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- Title
Central α-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice.
- Authors
Landry, Taylor; Laing, Brenton Thomas; Li, Peixin; Bunner, Wyatt; Rao, Zhijian; Prete, Amber; Sylvestri, Julia; Huang, Hu
- Abstract
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.
- Subjects
NEUROPEPTIDES; FIBROBLAST growth factor receptors; PATCH-clamp techniques (Electrophysiology); METABOLISM; NEURONS; TYPE 1 diabetes; NEURAL physiology; CELL receptors; GLUCOSE metabolism; ANIMAL experimentation; CELL culture; CELLULAR signal transduction; COMPARATIVE studies; DIABETES; ENERGY metabolism; GLYCOSIDASES; GROWTH factors; RESEARCH methodology; MEDICAL cooperation; MICE; PHOSPHOTRANSFERASES; RESEARCH; EVALUATION research; PARENTERAL infusions; CELL physiology
- Publication
Diabetes, 2020, Vol 69, Issue 7, p1368
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db19-0941