AgRP knockdown blocks long-term appetitive, but not consummatory, feeding behaviors in Siberian hamsters

Arcuate hypothalamus-derived agouti-related protein (AgRP) and neuropeptide Y (NPY) are critical for maintaining energy homeostasis. Fasting markedly upregulates AgRP/NPY expression and circulating ghrelin, and exogenous ghrelin treatment robustly increases acute food foraging and food intake, and chronic food hoarding behaviors in Siberian hamsters. We previously demonstrated that 3rd ventricular AgRP injection robustly stimulates acute and chronic food hoarding, largely independent of food foraging and intake. By contrast, 3rd ventricular NPY injection increases food foraging, food intake, and food hoarding, but this effect is transient and gone by 24 h post-injection. Because of this discrepancy in AgRP/NPY-induced ingestive behaviors, we tested whether selective knockdown of AgRP blocks fasting and ghrelin-induced increases in food hoarding. AgRP gene knockdown by a novel DICER small interfering RNA (AgRP-DsiRNA) blocked food-deprivation induced increases in AgRP expression, but had no effect on NPY expression. AgRP-DsiRNA attenuated acute (1 day), and significantly decreased chronic (4-6 days), food deprivation-induced increases in food hoarding. In addition, AgRP-DsiRNA treatment blocked exogenous ghrelin-induced increases in food hoarding through day 3, but had no effect on basal food foraging, food intake, or food hoarding prior to ghrelin treatment. Lastly, chronic AgRP knockdown had no effect on body mass, fat mass, or lean mass in either food deprived or ad libitum fed hamsters. These data collectively suggest that the prolonged increase in food hoarding behavior following energetic challenges, and food deprivation especially, is primarily regulated by downstream AgRP signaling.