| First Author | Landry T | Year | 2020 |
| Journal | Diabetes | Volume | 69 |
| Issue | 7 | Pages | 1368-1381 |
| PubMed ID | 32332158 | Mgi Jnum | J:292725 |
| Mgi Id | MGI:6445983 | Doi | 10.2337/db19-0941 |
| Citation | Landry T, et al. (2020) Central alpha-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice. Diabetes 69(7):1368-1381 |
| abstractText | alpha-Klotho is a circulating factor with well-documented antiaging properties. However, the central role of alpha-klotho in metabolism remains largely unexplored. The current study investigated the potential role of central alpha-klotho to modulate neuropeptide Y/agouti-related peptide (NPY/AgRP)-expressing neurons, energy balance, and glucose homeostasis. Intracerebroventricular administration of alpha-klotho suppressed food intake, improved glucose profiles, and reduced body weight in mouse models of type 1 and 2 diabetes. Furthermore, central alpha-klotho inhibition via an anti-alpha-klotho antibody impaired glucose tolerance. Ex vivo patch clamp electrophysiology and immunohistochemical analysis revealed that alpha-klotho suppresses NPY/AgRP neuron activity, at least in part, by enhancing miniature inhibitory postsynaptic currents. Experiments in hypothalamic GT1-7 cells observed that alpha-klotho induces phosphorylation of AKT(ser473), ERK(thr202/tyr204), and FOXO1(ser256) as well as blunts AgRP gene transcription. Mechanistically, fibroblast growth factor receptor 1 (FGFR1) inhibition abolished the downstream signaling of alpha-klotho, negated its ability to modulate NPY/AgRP neurons, and blunted its therapeutic effects. Phosphatidylinositol 3 kinase (PI3K) inhibition also abolished alpha-klotho's ability to suppress food intake and improve glucose clearance. These results indicate a prominent role of hypothalamic alpha-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. |
