Obesity is the most common metabolic disease, resulting from the ingestion of calories in excess of ongoing requirements. Increased prevalence of obesity has resulted in rapidly accelerating rates of obesity related disorders such as type 2 diabetes and cardiovascular disease. The pathogenesis of obesity remains incompletely understood. In the current application, we propose to investigate a novel role for synphilin-1 in food intake and body weight control. Synphilin-1, a cytoplasmic protein, interacts with alpha-synuclein and parkin and has implications in Parkinson's disease pathogenesis related to protein aggregation. Through work examining the phenotype of a synphillin-1 transgenic mouse (SP1), we have evidence that synphilin-1 over- expression significantly increases body weight and does so through increasing food intake. We have found that synphilin-1 is highly expressed in neurons of hypothalamic nuclei involved in energy balance, suggesting that synphilin-1 may be affecting energy balance by modulating hypothalamic signaling. Our preliminary data suggest that synphilin-1 may affect food intake and body weight through increases in orexigenic genes: NPY and AgRP expression in hypothalamic neurons. Recently, studies have suggested that AMP-activated kinase (AMPK) is a central neuronal energy sensor that plays a major role in maintaining energy homeostasis. Our preliminary data showed that expression of human synphilin-1 increased AMPK phosphorylation in cultured N1E-115 cells and at the PVN site, and further showed that synphilin-1 interacted with AMPK as indicated by co-immunoprecipitation. Thus, in this proposal, we will test the hypothesis that synphilin-1 modulates hypothalamic feeding related gene expression and AMPK signaling cascades resulting in hyperphagia and obesity.
In Aim 1, we will characterize changes in food intake, body weight and patterns of hypothalamic gene expression in responses to overexpression of synphilin-1. We will specifically assess the bases for the increased meal size that characterizes the hyperphagia in SP1 mice by testing responses to central and peripheral peptide administration and characterizing their taste preferences.
In Aim 2, we will investigate the role of endogenous hypothalamic synphilin-1 in response to alterations in metabolic status.
In Aim 3, we will test the hypothesis that synphilin-1 alters AMPK signaling cascades and its related cell energy events in an in vitro cell culture system.
In Aim 4, we will test the hypothesis that synphilin-1 activates AMPK signaling in hypothalamus resulting in hyperphagia and obesity in vivo using overexpression and siRNA knockdown approaches. These studies will provide insight into the molecular mechanisms underlying synphilin-1-induced hyperphagia and obesity, will enlarge our knowledge of the biological functions of synphilin-1, and may provide a unique genetic obesity model for future studies of the pathogenesis of obesity.

Public Health Relevance

We propose to investigate the role and the molecular mechanisms of synphilin-1 protein in regulating food intake and body weight using behavioral, pharmacological and cell biological approaches. These studies will greatly increase our understanding of the biological functions of synphilin-1 and will provide new insights into the molecular mechanisms underlying obesity and related disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
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Hyde, James F
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University of Maryland Baltimore
Schools of Pharmacy
United States
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Smith, Wanli W; Smith, Megan; Yang, Dejun et al. (2015) CCK Response Deficiency in Synphilin-1 Transgenic Mice. PLoS One 10:e0142314
Li, Xueping; Treesukosol, Yada; Moghadam, Alexander et al. (2014) Behavioral characterization of the hyperphagia synphilin-1 overexpressing mice. PLoS One 9:e91449
Li, Tianxia; Liu, Jingnan; Smith, Wanli W (2014) Synphilin-1 binds ATP and regulates intracellular energy status. PLoS One 9:e115233
Smith, Wanli W; Thomas, Joseph; Liu, Jingnan et al. (2014) From fat fruit fly to human obesity. Physiol Behav 136:15-21
Li, X; Tamashiro, K L K; Liu, Z et al. (2012) A novel obesity model: synphilin-1-induced hyperphagia and obesity in mice. Int J Obes (Lond) 36:1215-21
Liu, J; Li, T; Yang, D et al. (2012) Synphilin-1 alters metabolic homeostasis in a novel Drosophila obesity model. Int J Obes (Lond) 36:1529-36