Research

Research

Klotho and Phosphate Metabolism

The klotho mouse, the first laboratory animal model for human aging in general that manifests multiple aging phenotypes in a single individual.

FGF23 is a bone-derived hormone that acts on the kidneys to suppress phosphate reabsorption. Klotho is required for FGF23 to bind FGF receptors and activate FGF signaling. This is consistent with the fact that Klotho-deficient mice and FGF23-deficient mice develop hyperphosphatemia.

Interestingly, these mice also develop identical aging-like phentoypes, suggesting that phosphate metabolism may affect aging processes.

The long-term goals of this project are to understand the mechanim by which Klotho and FGF23 regulate phosphate metabolism, to develop therapeutic intervention in hyper- and hypo-phosphatemia, and to understand the the relation between phosphate metabolism and aging.

Beta-Klotho and Energy Metabolism

FGF15 (the mouse ortholog of human FGF19) is secreted from the intestine in response to bile acid released upon feeding. It then acts on the liver to suppress bile acid synthesis.

FGF21 is a liver-derived hormone secreted upon fasting and acts on adipocytes to promote lipolysis. Both FGF15/19 and FGF21 require beta-Klotho to bind FGF receptors and activate FGF signaling.

The long-term goals of this project are to understand the mechanism by which beta-Klotho and these metabolic FGFs regulate bile acid and fatty acid metabolism; to develop novel therapeutic intervention in diabetes, obesity, and hypercholesterolemia; and to explore potential effects of beta-Klotho and these metabolic FGFs on aging processes.