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Leptin deficiency reverses high metabolic state and weight loss without affecting central pathology in the R6/2 mouse model of Huntington's disease

Sjögren, Marie LU ; Soylu-Kucharz, Rana LU ; Dandunna, Unali LU ; Stan, Tiberiu Loredan LU ; Cavalera, Michele LU ; Sandelius, Åsa; Zetterberg, Henrik LU and Björkqvist, Maria LU (2019) In Neurobiology of Disease 132.
Abstract

Body weight has been shown to be a predictor of clinical progression in Huntington's disease (HD). Alongside widespread neuronal pathology, both HD patients and the R6/2 mouse model of HD exhibit weight loss and increased energy expenditure, providing a rationale for targeting whole-body energy metabolism in HD. Leptin-deficient mice display low energy expenditure and increased body weight. We therefore hypothesized that normalizing energy metabolism in R6/2 mice, utilizing leptin- deficiency, would lead to a slower disease progression in the R6/2 mouse. In this study, we show that R6/2 mice on a leptin-deficient genetic background display increased body weight and increased fat mass compared to R6/2 mice, as well as wild type... (More)

Body weight has been shown to be a predictor of clinical progression in Huntington's disease (HD). Alongside widespread neuronal pathology, both HD patients and the R6/2 mouse model of HD exhibit weight loss and increased energy expenditure, providing a rationale for targeting whole-body energy metabolism in HD. Leptin-deficient mice display low energy expenditure and increased body weight. We therefore hypothesized that normalizing energy metabolism in R6/2 mice, utilizing leptin- deficiency, would lead to a slower disease progression in the R6/2 mouse. In this study, we show that R6/2 mice on a leptin-deficient genetic background display increased body weight and increased fat mass compared to R6/2 mice, as well as wild type littermates. The increased body weight was accompanied by low energy expenditure, illustrated by a reduction in respiratory exchange rate. Leptin-deficient R6/2 mice had large white adipocytes with white adipocyte gene expression characteristics, in contrast to white adipose tissue in R6/2 mice, where white adipose tissue showed signs of browning. Leptin-deficient R6/2 mice did not exhibit improved neuropathological measures. Our results indicate that lowering energy metabolism in HD, by increasing fat mass and reducing respiratory exchange rate, is not sufficient to affect neuropathology. Further studies targeting energy metabolism in HD are warranted.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adipose tissue, Energy metabolism, Huntington's disease, Leptin-deficiency, Oxygen consumption
in
Neurobiology of Disease
volume
132
publisher
Elsevier
external identifiers
  • scopus:85070893907
ISSN
0969-9961
DOI
10.1016/j.nbd.2019.104560
language
English
LU publication?
yes
id
7b1b37ec-035c-4500-aa9a-bb3256f0333f
date added to LUP
2019-09-09 08:42:48
date last changed
2019-09-26 04:41:41
@article{7b1b37ec-035c-4500-aa9a-bb3256f0333f,
  abstract     = {<p>Body weight has been shown to be a predictor of clinical progression in Huntington's disease (HD). Alongside widespread neuronal pathology, both HD patients and the R6/2 mouse model of HD exhibit weight loss and increased energy expenditure, providing a rationale for targeting whole-body energy metabolism in HD. Leptin-deficient mice display low energy expenditure and increased body weight. We therefore hypothesized that normalizing energy metabolism in R6/2 mice, utilizing leptin- deficiency, would lead to a slower disease progression in the R6/2 mouse. In this study, we show that R6/2 mice on a leptin-deficient genetic background display increased body weight and increased fat mass compared to R6/2 mice, as well as wild type littermates. The increased body weight was accompanied by low energy expenditure, illustrated by a reduction in respiratory exchange rate. Leptin-deficient R6/2 mice had large white adipocytes with white adipocyte gene expression characteristics, in contrast to white adipose tissue in R6/2 mice, where white adipose tissue showed signs of browning. Leptin-deficient R6/2 mice did not exhibit improved neuropathological measures. Our results indicate that lowering energy metabolism in HD, by increasing fat mass and reducing respiratory exchange rate, is not sufficient to affect neuropathology. Further studies targeting energy metabolism in HD are warranted.</p>},
  articleno    = {104560},
  author       = {Sjögren, Marie and Soylu-Kucharz, Rana and Dandunna, Unali and Stan, Tiberiu Loredan and Cavalera, Michele and Sandelius, Åsa and Zetterberg, Henrik and Björkqvist, Maria},
  issn         = {0969-9961},
  keyword      = {Adipose tissue,Energy metabolism,Huntington's disease,Leptin-deficiency,Oxygen consumption},
  language     = {eng},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Leptin deficiency reverses high metabolic state and weight loss without affecting central pathology in the R6/2 mouse model of Huntington's disease},
  url          = {http://dx.doi.org/10.1016/j.nbd.2019.104560},
  volume       = {132},
  year         = {2019},
}