posted on 2020-04-20, 22:50authored byAda AdminAda Admin, Taylor Landry, Brenton Thomas Laing, Peixin Li, Wyatt Bunner, Zhijian Rao, Amber Prete, Julia Sylvestri, Hu Huang
α-Klotho is a circulating factor
with well-documented anti-aging properties; however, the central role of
α-klotho in metabolism remains largely unexplored. The current study
investigated the potential role of central α-klotho to modulate NPY/AgRP
neurons, energy balance, and glucose homeostasis. Intracerebroventricular (ICV)
administration of α-klotho suppressed food intake, improved glucose profiles,
and reduced body weight in mouse models of Type I and II diabetes. Furthermore,
central α-klotho inhibition via an anti-α-klotho antibody impaired glucose
tolerance. Ex vivo patch clamp electrophysiology and immunohistochemical
analysis revealed that α-klotho suppresses NPY/AgRP neuron activity, at least
in part, by enhancing mIPSC’s. Experiments in hypothalamic GT1-7 cells observed
α-klotho induces phosphorylation of AKTser473, ERKthr202/tyr204,
and FOXO1ser256, as well as blunts AgRP gene transcription.
Mechanistically, fibroblast growth factor 1 (FGFR1) inhibition abolished the
downstream signaling of α-klotho, negated its ability to modulate NPY/AgRP
neurons, and blunted its therapeutic effects. PI3 kinase inhibition also
abolished α-klotho’s ability to suppress food intake and improve glucose
clearance. These results indicate a prominent role of hypothalamic
α-klotho/FGFR1/PI3K signaling in the modulation of NPY/AgRP neuron activity and
maintenance of energy homeostasis, thus providing new insight into the
pathophysiology of metabolic disease.
The funding for this project was provided by East Carolina University start up and the National Institute of Diabetes and Digestive and Kidney Disease (DK121215) to HH.