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The role of Klotho in energy metabolism

Nature Reviews Endocrinology volume 8, pages 579–587 (2012)Cite this article

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Abstract

A disproportionate expansion of white adipose tissue and abnormal recruitment of adipogenic precursor cells can not only lead to obesity but also impair glucose metabolism, which are both common causes of insulin resistance and diabetes mellitus. The development of novel and effective therapeutic strategies to slow the progression of obesity, diabetes mellitus and their associated complications will require improved understanding of adipogenesis and glucose metabolism. Klotho might have a role in adipocyte maturation and systemic glucose metabolism. Klotho increases adipocyte differentiation in vitro, and mice that lack Klotho activity are lean owing to reduced white adipose tissue accumulation; moreover, mice that lack the Kl gene (which encodes Klotho) are resistant to obesity induced by a high-fat diet. Knockout of Kl in leptin-deficient Lepob/ob mice reduces obesity and increases insulin sensitivity, which lowers blood glucose levels. Energy metabolism might also be influenced by Klotho. However, further studies are needed to explore the possibility that Klotho could be a novel therapeutic target to reduce obesity and related complications, and to determine whether and how Klotho might influence the regulation and function of a related protein, β-Klotho, which is also involved in energy metabolism.

Key Points

  • Klotho exists in membrane-bound and secreted forms; the secreted form is generated both by alternative splicing and by shedding of the extracellular domain of the transmembrane form

  • Klotho increases organ-specific FGF-23 function in the systemic regulation of phosphate metabolism in the kidney

  • Klotho might also have a role in energy metabolism

  • Reducing or eliminating Klotho activity in mice results in reduced white adipose tissue accumulation

  • Kl-mutant mice (both Klkl/kl and Kl−/−) are hypoglycaemic (owing to increased insulin sensitivity) and resistant to obesity induced by a high-fat diet

  • Reducing or eliminating Klotho activity from Kl−/−Lepob/ob mice results in mice with decreased obesity and increased insulin sensitivity

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Figure 1: Schematic diagram of the Klotho protein structure.
Figure 2: Potential influence of Klotho on adipocyte development.
Figure 3: Physiological effects of Klotho inactivation.
Figure 4: Effects of Klotho on liver structure.

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Acknowledgements

M. S. Razzaque thanks several members of his research group at the Harvard School of Dental Medicine for technical assistance: Mutsuko Ohnishi, Junko Akiyoshi, Satoko Osuka, Yongguen Hong, Khadijah Turkistani, Ismail Eddafali and Basel Karzoun. Thanks also to Syed Rafi for critically reading the manuscript. M. S. Razzaque acknowledges grant R01-DK077276 from the National Institute of Diabetes and Digestive and Kidney Diseases and institutional support from the Harvard School of Dental Medicine.

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    M. Shawkat Razzaque

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Razzaque, M. The role of Klotho in energy metabolism. Nat Rev Endocrinol 8, 579–587 (2012). https://doi.org/10.1038/nrendo.2012.75

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