Central α-Klotho is a Novel Regulator of Arcuate Neurons and Peripheral Metabolism
The arcuate nucleus of the hypothalamus (ARC) is a critical nexus of neuron populations that interpret peripheral signals of energy status and deliver diverse efferent outputs to metabolically active tissues. These neurons are critical to maintaining energy homeostasis, and disruption of their complex neurocircuitry results in metabolic disease phenotypes. The goals of this dissertation were to investigate the novel role for the circulating [alpha]-klotho protein to regulate neurons within the ARC to modulate peripheral metabolism. Intracerebroventricular administration of a recombinant [alpha]-klotho in lean, obese, and type I diabetic mice for 1-12 days revealed a novel role for [alpha]-klotho to regulate whole body energy and glucose metabolism. [alpha]-Klotho-treated mice experienced suppressed food intake, increased energy expenditure, and improved glucose clearance. Central [alpha]-klotho-mediated regulation of peripheral glucose metabolism was determined to be independent from body weight and insulin sensitivity but may be due to reduced hepatic gluconeogenic gene expression and improved insulin secretion. Furthermore, cerebrospinal fluid collected from humans demonstrated body weight is strongly and negatively correlated to [alpha]-klotho concentrations, suggesting central [alpha]-klotho is also important to energy homeostasis in humans. Experiments utilizing ex vivo patch clamp electrophysiology, immunohistochemical detection of the neuronal activation marker cFOS, and the immortal GT1-7 hypothalamic cell line demonstrated a novel role for [alpha]-klotho to regulate neurons in the ARC. [alpha]-Klotho decreased activity of the orexigenic neuropeptide Y/agouti-related peptide neuron population and increased activity of a subset of the anorexigenic proopiomelanocortin neuron population. [alpha]-Klotho was also shown to regulate the non-neuronal ARC astrocytes, which are involved in hormonal transport, nutrient-sensing, and neuronal health. Mechanistically, ICV pretreatment with inhibitors of fibroblast growth factor receptors (FGFR's) or PI3kinase signaling attenuated the therapeutic effects of [alpha]-klotho, as well as its ability to modulate hypothalamic neuron activity. Overall, these studies identify a novel [alpha]-klotho[rightward pointing arrow]FGFR[rightward pointing arrow]PI3kinase signaling axis in ARC neurons that is critically involved in homeostatic regulation of energy and glucose metabolism. Identification of this molecular mechanism may facilitate the development of novel therapeutic approaches to metabolic disease and may also identify [alpha]-klotho as a preclinical marker of these disorders.
Landry, Taylor. (April 2021). Central α-Klotho is a Novel Regulator of Arcuate Neurons and Peripheral Metabolism (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/9119.)
Landry, Taylor. Central α-Klotho is a Novel Regulator of Arcuate Neurons and Peripheral Metabolism. Doctoral Dissertation. East Carolina University, April 2021. The Scholarship. http://hdl.handle.net/10342/9119. December 06, 2023.
Landry, Taylor, “Central α-Klotho is a Novel Regulator of Arcuate Neurons and Peripheral Metabolism” (Doctoral Dissertation., East Carolina University, April 2021).
Landry, Taylor. Central α-Klotho is a Novel Regulator of Arcuate Neurons and Peripheral Metabolism [Doctoral Dissertation]. Greenville, NC: East Carolina University; April 2021.
East Carolina University