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Disruption of klotho Gene Causes an Abnormal Energy Homeostasis in Mice

https://doi.org/10.1006/bbrc.2000.3864Get rights and content

Abstract

klotho mice, which genetically lack klotho gene expression, are characterized with various systemic phenotypes resembling human aging, and also with growth retardation. Here we show that klotho mice have a barely detectable amount of the white adipose tissue but their brown adipose tissue (BAT) is comparably preserved. Glucose tolerance and insulin sensitivity in klotho mice are increased compared to those in wild-type mice as revealed by intraperitoneal glucose and insulin tolerance tests. Uncoupling protein-1 gene expression of BAT and body temperature in klotho mice are lower than those in wild-type mice, suggesting that klotho mice have less energy expenditure than wild-type mice. Histological examination suggests that klotho mice possess less energy storage than wild-type mice with respect to glycogen in the liver and lipid in BAT. All these changes of parameters for energy homeostasis in klotho mice are very similar to those reported under food-restricted conditions. However, the amount of food intake is not different between klotho and wild-type mice when normalized for body weight. The present study elucidates the importance of klotho gene expression for the maintenance of normal energy homeostasis.

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    Approximately 24 years ago the α-klotho gene was discovered when a study revealed mutation of a single gene within Chromosome 13 results in a rapid, premature aging phenotype [1]. α-Klotho overexpression has since been researched for its ability to prolong the lifespan 20–30% in rodents [2], as well as its therapeutic potential in various neurological [3–7], metabolic [8–15], cardiorespiratory [16–25], osmolar, [26–29] and cancer-related diseases/disorders [30]. More recently, in an attempt to combat the unrelenting obesity and diabetes epidemics, studies have begun to elucidate the specific roles of α-klotho in the regulation of energy and substrate metabolism.

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  • 1,25-Dihydroxyvitamin D and Klotho: A Tale of Two Renal Hormones Coming of Age

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    Klotho knockout mice exhibit less energy storage and expenditure compared to wild-type mice (Mori et al., 2000), as well as attenuated insulin production and enhanced insulin sensitivity (Utsugi et al., 2000; Wolf et al., 2008). Apparently, klotho suppresses the downstream signaling pathways of both the insulin receptor (mediated by insulin receptor substrate (IRS)), and the insulin-like growth factor 1 receptor (IGF-1R), without directly associating with either of these receptors (Mori et al., 2000; Yamamoto et al., 2005). Instead, klotho likely affects IRS and IGF-1R activity via modulation of the forkhead box proteins (FOXOs).

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Abbreviations used: BAT, brown adipose tissue; WAT, white adipose tissue; PEPCK, phosphoenolpyruvate carboxykinase; UCP-1, uncoupling protein-1; BW, body weight.

1

To whom correspondence should be addressed at Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Fax: +81-75-771 9452. E-mail: [email protected].

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