Peripheral reduction of FGFR4 with antisense oligonucleotides increases metabolic rate and lowers adiposity in diet-induced obese mice.
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.
Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., Carlsbad, California, USA. xyu@isisph.com
Xing Xian
XX
Yu
Lynnetta M
LM
Watts
Vara Prasad
VP
Manchem
Kaushik
K
Chakravarty
Brett P
BP
Monia
Michael L
ML
McCaleb
Sanjay
S
Bhanot
D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects*; D001647:Bile Acids and Salts / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D031204:Caloric Restriction; D004032:Diet; D004359:Drug Therapy, Combination; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000235:genetics / Q000473:pathology; D005247:Feeding Behavior / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant
D001647:Bile Acids and Salts; D005227:Fatty Acids; D007328:Insulin; D016376:Oligonucleotides, Antisense; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; D051499:Receptor, Fibroblast Growth Factor, Type 4; D000077285:Rimonabant