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

Author(s)

Orellana, Ana Maria Marques ; Mazucanti, Caio Henrique ; Andreotti, Diana Zukas ; Lima, Larissa de Sa ; Kawamoto, Elisa Mitiko ; Scavone, Cristoforo

• Document type: Journal article
• Source: European Journal of Pharmacology; v. 997, p. 10-pg., 2025-06-15.

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-2,6bisphosphatase 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. (AU)

• FAPESP's process: 16/22996-9 - Evaluation of physical exercise effects on cognition of neuronal-PTEN deleted animals
• Grantee: Elisa Mitiko Kawamoto Iwashe
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/06009-6 - Neuroplasticity -induced by challenge Na, K-ATPase, Klotho, glutamate, and neuroinflammation signaling cascades to reveal new therapeutic targets for aging and neurodegenerative diseases
• Grantee: Cristoforo Scavone
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/12974-6 - Evaluation of PTEN inhibition and compartmentalization effects in the presence of neuroinflammation: participation of glutamatergic signaling
• Grantee: Elisa Mitiko Kawamoto Iwashe
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/07427-8 - Aging and neuroprotection: effects of Klotho protein in energetic metabolism, Na,K-ATPase signaling and adaptative response in central nervous system
• Grantee: Cristoforo Scavone
• Support Opportunities: Research Projects - Thematic Grants
• 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