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Central α-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice
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posted on 2020-04-20, 22:50 authored by Ada AdminAda Admin, Taylor Landry, Brenton Thomas Laing, Peixin Li, Wyatt Bunner, Zhijian Rao, Amber Prete, Julia Sylvestri, Hu Huangα-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.