Abstract
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.
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References
Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ et al. Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet 1999; 22: 110–114.
Ribeiro CS, Carneiro K, Ross CA, Menezes JR, Engelender S . Synphilin-1 is developmentally localized to synaptic terminals, and its association with synaptic vesicles is modulated by alpha-synuclein. J Biol Chem 2002; 277: 23927–23933.
Nagano Y, Yamashita H, Takahashi T, Kishida S, Nakamura T, Iseki E et al. Siah-1 facilitates ubiquitination and degradation of synphilin-1. J Biol Chem 2003; 278: 51504–51514.
Wakabayashi K, Engelender S, Yoshimoto M, Tsuji S, Ross CA, Takahashi H . Synphilin-1 is present in Lewy bodies in Parkinson's disease. Ann Neurol 2000; 47: 521–523.
Bandopadhyay R, Kingsbury AE, Muqit MM, Harvey K, Reid AR, Kilford L et al. Synphilin-1 and parkin show overlapping expression patterns in human brain and form aggresomes in response to proteasomal inhibition. Neurobiol Dis 2005; 20: 401–411.
Smith WW, Margolis RL, Li X, Troncoso JC, Lee MK, Dawson VL et al. Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J Neurosci 2005; 25: 5544–5552.
Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J et al. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 2001; 7: 1144–1150.
Szargel R, Rott R, Engelender S . Synphilin-1 isoforms in Parkinson's disease: regulation by phosphorylation and ubiquitylation. Cell Mol Life Sci 2008; 65: 80–88.
O’Farrell C, Murphy DD, Petrucelli L, Singleton AB, Hussey J, Farrer M et al. Transfected synphilin-1 forms cytoplasmic inclusions in HEK293 cells. Brain Res Mol Brain Res 2001; 97: 94–102.
Lee G, Tanaka M, Park K, Lee SS, Kim YM, Junn E et al. Casein kinase II-mediated phosphorylation regulates alpha-synuclein/synphilin-1 interaction and inclusion body formation. J Biol Chem 2004; 279: 6834–6839.
Avraham E, Szargel R, Eyal A, Rott R, Engelender S . Glycogen synthase kinase 3beta modulates synphilin-1 ubiquitylation and cellular inclusion formation by SIAH: implications for proteasomal function and Lewy body formation. J Biol Chem 2005; 280: 42877–42886.
Marx FP, Soehn AS, Berg D, Melle C, Schiesling C, Lang M et al. The proteasomal subunit S6 ATPase is a novel synphilin-1 interacting protein--implications for Parkinson's disease. FASEB J 2007; 21: 1759–1767.
varez-Castelao B, Castano JG . Synphilin-1 inhibits alpha-synuclein degradation by the proteasome. Cell Mol Life Sci 2010; 68: 2643–2654.
Li X, Liu Z, Tamashiro K, Shi B, Rudnicki DD, Ross CA et al. Synphilin-1 exhibits trophic and protective effects against Rotenone toxicity. Neuroscience 2010; 165: 455–462.
Giaime E, Sunyach C, Herrant M, Grosso S, Auberger P, McLean PJ et al. Caspase-3-derived C-terminal product of synphilin-1 displays antiapoptotic function via modulation of the p53-dependent cell death pathway. J Biol Chem 2006; 281: 11515–11522.
Smith WW, Liu Z, Liang Y, Masuda N, Swing DA, Jenkins NA et al. Synphilin-1 attenuates neuronal degeneration in the A53T {alpha}-synuclein transgenic mouse model. Hum Mol Genet 2010; 19: 2087–2098.
Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS et al. Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala- 53 --> Thr mutation causes neurodegenerative disease with alpha- synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 2002; 99: 8968–8973.
Pletnikov MV, Rubin SA, Schwartz GJ, Moran TH, Sobotka TJ, Carbone KM . Persistent neonatal Borna disease virus (BDV) infection of the brain causes chronic emotional abnormalities in adult rats. Physiol Behav 1999; 66: 823–831.
Tamashiro KL, Wakayama T, Akutsu H, Yamazaki Y, Lachey JL, Wortman MD et al. Cloned mice have an obese phenotype not transmitted to their offspring. Nat Med 2002; 8: 262–267.
Gao S, Kinzig KP, Aja S, Scott KA, Keung W, Kelly S et al. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proc Natl Acad Sci USA 2007; 104: 17358–17363.
Tremblay A, Therrien F . Physical activity and body functionality: implications for obesity prevention and treatment. Can J Physiol Pharmacol 2006; 84: 149–156.
Vargas RH, Ornelas LF, Gonzalez IL, Escovar JR, Zurita M, Reynaud E . Synphilin suppresses alpha-synuclein neurotoxicity in a Parkinson's disease Drosophila model. Genesis 2011; 49: 392–402.
Jin HG, Yamashita H, Nakamura T, Fukuba H, Takahashi T, Hiji M et al. Synphilin-1 transgenic mice exhibit mild motor impairments. Neurosci Lett 2008; 445: 12–17.
Krenz A, Falkenburger BH, Gerhardt E, Drinkut A, Schulz JB . Aggregate formation and toxicity by wild-type and R621C synphilin-1 in the nigrostriatal system of mice using adenoviral vectors. J Neurochem 2009; 108: 139–146.
Nuber S, Franck T, Wolburg H, Schumann U, Casadei N, Fischer K et al. Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice. Neurogenetics 2010; 11: 107–120.
Ladenheim EE, Behles RR, Bi S, Moran TH . Gastrin-releasing peptide messenger ribonucleic acid expression in the hypothalamic paraventricular nucleus is altered by melanocortin receptor stimulation and food deprivation. Endocrinology 2009; 150: 672–678.
Moran TH . Gut peptide signaling in the controls of food intake. Obesity (Silver Spring) 2006; 14 (Suppl 5): 250S–253S.
Acknowledgements
We thank Yi Yu, Jayson Hyun, Megan Smith and Guangjing Zhu for technical support. We thank Dr T Dawson for read the manuscript. This work was supported by National Institutes of Health, Grants: DK083410 to WWS, NS38377 to CAS, DK19302 and DK068054, and the Paul R. McHugh Chair for Motivated Behavior to THM.
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Li, X., Tamashiro, K., Liu, Z. et al. A novel obesity model: synphilin-1-induced hyperphagia and obesity in mice. Int J Obes 36, 1215–1221 (2012). https://doi.org/10.1038/ijo.2011.235
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DOI: https://doi.org/10.1038/ijo.2011.235
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