A protein that has been under study for its role in cancer could represent a surprising new treatment for metabolic syndrome and associated disorders, such as type 2 diabetes and fatty liver disease. Studies in an obese mouse model by scientists at the Georgetown Lombardi Comprehensive Cancer Center showed that forcing expression of the natural protein fibroblast growth factor binding protein 3 (FGFBP3, or BP3) led to dramatic weight loss and “striking” reductions in fat mass, hyperglycemia, and reversal of fatty liver disease, with no apparent side effects.
“We found that eight BP3 treatments over 18 days was enough to reduce the fat in obese mice by over a third,” says the study’s senior investigator Anton Wellstein, M.D., Ph.D., a professor of oncology and pharmacology at Georgetown University. “… BP3 exerts a striking contribution to metabolic control.”
The Georgetown University researchers suggest that feasibly, clinical trials of recombinant human BP3 could start after another round of preclinical studies. The team, together with colleagues at New York University School of Medicine, and the Karolinska Institutet in Sweden, reported their findings in Scientific Reports, in a paper titled, “Fibroblast growth factor binding protein 3 (FGFBP3) impacts carbohydrate and lipid metabolism.”
BP3 is one of a family of FGF proteins, which are found in many organisms, and are involved in a wide range of biological processes, such as regulating cell growth and wound healing. Some FGF also have endocrine functions. BP1, BP2, and BP3, for example, are “chaperone” proteins that bind and mobilize other FGFs.
Dr. Wellstein’s team first showed that knockout mice deficient in BP3 demonstrated altered lipid metabolism pathways, and reduced serum and liver triglycerides. There were also “trends of hyperinsulinemia and upregulation of key hepatic gluconeogenic genes that can result in an increase of fasting blood glucose and abnormal insulin resistance,” the authors note. The combined results of tests in the BP3 knockout animals indicated that endogenous BP3 is involved in controlling glucose and lipid metabolic pathways.
The researchers then forced BP3 expression in a leptin-deficient mouse model of obesity (ob/ob mice) that exhibits metabolic disease. Administering a murine BP3 (mBP3)-expressing vector to these animals over 18 days led to significant weight loss, reduced hyperglycemia, reduced fat mass, and reduced fatty liver. “The mBP3 expressing ob/ob mice exhibited significantly lower body weight and weight gain relative to control littermates, paralleled by a reduction of visceral white adipose tissues (WAT) and interscapular brown adipose tissues (iBAT),” they write. “Administration of mBP3 significantly reduced hyperglycemia.”
Blood glucose levels were also reduced in the animals expressing exogenous mPB3. Significantly, exogenous mBP3 expression was associated with a significant decrease of serum non-esterifed fatty acids (NEFA), and increased levels of FGF21 and adiponectin, whereas levels of triclycerides, cholesterol, phospholipids, and glucagon weren’t changed. “Strikingly, commensurate with the reduced NEFA and increased FGF21 and adiponectin levels in the serum, livers of mBP3 expressing ob/ob mice displayed a significant reduction of steatosis and were almost indistinguishable microscopically from healthy livers,” the authors stated. Chronic expression of BP3 in the ob/ob obese mice also led to inhibition of gluconeogenic and pyogenic gene expression. Analyses indicated that chronic BP3 treatment acts to suppress rate-limiting genes that are involved in regulating metabolic pathways in the liver and WAT that control the synthesis of lipids and glucose.
The researchers next tested the effects of exogenous mBP3 expression in a diet-induced obese (DIO) mouse model that closely mimics the cause of human obesity. The results in this model were similar to those in the ob/ob mouse, demonstrating that chronic BPE expression was associated with a “significant anti-obesity and antidiabetogenic effect.” In these animals circulating insulin, FGF21, adiponectin, and NEFA remained unchanged, although the mBP3-treated mice demonstrated lower blood glucose, and modulation of genes involved in lipogenesis and the synthesis of triglycerides. Further tests indicated that BP3 binds to the FGF proteins 19, 21, and 23, which are involved in controlling metabolism. FGF19 and FGF21 signaling regulates the storage and use of carbohydrates and fats, whereas FGF23 controls phosphate metabolism.
“We found that BP3 exerts a striking contribution to metabolic control,” Dr. Wellstein says. “When you have more BP3 chaperone available, FGF19 and FGF21 effect is increased through the increase of their signaling. That makes BP3 a strong driver of carbohydrate and lipid metabolism. It’s like having a lot more taxis available in New York City to pick up all the people who need a ride. With metabolism revved up, sugar in the blood, and fat processed in the liver are used for energy and is not stored. And warehouses of fat are tapped as well. For example, the job of FGF21 is to control break down of fat, whether it is stored or just eaten.”
Obesity affects more than 650 million people worldwide, and is the major driver for metabolic syndrome, which encompasses insulin resistance, glucose intolerance, hypertension, and dyslipidemia, the researchers note. “Our studies show that the interaction between BP3 and endocrine FGFs could be leveraged for a novel approach to the treatment of metabolic disease and the associated symptoms … the striking reduction of fat mass and fatty liver disease, as well as hyperglycemia and the lack of a mitogenic response, make BP3 an attractive candidate for the treatment of metabolic disease.”