Brown is the new white: consequences of white adipose tissue alterations in Huntington's disease

Abstract: Huntington's disease (HD) is a devastating, inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Peripheral symptoms, such as skeletal muscle wasting, progressive weight loss, altered body composition and endocrine disturbances exist alongside neurodegeneration. Both the mutant gene and protein are expressed in cells and tissues throughout the body.Weight loss precedes clinical symptoms, suggesting a direct effect of mutant huntingtin. Alterations in adipose tissue have been reported prior to weight loss in animal models of HD. White adipose tissue (WAT) affects whole body energy metabolism via its role as an energy source and WAT alterations may influence peripheral features of HD, such as muscle wasting and weight loss. We therefore investigated peripheral tissues, namely WAT, as a potential model to investigate molecular pathways of HD.We show that WAT of the R6/2 mouse model of HD undergoes browning, as indicated by increased expression of the brown adipocyte marker, uncoupling protein 1 (Ucp1), at both mRNA and protein levels. This increase is enhanced by repeated cold exposure and leads to an increase in uncoupled mitochondrial oxygen consumption. We also show reduced lipolytic function in R6/2 WAT and upregulation of brown markers in Q175 WAT (Paper I).Next, we show that subcutaneous WAT of human HD gene carriers is altered, suggesting dysregulated fatty acid metabolism, and highlight a key role for CREB1, a transcription factor involved in white adipocyte browning (Paper II).Following this, we investigated the gastric hormone, ghrelin’s effects on peripheral tissues of HD mice. We found ghrelin to postpone the body weight decrease in HD mice, and trends towards rescuing the dysregulation of key genes involved in fat metabolism (Paper III).Finally, we show subtle alterations in gastric mucosal cells of late stage HD patients, with a reduced expression of gastrin-producing G-cells in antrum biopsies, and an increased expression of pepsinogen-producing chief cells of the fundus (Paper IV).Taken together, the results in this thesis suggest that HD mouse WAT undergoes browning, characterised by increased Ucp1 expression, leading to functional consequences. These changes may contribute to the weight loss and/or metabolic disturbances observed in HD. As the presence of brown-like adipocytes in WAT affects overall energy expenditure, it is highly relevant for further investigation in human HD.