Metabolic abnormalities and hypoleptinemia in α-synuclein A53T mutant mice.
Parkinson's disease (PD) patients frequently display loss of body fat mass and increased energy expenditure, and several studies have outlined a relationship between these metabolic abnormalities and disease severity, yet energy metabolism is largely unstudied in mouse models of PD. Here we characterize metabolic and physiologic responses to a high calorie diet (HCD) in mice expressing in neurons a mutant form of human α-synuclein (A53T) that causes dominantly inherited familial forms of the disease. A53T (SNCA) and wild type (WT) littermate mice were placed on a HCD for 12 weeks and evaluated for weight gain, food intake, body fat, blood plasma leptin, hunger, glucose tolerance, and energy expenditure. Results were compared with both SNCA and WT mice on a control diet. Despite consuming similar amounts of food, WT mice gained up to 66% of their original body weight on a HCD, whereas SNCA mice gained only 17%. Further, after 12 weeks on a HCD, magnetic resonance imaging analysis revealed that WT mice had significantly greater total and visceral body fat compared with SNCA mice (p < 0.007). At the age of 24 weeks SNCA mice displayed significantly increased hunger compared with WT (p < 0.03). At the age of 36 weeks, SNCA mice displayed significant hypoleptinemia compared with WT, both on a normal diet and a HCD (p < 0.03). The HCD induced insulin insensitivity in WT, but not SNCA mice, as indicated by an oral glucose tolerance test. Finally, SNCA mice displayed greater energy expenditure compared with WT, as measured in a Comprehensive Laboratory Animal Monitoring System, after 12 weeks on a HCD. Thus, SNCA mice are resistant to HCD-induced obesity and insulin resistance and display reduced body fat, increased hunger, hypoleptinemia and increased energy expenditure. Our findings reveal a profile of metabolic dysfunction in a mouse model of PD that is similar to that of human PD patients, thus providing evidence that α-synuclein pathology is sufficient to drive such metabolic abnormalities and providing an animal model for discovery of the underlying mechanisms and potential therapeutic interventions.
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Sarah M
SM
Rothman
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Kathleen J
KJ
Griffioen
Magnetic Resonance Imaging & Spectroscopy Section, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Kenneth W
KW
Fishbein
Magnetic Resonance Imaging & Spectroscopy Section, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Richard G
RG
Spencer
Longitudinal Studies Section, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Sokratis
S
Makrogiannis
Laboratory of Clinical Investigation National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Wei-Na
WN
Cong
Laboratory of Clinical Investigation National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Bronwen
B
Martin
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA. Electronic address: mark.mattson@nih.gov.
Mark P
MP
Mattson
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D002149:Energy Intake; D004734:Energy Metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000097:blood* / Q000172:deficiency*; D008297:Male; D051379:Mice; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics*
D020738:Leptin; D051844:alpha-Synuclein
Body fat; Energy metabolism; Insulin; Leptin; Parkinson's disease