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

Research output: Contribution to journalArticle

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 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.

Details

Authors
Organisations
External organisations
  • Sahlgrenska University Hospital
  • University College London
  • University of Gothenburg
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology

Keywords

  • Adipose tissue, Energy metabolism, Huntington's disease, Leptin-deficiency, Oxygen consumption
Original languageEnglish
Article number104560
JournalNeurobiology of Disease
Volume132
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes

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