Central α-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice
In: Diabetes, Jg. 69 (2020-04-24), S. 1368-1381
Online
unknown
Zugriff:
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.
Titel: |
Central α-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice
|
---|---|
Autor/in / Beteiligte Person: | Brenton Thomas Laing ; Landry, Taylor ; Rao, Zhijian ; Li, Peixin ; Bunner, Wyatt ; Prete, Amber ; Sylvestri, Julia ; Huang, Hu |
Link: | |
Zeitschrift: | Diabetes, Jg. 69 (2020-04-24), S. 1368-1381 |
Veröffentlichung: | American Diabetes Association, 2020 |
Medientyp: | unknown |
ISSN: | 1939-327X (print) ; 0012-1797 (print) |
DOI: | 10.2337/db19-0941 |
Schlagwort: |
|
Sonstiges: |
|