Centrally circulating α-klotho inversely correlates with human obesity and modulates arcuate cell populations in mice

Taylor Landry; Peixin Li; Daniel Shookster; Zhiying Jiang; Hongli Li; Brenton Thomas Laing; Wyatt Bunner; Theodore Langton; Qingchun Tong; Hu Huang

Molecular Metabolism (Feb 2021)

Centrally circulating α-klotho inversely correlates with human obesity and modulates arcuate cell populations in mice

Taylor Landry,
Peixin Li,
Daniel Shookster,
Zhiying Jiang,
Hongli Li,
Brenton Thomas Laing,
Wyatt Bunner,
Theodore Langton,
Qingchun Tong,
Hu Huang

Affiliations

Taylor Landry: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA; Department of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, College of Human Performance and Health, East Carolina University, Greenville, NC, USA
Peixin Li: Department of Comprehensive Surgery, Medical and Health Center, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China
Daniel Shookster: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA; Department of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, College of Human Performance and Health, East Carolina University, Greenville, NC, USA
Zhiying Jiang: Brown Foundation Institute of Molecular Medicine of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Hongli Li: Brown Foundation Institute of Molecular Medicine of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Brenton Thomas Laing: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA; Department of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, College of Human Performance and Health, East Carolina University, Greenville, NC, USA
Wyatt Bunner: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA; Department of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, College of Human Performance and Health, East Carolina University, Greenville, NC, USA
Theodore Langton: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA; Department of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, College of Human Performance and Health, East Carolina University, Greenville, NC, USA
Qingchun Tong: Brown Foundation Institute of Molecular Medicine of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Hu Huang: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA; Department of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, College of Human Performance and Health, East Carolina University, Greenville, NC, USA; Department of Physiology, East Carolina University, Greenville, NC, USA; Corresponding author. Hu Huang, Department of Kinesiology and Physiology, East Carolina Diabetes and Obesity Institute, East Carolina University, 115 Heart Drive, Greenville, NC, 27834, USA. Tel.: +252 737 2879.

Journal volume & issue: Vol. 44
p. 101136

Abstract

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Objective: Our laboratory recently identified the centrally circulating α-klotho protein as a novel hypothalamic regulator of food intake and glucose metabolism in mice. The current study aimed to investigate novel molecular effectors of central α-klotho in the arcuate nucleus of the hypothalamus (ARC), while further deciphering its role regulating energy balance in both humans and mice. Methods: Cerebrospinal fluid (CSF) was collected from 22 adults undergoing lower limb orthopedic surgeries, and correlations between body weight and α-klotho were determined using an α-klotho enzyme-linked immunosorbent assay (ELISA) kit. To investigate the effects of α-klotho on energy expenditure (EE), 2-day intracerebroventricular (ICV) treatment was performed in diet-induced obesity (DIO) mice housed in TSE Phenomaster indirect calorimetry metabolic cages. Immunohistochemical staining for cFOS and patch clamp electrophysiology were used to determine the effects of central α-klotho on proopiomelanocortin (POMC) and tyrosine hydroxylase (TH) neurons. Additional stainings were performed to determine novel roles for central α-klotho to regulate non-neuronal cell populations in the ARC. Lastly, ICV pretreatment with fibroblast growth factor receptor (FGFR) or PI3kinase inhibitors was performed to determine the intracellular signaling involved in α-klotho-mediated regulation of ARC nuclei. Results: Obese/overweight human subjects had significantly lower CSF α-klotho concentrations compared to lean counterparts (1,044 ± 251 vs. 1616 ± 218 pmol/L, respectively). Additionally, 2 days of ICV α-klotho treatment increased EE in DIO mice. α-Klotho had no effects on TH neuron activity but elicited varied responses in POMC neurons, with 44% experiencing excitatory and 56% experiencing inhibitory effects. Inhibitor experiments identified an α-klotho→FGFR→PI3kinase signaling mechanism in the regulation of ARC POMC and NPY/AgRP neurons. Acute ICV α-klotho treatment also increased phosphorylated ERK in ARC astrocytes via FGFR signaling. Conclusion: Our human CSF data provide the first evidence that impaired central α-klotho function may be involved in the pathophysiology of obesity. Furthermore, results in mouse models identify ARC POMC neurons and astrocytes as novel molecular effectors of central α-klotho. Overall, the current study highlights prominent roles of α-klotho→FGFR→PI3kinase signaling in the homeostatic regulation of ARC neurons and whole-body energy balance.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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