Calorie seeking, but not hedonic response, contributes to hyperphagia in a mouse model for Prader–Willi syndrome

Abstract

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by deletion or inactivation of paternally expressed imprinted genes on human chromosome 15q11-q13, the most recognised feature of which is hyperphagia. This is thought to arise as a consequence of abnormalities in both the physiological drive for food and the rewarding properties of food. Although a number of mouse models for PWS exist, the underlying variables dictating maladaptive feeding remain unknown. Here, feeding behaviour in a mouse model in which the imprinting centre (IC) of the syntenic PWS interval has been deleted (PWS ICdel mice) is characterised. It is demonstrated that PWS ICdel mice show hyperghrelinaemia and increased consumption of food both following overnight fasting and when made more palatable with sucrose. However, hyperphagia in PWS ICdel mice was not accompanied by any changes in reactivity to the hedonic properties of palatable food (sucrose or saccharin), as measured by lick-cluster size. Nevertheless, overall consumption by PWS ICdel mice for non-caloric saccharin in the licking test was significantly reduced. Combined with converging findings from a continuous reinforcement schedule, these data indicate that PWS ICdel mice show a marked heightened sensitivity to the calorific value of food. Overall, these data indicate that any impact of the rewarding properties of food on the hyperphagia seen in PWS ICdel mice is driven primarily by calorie content and is unlikely to involve hedonic processes. This has important implications for understanding the neural systems underlying the feeding phenotype of PWS and the contribution of imprinted genes to abnormal feeding behaviour more generally.

Paradoxical leanness in the imprinting-centre deletion mouse model for Prader–Willi syndrome

“…PWS-IC del mice display marked abdominal leanness (1; current study) despite a preponderance of obesogenic signals (underactive GH axis (current study), proportionate hyperphagia (with pronounced food hoarding) (current study; Davies et al . 2015), hyperghrelinaemia (current study; Davies et al . 2015) and reduced physical activity (Doe et al .…”

“…2001, Lawrence et al . 2002, Keen-Rhinehart & Bartness 2005), the elevation in food intake and diet hoarding may result from the sustained hyperghrelinaemia seen in this model (Davies et al . 2015) and in humans with PWS (Cummings et al .…”

“…As PWS-IC del animals on a pure C57BL/6J background suffer severe postnatal lethality, we crossed IC del -positive males with CD1 females and selectively culled WT littermates (identified on the basis of their increased size 48 h after birth) leaving only 1 or 2 WT pups per litter, as previously described (Chamberlain et al . 2004, Davies et al . 2015).…”

Working-for-Food Behaviors: A Preclinical Study in Prader-Willi Mutant Mice

“…PWS is characterized by developmental delays, feeding problems, hyperphagia, behavioral disorders, and sleep-wake disturbances (Peters 2014; Tucci 2016). In preclinical investigations, mouse models with different deletions at the orthologous locus on mouse chromosome 7C have shown the main features of the human syndrome, such as growth retardation (Rozhdestvensky et al 2016), hyperphagia (Davies et al 2015), and sleep abnormalities (Lassi et al 2016). Small nucleolar RNA 116 (Snord116, also called MBII-85), a paternally expressed noncoding gene that modifies other small nuclear RNAs (snoRNAs), is considered one of the key players in PWS (Peters 2014).…”

“…However, food intake is also structured by fundamental cognitive/behavioral processes, such as clock-dependent mechanisms (Mistlberger 2011). By studying the PWSICdel mouse line, Davies et al (2015) reported that hyperphagia in these PWS mutant mice is due to a constant need for calories, and that the related behavior is not due to an increased hedonic value of food intake. In particular, the PWSICdel mice presented similar behavioral licking responses compared to control mice toward palatable food.…”