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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Publications at this Location » Publication #295078

Title: Evaluation of the synuclein-y (SNCG) gene as a PPARy target in murine adipocytes, dorsal root ganglia somatosensory neurons, and human adipose tissue

Author
item Dunn, Tamara - University Of California
item Akiyama, Tasuku - University Of California
item Lee, Hyun - Seoul National University
item Kim, Jae - Seoul National University
item Knotts, Trina - University Of California
item Smith, Stephen - Sanford And Burnham Medical Research Institute
item Sears, Dorothy - University Of California
item Carstens, Earl - University Of California
item Adams, Sean

Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/30/2014
Publication Date: 3/10/2015
Citation: Dunn, T.N., Akiyama, T., Lee, H.W., Kim, J.B., Knotts, T.A., Smith, S.R., Sears, D.D., Carstens, E., Adams, S.H. 2015. Evaluation of the synuclein-y (SNCG) gene as a PPARy target in murine adipocytes, dorsal root ganglia somatosensory neurons, and human adipose tissue. PLoS One. 10(3):e0115830. doi: 10.1371/journal.pone.0115830.

Interpretive Summary: Synuclein-gamma (Sncg)is highly expressed in both adipocytes and peripheral nervous system (PNS) somatosensory neurons, but how it is involved in cross-talk between fat and the brain remains to be determined. It has been shown recently to be very important to regulation of proper fat storage in adipose (fat tissue), and is expressed at high levels in obese adipose. These aspects indicate a key role for this protein in maintaining healthy metabolism. The regulation of synuclein-gamma remains unclear, especially in peripheral neurons, and it is possible that fatty acid metabolites may be involved through action at the nuclear transcription factor PPARgamma. We tested the hypothesis that the synuclein-gamma gene is a bona fide PPAR' target in murine adipocytes, and determined if PPARgamma regulation of Sncg manifests in PNS neurons as well. Sncg mRNA expression was significantly decreased in mature adipocytes (fat cells) up to 68% by the thiazoladinedione (TZD) PPARgamma agonist rosiglitazone, and this effect was diminished with the addition of the PPARgamma antagonist T0070907. Chromatin immunoprecipitation (ChIP) experiments confirmed that PPARgamma protein binds at least two promoter sequences of murine Sncg during 3T3-L1 adipogenesis. In clinical subcutaneous adipose samples from two independent cohorts of subjects treated with the TZD pioglitazone for >11 wks, synuclein-gamma mRNA expression was reduced; however, this response was highly variable and seemed to manifest most robustly in type 2 diabetic subjects. There were strong correlations between SNCG and leptin (LEP, a powerful hormone regulating food intake and energy balance) gene expression in human SC-WAT (r=0.669; r=0.711; p<0.0001). In contrast to adipocytes, rosiglitizone treatment did not affect Sncg mRNA expression in murine primary cultured dorsal root ganglion cells, suggesting that PPARgammma regulation of the gene is context- or adipose-specific. The results support the concept that synuclein-gamma shares some, but not all, gene regulators with leptin. The concept that the synuclein-gamma gene is regulated by metabolic cues in adipocytes is logical based on recent evidence for an important role for synuclein-gamma in the regulation of adipocyte lipid droplet maintenance and dynamics.

Technical Abstract: Synuclein-gamma is highly expressed in both adipocytes and peripheral nervous system (PNS) somatosensory neurons. Its mRNA is induced during adipogenesis, increased in obese human white adipose tissue (WAT), may be coordinately regulated with leptin, and is decreased following treatment of murine 3T3-L1 adipocytes with the PPAR' agonist GW1929, suggesting a role for synuclein- in metabolism. However, the regulation of synuclein-gamma by PPAR' remains unclear, especially in peripheral neurons. We tested the hypothesis that the synuclein-gamma gene (Sncg) is a bona fide PPAR' target in murine adipocytes, and determined if PPAR' regulation of Sncg manifests in PNS neurons as well. Sncg mRNA expression was significantly decreased in mature 3T3-L1 adipocytes up to 68% by the thiazoladinedione (TZD) PPAR' agonist rosiglitazone, and this effect was diminished with the addition of the PPAR' antagonist T0070907. Leptin (Lep gene) expression was also reduced by TZD, but this was not countered by addition of T0070907, suggesting differences in its molecular regulation vs. Sncg. Consistent with this, the LXR agonist T0901317 significantly reduced Lep expression by 64% while not impacting that of Sncg. Chromatin immunoprecipitation (ChIP) experiments confirmed that PPAR' protein binds at least two promoter sequences of murine Sncg during 3T3-L1 adipogenesis. In clinical subcutaneous WAT samples from two independent cohorts of subjects treated with the TZD pioglitazone for >11 wks, SNCG mRNA expression was reduced; however, this response was highly variable and seemed to manifest most robustly in type 2 diabetic subjects. There were strong correlations between SNCG and leptin (LEP) gene expression in human SC-WAT (r=0.669; r=0.711; p<0.0001). In contrast to adipocytes, rosiglitizone treatment did not affect Sncg mRNA expression in murine primary cultured dorsal root ganglion cells, suggesting that PPAR' regulation of the gene is context- or adipose-specific. The results support the concept that synuclein-gamma shares some, but not all, gene regulators with leptin. The concept that the synuclein-gamma gene is regulated by metabolic cues such as PPAR' agonism in adipocytes is logical based on recent evidence for an important role for synuclein-gamma in the regulation of adipocyte lipid droplet maintenance and dynamics.