Body weight is modulated by levels of full-length huntingtin

Huntington disease is an adult-onset neurodegenerative disorder that is caused by the expansion of a polyglutamine tract within the Huntingtin (htt) protein. Wild-type htt has been shown to be involved in transcription, transport and cell survival. Here, we demonstrate that increased expression of full-length wild-type htt in mice is associated with a dose-dependent increase in body weight which results from an increase in both total fat mass and fat-free mass. Conversely, we show that a reduction in the levels of wild-type htt is associated with decreased body weight. Examination of individual organ weights revealed that the weight of the heart, liver, kidneys, lungs and spleen increased with the over-expression of wild-type htt, whereas the brain and testis were unaltered. On the basis of these initial findings, we examined mice that over-express full-length mutant htt to determine the effect of polyglutamine expansion on this novel function of wild-type htt. We found that over-expression of full-length mutant htt, but not an N-terminal fragment of mutant htt, also increased body weight and organ weight, except in the brain and testis where mutant htt appears to be toxic. In these mice, the majority of weight gain could be accounted for by increases in total fat mass. Further investigation of the weight gain phenotype revealed that the increases in weight were not accounted for by increased food consumption relative to body weight. Overall, we demonstrate that increased levels of both wild-type and mutant full-length htt are associated with increased body weight.