Analysis of White Adipose Tissue Gene Expression Reveals CREB1 Pathway Altered in Huntington’s Disease

Abstract

BACKGROUND: In addition to classical neurological symptoms, Huntington´s disease (HD) is

SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease

“…In contrast to SIRT1‐overexpressing mice , we detected a reduction rather than an increase in OX2R in the LHA and the VMH in HD, but this could be due to the reduction in NKX2‐1 in the VMH in HD, as Nkx‐2.1 is a critical transcription factor for the SIRT1‐mediated upregulation of OX2R . Furthermore, SIRT1 regulates CREB‐1‐mediated transcription , which has recently been shown to be increased in adipose tissue from HD patients . Here, we show increased levels of CREB‐1 also in the VMH in HD.…”

White Adipose Tissue Browning in the R6/2 Mouse Model of Huntington’s Disease

“…Impaired gene expression and lipid accumulation was demonstrated in adipocytes expressing mutant Htt, replicating findings seen in mouse models of disease [ 15 ]. Supportive of this, we recently showed an altered gene expression profile in human HD subcutaneous WAT [ 16 ].…”

“…Potentially CREB1 plays a role in the here observed inguinal WAT browning, as CREB activation leads to downstream activation of UCP1 [ 43 ]. Interestingly, we recently showed CREB1 to be a highly significant transcription factor altered in human premanifest HD subcutaneous adipose tissue [ 16 ].…”

“…Reduced miR-27 was shown to directly target key components of brown adipose transcription, such as Pparα and Creb1 [ 46 ]. We have in this study demonstrated upregulation of Pparα and have previously highlighted the CREB1 pathway to be altered in premanifest human HD adipose tissue [ 16 ]. Possibly, since miR-27 is downregulated following prolonged cold exposure, and HD mice show progressive hypothermia [ 38 ], altered levels of miR-27 in HD mice could be involved in browning of their WAT.…”

Effects of mutant huntingtin inactivation on Huntington disease‐related behaviours in the BACHD mouse model

“…We first aimed to remove mutant HTT early during development in a widespread fashion within the CNS by crossing BACHD mice with Nestin-Cre mice, with the hypothesis that these animals would show significant improvements. The aim was to investigate whether their phenotype would completely normalise given that peripheral pathology has also been suggested to play a role in HD [22][23][24][25][26]. We then refined the design and limited the inactivation of mutant HTT selectively to dopamine D2 receptor-expressing projection neurons of the indirect striatal pathway.…”