Klotho Proteins Eyed for Future Therapies for Diabetes, Obesity, and Kidney Disease

Researchers working with mice have found that the protein beta-Klotho is a required co-factor for fibroblast growth factor 21 (FGF21), a blood hormone that lowers blood glucose levels in diabetic and obese mice.
Beta-Klotho is a single-pass transmembrane protein whose expression is induced during differentiation from pre-adipocytes to adipocytes. Previous studies had shown that mutant mice lacking the Klotho gene appeared normal until about a month of age, and then began showing signs of age, such as skin atrophy, osteoporosis, arteriosclerosis, and emphysema. The animals died prematurely after about two months.
In the current study, investigators at the University of Texas Southwestern Medical Center (Dallas, USA) studied the interaction between beta-Klotho and FGF21. They reported in the April 23, 2007, online edition of the Proceedings of the [U.S.] National Academy of Sciences that beta- Klotho physically interacted with FGF receptors 1c and 4, thereby increasing the ability of these FGF receptors to bind FGF21 and to activate the MAP (mitogen-activated protein) kinase cascade. Knockdown of beta-Klotho expression by siRNA in adipocytes diminished glucose uptake induced by FGF21. Treatment of mice with FGF21induced MAP kinase phosphorylation in white adipose tissue and not in tissues without beta-Klotho expression.
"The ability to stimulate glucose processing is key to proper metabolism, so this Klotho protein, known as beta-Klotho, is a novel target for developing drugs that can enhance or block the metabolic activity of this hormone, which has been shown to be able to lower blood glucose in mice,” said senior author Dr. Makoto Kuro-o, associate professor of pathology at the University of Texas Southwestern Medical Center. "Klotho's role in regulating the metabolic activity of the growth hormones is essential. Klotho's actions determine the metabolic activity of these fibroblast growth factors, making them targets for drugs that either block or enhance the metabolic activity. Klotho proteins thus will be important players in future therapies for human conditions such as diabetes, obesity, and kidney disease.”


Related Links:
University of Texas Southwestern Medical Center