Fibroblast growth factor binding protein 3 binds to FGF19, FGF21, and FGF23; interaction between BP3 and FGF19 stabilizes ligand/receptor complex and enhances downstream signalling. No impacts on embryo viability or overall survival were observed with ablation of endogenous BP3, but it was associated with abnormal GTT and reduced levels of triglycerides suggesting increased risk for metabolic disease. FGF19 & 21 are insulin independent carbohydrate and lipid metabolism modulators.; FGF knockout mice develop glucose intolerance and insulin resistance, and BP3-/- mice show similar trends of hyperinsulinemia and upregulation of hepatic gluconeogenic genes.
BP3 treatment in obese mice was observed to reduce body weight, hyperglycemia, fat mass, and steatosis most likely due to increase of serum adiponectin and reduction of circulating NEFA and intrahepatic lipids without inducing hepatocellular mitogenic responses, resulting in suppression of rate limiting genes regulating metabolic pathways in the liver and WAT that control synthesis of lipid and glucose.
Obesity is a growing global epidemic affecting more than 650 million people. Metabolic syndrome drives obesity which encompasses insulin resistance, hypertension, glucose intolerance, and dyslipidemia. Interaction between BP3 and endocrine FGFs has been demonstrated to hold significant promise in being used as an approach to treatment of metabolic disease and many of the associated symptoms using FGF19 and FGF21 as potential therapeutic agents.
Mitogenic effects of FGF19 and induction of hepatocellular carcinoma in FGF19 transgenic mice and mice treated with recombinant protein raise concerns; however FGF21 lacks proliferative activity in both in vivo and in vitro studies. Endocrinization of FGF21 has been reported to exhibit anti-diabetogenic and non-mitogenic effects in mice. When chronically delivered to ob/ob mice BPS fails to induce hepatocellular mitogenic responses matching with lack of mitogenic effects reported for FGF19 and FGF21.
Forcing expression of the natural protein fibroblast growth factor binding protein 3 led to weight loss and reductions in fat mass, hyperglycemia, blood glucose levels, NEFAs, and reversal of fatty liver disease without any apparent side effects; chronic expression of BP3 led to inhibition of gluconeogenic and pyogenic gene expression. 8 treatments with BP3 over 18 days was observed to be enough to reduce the fat in obese mice by over one third, according to the researchers.
Scientist from Georgetown Lombardi Comprehensive Cancer Center, New York University School of Medicine, and the Karolinska Institutet concluded that the reduction of fat mass, fatty liver disease, and hyperglycemia observed in mice along with the lack of mitogenic responses make a compelling case for the attractiveness of BP3 as a candidate for the treatment of metabolic disease.
