Obesity is a primary risk factor for multiple metabolic disorders. Many drugs for the treatment of
obesity, which mainly act through CNS as
appetite suppressants, have failed during development or been removed from the market due to unacceptable adverse effects. Thus, there are very few efficacious drugs available and remains a great unmet medical need for
anti-obesity drugs that increase energy expenditure by acting on peripheral tissues without severe side effects. Here, we report a novel approach involving antisense inhibition of
fibroblast growth factor receptor 4 (FGFR4) in peripheral tissues. Treatment of diet-induce obese (DIO) mice with FGFR4
antisense oligonucleotides (ASO) specifically reduced liver FGFR4 expression that not only resulted in decrease in
body weight (BW) and adiposity in free-feeding conditions, but also lowered BW and adiposity under
caloric restriction. In addition, combination treatment with FGFR4 ASO and
rimonabant showed additive reduction in BW and adiposity. FGFR4 ASO treatment increased basal metabolic rate during free-feeding conditions and, more importantly, prevented adaptive decreases of metabolic rate induced by
caloric restriction. The treatment increased
fatty acid oxidation while decreased lipogenesis in both liver and fat. Mechanistic studies indicated that anti-
obesity effect of FGFR4 ASO was mediated at least in part through an induction of plasma FGF15 level resulted from reduction of hepatic FGFR4 expression. The anti-
obesity effect was accompanied by improvement in plasma glycemia, whole body
insulin sensitivity, plasma
lipid levels and
liver steatosis. Therefore, FGFR4 could be a potential novel target and antisense reduction of hepatic FGFR4 expression could be an efficacious
therapy as an adjunct to diet restriction or to an
appetite suppressant for the treatment of
obesity and related metabolic disorders.