PT  - JOURNAL ARTICLE
AU  - Landry, Taylor
AU  - Laing, Brenton Thomas
AU  - Li, Peixin
AU  - Bunner, Wyatt
AU  - Rao, Zhijian
AU  - Prete, Amber
AU  - Sylvestri, Julia
AU  - Huang, Hu
TI  - Central α-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice
AID  - 10.2337/db19-0941
DP  - 2020 Jul 01
TA  - Diabetes
PG  - 1368--1381
VI  - 69
IP  - 7
4099  - http://diabetes.diabetesjournals.org/content/69/7/1368.short
4100  - http://diabetes.diabetesjournals.org/content/69/7/1368.full
SO  - Diabetes2020 Jul 01; 69
AB  - α-Klotho is a circulating factor with well-documented antiaging 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 neuropeptide Y/agouti-related peptide (NPY/AgRP)-expressing neurons, energy balance, and glucose homeostasis. Intracerebroventricular administration of α-klotho suppressed food intake, improved glucose profiles, and reduced body weight in mouse models of type 1 and 2 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 miniature inhibitory postsynaptic currents. Experiments in hypothalamic GT1-7 cells observed that α-klotho induces phosphorylation of AKTser473, ERKthr202/tyr204, and FOXO1ser256 as well as blunts AgRP gene transcription. Mechanistically, fibroblast growth factor receptor 1 (FGFR1) inhibition abolished the downstream signaling of α-klotho, negated its ability to modulate NPY/AgRP neurons, and blunted its therapeutic effects. Phosphatidylinositol 3 kinase (PI3K) 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.