A novel obesity model: synphilin-1-induced hyperphagia and obesity in mice

• Published in: International Journal of Obesity 2012-09, Vol.36 (9), p.1215-1221
• Main Authors: Li, X, Tamashiro, K L K, Liu, Z, Bello, N T, Wang, X, Aja, S, Bi, S, Ladenheim, E E, Ross, C A, Moran, T H, Smith, W W
• Format: Article
• Language: English
• Subjects: 631/443/319/1488; 692/1807/1808; 692/699/2743/393; 692/699/375/365/1718; Animals; Antibodies; Biological and medical sciences; Blotting, Western; Body Weight; Carrier Proteins - genetics; Carrier Proteins - metabolism; Carrier Proteins - pharmacology; Development and progression; Disease Models, Animal; Eating - drug effects; Energy balance; Epidemiology; Food; Health aspects; Health Promotion and Disease Prevention; Hyperphagia; Hyperphagia - metabolism; Hypothalamus - drug effects; Hypothalamus - metabolism; Immunohistochemistry; Internal Medicine; Kinases; Laboratories; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - pharmacology; Obesity; Obesity - metabolism; original-article; Parkinson's disease; Pathogenesis; Pharmaceutical sciences; Pharmacy; Proteins; Public Health; Transgenic animals
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2011.235

Aims: The pathogenesis of obesity remains incompletely understood and the exploration of the role of novel proteins in obesity may provide important insights into its causes and treatments. Here, we report a previously unidentified role for synphilin-1 in the control of food intake and body weight. Synphilin-1, a cytoplasmic protein, was initially identified as an interaction partner of alpha-synuclein, and has implications in Parkinson's disease pathogenesis related to protein aggregation. Subjects and methods: To study the in vivo role of synphilin-1, we characterized a human synphilin-1 transgenic mouse (SP1) by assessing synphilin-1 expression, plasma parameters, food intake and spontaneous activity to determine the major behavioral changes and their consequences in the development of the obesity phenotype. Results: Expression of human synphilin-1 in brain neurons in SP1 mice resulted in increased food intake, body weight and body fat. SP1 mice also displayed hyperinsulinemia, hyperleptinemia and impaired glucose tolerance. Pair-feeding SP1 mice to amounts consumed by non-transgenic mice prevented the increased body weight, adiposity, hyperinsulinemia and hyperleptinemia demonstrating that these were all the consequences of increased food intake. Transgenic expression of synphilin-1 was enriched in hypothalamic nuclei involved in feeding control, and fasting-induced elevated endogenous synphilin-1 levels at these sites, suggesting that synphilin-1 is an important player in the hypothalamic energy balance regulatory system. Conclusion: These studies identify a novel function of synphilin-1 in controlling food intake and body weight, and may provide a unique obesity model for future studies of obesity pathogenesis and therapeutics.