Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression
Research output: Contribution to journal › Journal article › Research › peer-review
Levels of full-length huntingtin (FL htt) influence organ and body weight, independent of polyglutamine length. The growth hormone-insulin like growth factor-1 (GH-IGF-1) axis is well established as a regulator of organ growth and body weight. In this study, we investigate the involvement of the IGF-1 pathway in mediating the effect of htt on body weight. IGF-1 expression was examined in transgenic mouse lines expressing different levels of FL wild-type (WT) htt (YAC18 mice), FL mutant htt (YAC128 and BACHD mice) and truncated mutant htt (shortstop mice). We demonstrate that htt influences body weight by modulating the IGF-1 pathway. Plasma IGF-1 levels correlate with body weight and htt levels in the transgenic YAC mice expressing human htt. The effect of htt on IGF-1 expression is independent of CAG size. No effect on body weight is observed in transgenic YAC mice expressing a truncated N-terminal htt fragment (shortstop), indicating that FL htt is required for the modulation of IGF-1 expression. Treatment with 17beta-estradiol (17beta-ED) lowers the levels of circulating IGF-1 in mammals. Treatment of YAC128 with 17beta-ED, but not placebo, reduces plasma IGF-1 levels and decreases the body weight of YAC128 animals to WT levels. Furthermore, given the ubiquitous expression of IGF-1 within the central nervous system, we also examined the impact of FL htt levels on IGF-1 expression in different regions of the brain, including the striatum, cerebellum of YAC18, YAC128 and littermate WT mice. We demonstrate that the levels of FL htt influence IGF-1 expression in striatal tissues. Our data identify a novel function for FL htt in influencing IGF-1 expression.
Original language | English |
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Journal | Human Molecular Genetics |
Volume | 19 |
Issue number | 8 |
Pages (from-to) | 1528-38 |
Number of pages | 11 |
ISSN | 0964-6906 |
DOIs | |
Publication status | Published - 15 Apr 2010 |
- Animals, Body Weight, Brain, Disease Models, Animal, Gene Expression, Humans, Huntington Disease, Insulin-Like Growth Factor I, Male, Mice, Mice, Transgenic, Nerve Tissue Proteins, Nuclear Proteins, Signal Transduction
Research areas
ID: 153451393