoyama Mazucanti
• Support Opportunities: Scholarships in Brazil - Doctorate