Inhibition of Food Intake by Neuropeptide Y Y5 Receptor Antisense Oligodeoxynucleotides

Abstract

The recently discovered rat neuropeptide Y (NPY) receptor, the Y5 subtype, has been proposed to mediate the NPY-induced feeding response and therefore plays a central role in the regulation of food intake. These conclusions were based on studies with peptidic agonists. We now report studies in which phosphothioate end-protected antisense oligodeoxynucleotides (ODNs) targeted to prepro NPY (prepro NPY antisense ODNs) or to the Y5 receptor (Y5 antisense ODNs) were used to assess the functional importance of this novel receptor subtype in vivo. NPY antisense ODNs given intracerebroventricularly to rats prevented the increase in hypothalamic NPY levels during food deprivation and inhibited fasting-induced food intake. Likewise, repeated intracerebroventricular injections of Y5 antisense ODNs prevented fasting-induced food intake in rats. Moreover, two Y5 antisense ODNs, targeted to different sequences of the receptor, significantly decreased basal food intake and inhibited the increase in food intake after intracerebroventricular injection of NPY. These effects proved to be selective, since the feeding response to galanin was not affected. Analysis of the structure of feeding behavior revealed that prepro NPY and Y5 receptor antisense ODNs reduced food intake by inducing decreases in meal size and meal duration analogous to the orexigenic effects of NPY that are mediated by increases in these parameters. Although changes in Y5 receptor density could not be measured, the results with Y5 antisense ODNs strongly suggest that this receptor subtype mediates the feeding response to exogenous and endogenous NPY. Selective Y5 antagonists may therefore be of therapeutic value for the treatment of obesity and eating disorders.

Insulin Detemir Causes Lesser Weight Gain in Comparison to Insulin Glargine: Role on Hypothalamic NPY and Galanin

“…Intracerebroventricular (ICV) administration of NPY and GAL can induce food intake in satiated rats [14], and NPY and GAL regulate food intake via the subtype receptors neuropeptide Y receptor type 5 (Y5) and galanin receptor 1 (GAL1), respectively. Selective Y5 and GAL1 antagonists may be effective in treatment of obesity and eating disorders [15–17]. This hypothesis alludes to a potential role for Y5 and GAL1 in food and energy regulation.…”

Dopaminergic Agonists Normalize Elevated Hypothalamic Neuropeptide Y and Corticotropin-Releasing Hormone, Body Weight Gain, and Hyperglycemia in ob/ob Mice

“…Moreover, central treatment of normal animals with NPY5 receptor antisense oligodeoxynucleotides reduces feeding and weight gain [44, 45]. Previous studies have established that dopamine D 1 /D 2 agonists synergize to improve the metabolic syndrome in ob/ob mice [7, 8, 9].…”

The role of NPY in metabolic homeostasis: implications for obesity therapy

“…Antisense oligonucleotides to inhibit NPY gene expression are reported to inhibit both normal [81] and fasting-induced food intake [82] whereas no effects were observed by Dryden et al [83]. Paradoxically, an increase in food intake was observed, as well [84].…”

“…Blockade of the Y5 receptor was addressed by antisense studies and ribozyme studies [82,88,89]. Intracerebroventricular injections of Y5 antisense oligonucleotides inhibited NPY-induced as well as basal food intake in rats [82,89].…”