Endocrine Abstracts

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder caused by a lack of paternal gene expression from 15q11–q13 and is characterised by failure to thrive in infancy, followed by hyperphagia due to abnormal satiety responses and increased motivation by food. We investigated growth and metabolism a mouse model in which the imprinting centre (IC) of the homologous PWS interval has been deleted (PWS-IC mice). Growth retardation only emerged post-natally, with adult PWS-IC mice weighing 40% less than controls, and tibial length reduced by 7%. In contrast, liver and brain weights were normal. Analysis of daily food intake over a 3-week period indicated that male PWS-IC mice showed proportionate hyperphagia, which became more pronounced after overnight fasting. In addition, PWS-IC mice displayed ‘food hoarding’ behaviour reminiscent of that seen in PWS individuals. This hyperphagia may result from the 3-fold elevation in circulating ghrelin levels. Despite hyperphagia and hyperghrelinaemia, PWS-IC mice were remarkably lean, with proportionate retroperitoneal, epididymal and inguinal white adipose tissue weights reduced by 82, 84 and 67% respectively; and proportionate interscapular brown adipose tissue weight reduced by 48%, with additional reductions in marrow adiposity and hepatic lipid content. This lack of body fat may explain the 1.3 °C reduction in surface body temperature in PWS-IC mice, consistent with reduced heat retention. In addition, despite proportionate over-eating, and in contrast to wild-type controls, PWS-IC mice did not gain fat mass, even when fed on a high-fat diet. Our data show that the neuroendocrine regulation of metabolism is severely compromised in PWS-IC mice and that loss of paternal gene expression from the PWS-cluster gives rise to hyperphagia, and hyperghrelinaemia, as seen in the human condition. However, unlike individuals with PWS, the PWS-IC mice do not become obese. Whether this difference is due to the elevated energy demands of increased heat loss remains unclear.