Background/Aims: α-Klotho is a circulating factor with well-documented anti-aging properties; however, the central role of α-Klotho in metabolism remains largely unexplored. We aimed to investigate the potential role of central α-klotho as a novel regulator of energy balance and glucose homeostasis.

Methods: Central administration of α-klotho was performed by using intracerebroventricular (ICV) injection for seven days in diet-induced obesity (DIO) and streptozotocin-injected (STZ) mice. hrNPY-GFP reporter mice were utilized for electrophysiology and immunofluorescent staining experiments to investigate the effects of α-klotho on NPY/AgRP neurons. To determine the mechanism/s of hypothalamic α-klotho, we used GT1-7 immortal hypothalamic cells in vitro along with ICV administration of fibroblast growth factor receptor 1 (FGFR1) antagonist in vivo.

Results: Central α-klotho administration decreased food intake and improved glucose profiles in DIO and STZ mice. Liver lipid content and gluconeogenic gene expression were also reduced. Electrophysiology and immunofluorescent staining revealed AgRP/NPY neurons exhibit hyperpolarization and reduced firing rate in response to α-klotho treatment. These effects are, at least partially, due to increased magnitude of mIPSC’s. In vitro, α-klotho blunted serum-starvation-induced AgRP gene expression and increased phosphorylation of ERK44/42, AKTser473, and Foxo1ser256. These downstream effects were abolished by pretreatment with inhibitors of either FGFR1 or PI3kinase. Furthermore, α-klotho-mediated suppression of food intake, but not glucose levels, was blunted in response to inhibition of FGFR1 signaling.

Conclusion: These results indicate a prominent role of hypothalamic α-klotho-FGFR1-PI3K signaling in regulation of NPY/AgRP neuron activity, energy balance, and glucose homeostasis, thus providing new insight into the pathophysiology of metabolic disease.


T. Landry: None. P. Li: None. W.P. Bunner: None. Z. Rao: None. H. Huang: None.


East Carolina University

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