RT Journal Article
SR Electronic
T1 Central α-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 1368
OP 1381
DO 10.2337/db19-0941
VO 69
IS 7
A1 Landry, Taylor
A1 Laing, Brenton Thomas
A1 Li, Peixin
A1 Bunner, Wyatt
A1 Rao, Zhijian
A1 Prete, Amber
A1 Sylvestri, Julia
A1 Huang, Hu
YR 2020
UL http://diabetes.diabetesjournals.org/content/69/7/1368.abstract
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.