Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression

TY - JOUR

T1 - Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression

AU - Pouladi, Mahmoud A

AU - Xie, Yuanyun

AU - Skotte, Niels Henning

AU - Ehrnhoefer, Dagmar E

AU - Graham, Rona K

AU - Kim, Jeong Eun

AU - Bissada, Nagat

AU - Yang, X William

AU - Paganetti, Paolo

AU - Friedlander, Robert M

AU - Leavitt, Blair R

AU - Hayden, Michael R

PY - 2010/1/22

Y1 - 2010/1/22

N2 - 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 17β-estradiol (17β-ED) lowers the levels of circulating IGF-1 in mammals. Treatment of YAC128 with 17β-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.

AB - 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 17β-estradiol (17β-ED) lowers the levels of circulating IGF-1 in mammals. Treatment of YAC128 with 17β-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.

KW - Animals

KW - Body Weight

KW - Brain

KW - Disease Models, Animal

KW - Gene Expression

KW - Humans

KW - Huntington Disease

KW - Insulin-Like Growth Factor I

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Nerve Tissue Proteins

KW - Nuclear Proteins

KW - Signal Transduction

U2 - 10.1093/hmg/ddq026

DO - 10.1093/hmg/ddq026

M3 - Journal article

C2 - 20097678

SN - 0964-6906

VL - 19

SP - 1528

EP - 1538

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 8

ER -