Abstract
BackgroundSeveral lines of evidence strongly suggest that agouti-related peptide (AGRP) plays a key role in the regulation of metabolic function but ablation of the AGRP gene has no apparent effect on metabolic function. Since specific pharmacological antagonists of AGRP do not presently exist, we assessed if reduction of hypothalamic AGRP mRNA by RNA interference (RNAI) would influence metabolic function, an outcome suggesting that pharmacological antagonists might constitute useful reagents to treat obesity.ResultsThe RNAI protocol specifically reduced hypothalamic expression of AGRP mRNA by 50% and resulted in reduction of AGRP peptide immunoreactivity. Physiologically, the reduction in AGRP levels was associated with increased metabolic rate and reduced body weight without changes in food intake.ConclusionAGRP can function to increase body weight and reduce metabolic rate without influencing food intake. The present study demonstrates that RNAI protocols can be used to assess physiological function of neuronal genes in vivo.
Highlights
Several lines of evidence strongly suggest that agouti-related peptide (AGRP) plays a key role in the regulation of metabolic function but ablation of the AGRP gene has no apparent effect on metabolic function
This result indicates that AGRP normally acts to reduce metabolic rate, consistent with conclusions from indirect evidence based on pair-fed animals treated with AGRP [11]
This protocol has allowed us to assess the physiological function of an endogenous neuronal gene
Summary
Several lines of evidence strongly suggest that agouti-related peptide (AGRP) plays a key role in the regulation of metabolic function but ablation of the AGRP gene has no apparent effect on metabolic function. Agouti-related peptide (AGRP) gene expression is elevated by fasting and in obesity due to leptin insufficiency [1,2], while reversal of obese phenotypes by adrenalectomy reverses the elevation of AGRP mRNA [3]. Injections of synthetic analogs of AGRP, and of AGRP itself, stimulate food intake and body weight [4,5]. Together with the observation that transgenic over-expression of the AGRP gene leads to hyperphagia and obesity [1], these data suggest that antagonism of AGRP may reduce food intake and body weight, potentially serving as a therapy for obesity.
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