Central a-klotho suppresses NPY/aGRP neuron activity and regulates metabolism in mice

Abstract

a-Klotho is a circulating factor with well-documented antiaging properties. However, the central role of a-klotho in metabolism remains largely unexplored. The current study investigated the potential role of central a-klotho to modulate neuropeptide Y/agouti-related peptide (NPY/AgRP)-expressing neurons, energy balance, and glucose homeostasis. Intracerebroventricular administration of a-klotho suppressed food intake, improved glucose profiles, and reduced body weight in mouse models of type 1 and 2 diabetes. Furthermore, central a-klotho inhibition via an anti–a-klotho antibody impaired glucose tolerance. Ex vivo patch clamp electro-physiology and immunohistochemical analysis revealed that a-klotho suppresses NPY/AgRP neuron activity, at least in part, by enhancing miniature inhibitory postsyn-aptic currents. Experiments in hypothalamic GT1-7 cells observed that a-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 a-klotho, negated its ability to modulate NPY/AgRP neurons, and blunted its therapeutic effects. Phosphatidyli-nositol 3 kinase (PI3K) inhibition also abolished a-klotho’s ability to suppress food intake and improve glucose clear-ance. These results indicate a prominent role of hypothalamic a-klotho/FGFR1/PI3K signaling in the modulation of NPY/ AgRP neuron activity and maintenance of energy homeosta-sis, thus providing new insight into the pathophysiology of metabolic disease.