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

Neurobiology of Disease

Rana Soylu-Kucharz¹  Åsa Sandelius²  Henrik Zetterberg³  Maria Björkqvist³  Michele Cavalera⁴  Marie Sjögren⁴  Unali Dandunna⁴  Tiberiu Loredan Stan⁴ 

[1] Corresponding author at: Wallenberg Neuroscience Center EMV, BMCA10, Lund University, 22184 Lund, Sweden.;Department of Clinical Sciences, Cardiovascular Research, Translational Studies, Lund University, Malmö, Sweden;Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden;Wallenberg Neuroscience Center, Brain Disease Biomarker Unit, Department of Experimental Medical Sciences, Lund University, Lund, Sweden;

关键词: Leptin-deficiency;    Energy metabolism;    Oxygen consumption;    Adipose tissue;    Huntington's disease;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown