Obesity and antisense oligonucleotide against fibroblast growth factor
One condition in which antisense oligonucleotide (ASO) based therapy is being considered is obesity, as mentioned in the original article in this thread, although the situation is complicated as the molecular mechanisms underlying obesity are complex. Drugs currently available for obesity tend to be based on appetite suppression and many have failed or been withdrawn due to adverse indications. One recent article has addressed the possibility of developing a novel ASO-based strategy against fibroblast growth factor signalling, which would address a need to identify therapeutic agents which could act on peripheral tissues to increase energy expenditure.
ASO against fibroblast growth factor receptor 4 (FGFR4) was used to treat a diet-induced obese (DIO) mouse model. Liver FGFR4 expression was reduced leading to decreased body weight and adiposity both under free-feeding and calorific restriction conditions. The FGFR4 ASO exerted an additive reduction of body weight and adiposity when administered in combination with rimonabant, an anti-obesity agent which blocks endogenous cannabinoid binding to neuronal CB1 receptors. FGFR4 ASO increased basal metabolic rate during free-feeding conditions and prevented reductions of metabolic rate induced by caloric restriction, which can work against weight loss in response to dietary modification. It also increased fatty acid oxidation and decreased lipogenesis. Reduced FGFR4 was determined to induce plasma FGF15 expression which was proposed to mediate the anti-obesity effects of the FGFR4 ASO. Other indicators including plasma glycemia, whole body insulin sensitivity, plasma lipid levels and liver steatosis were all improved by the FGFR4 ASO treatment. Thus FGFR4 ASO treatment is indicated as a potentially novel addition to the armoury of anti-obesity treatment, in combination with either appetite suppression or diet restriction. Further work is on-going.
Source
YU, X.X. et al., 2013. Peripheral reduction of FGFR4 with antisense oligonucleotides increases metabolic rate and lowers adiposity in diet-induced obese mice. Plos One, 8(7), pp. e66923-e66923
One condition in which antisense oligonucleotide (ASO) based therapy is being considered is obesity, as mentioned in the original article in this thread, although the situation is complicated as the molecular mechanisms underlying obesity are complex. Drugs currently available for obesity tend to be based on appetite suppression and many have failed or been withdrawn due to adverse indications. One recent article has addressed the possibility of developing a novel ASO-based strategy against fibroblast growth factor signalling, which would address a need to identify therapeutic agents which could act on peripheral tissues to increase energy expenditure.
ASO against fibroblast growth factor receptor 4 (FGFR4) was used to treat a diet-induced obese (DIO) mouse model. Liver FGFR4 expression was reduced leading to decreased body weight and adiposity both under free-feeding and calorific restriction conditions. The FGFR4 ASO exerted an additive reduction of body weight and adiposity when administered in combination with rimonabant, an anti-obesity agent which blocks endogenous cannabinoid binding to neuronal CB1 receptors. FGFR4 ASO increased basal metabolic rate during free-feeding conditions and prevented reductions of metabolic rate induced by caloric restriction, which can work against weight loss in response to dietary modification. It also increased fatty acid oxidation and decreased lipogenesis. Reduced FGFR4 was determined to induce plasma FGF15 expression which was proposed to mediate the anti-obesity effects of the FGFR4 ASO. Other indicators including plasma glycemia, whole body insulin sensitivity, plasma lipid levels and liver steatosis were all improved by the FGFR4 ASO treatment. Thus FGFR4 ASO treatment is indicated as a potentially novel addition to the armoury of anti-obesity treatment, in combination with either appetite suppression or diet restriction. Further work is on-going.
Source
YU, X.X. et al., 2013. Peripheral reduction of FGFR4 with antisense oligonucleotides increases metabolic rate and lowers adiposity in diet-induced obese mice. Plos One, 8(7), pp. e66923-e66923
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