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United States Department of Agriculture

Agricultural Research Service

Research Project: Linking Foods, Behavior and Metabolism to Promote a Healthy Body Weight

Location: Obesity and Metabolism Research

Title: Increased lipolysis and altered lipid homeostasis protect y-synuclein null mutant mice from diet-induced obesity )

Author
item Millership, Steven
item Ninkina, Natalia
item Guschina, Irina
item Norton, Jessica
item Brambilla, Ricardo
item Oort, Pieter
item Adams, Sean
item Dennis, Rowena
item Voshol, Peter
item Rochford, Justin
item Buchman, Vladimir

Submitted to: Proceedings of the National Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/12/2012
Publication Date: 12/18/2012
Citation: Millership, S., Ninkina, N., Guschina, I., Norton, J., Brambilla, R., Oort, P.J., Adams, S.H., Dennis, R.J., Voshol, P.J., Rochford, J.J., Buchman, V.L. 2012. Increased lipolysis and altered lipid homeostasis protect y-synuclein null mutant mice from diet-induced obesity . Proceedings of the National Academy of Sciences. 109(51):20943-20948.

Interpretive Summary: Synucleins are a family of homologous, predominantly neuronal proteins known for their involvement in neurodegeneration. In neurons a-synuclein promotes assembly of SNARE complexes required for fusion of synaptic vesicles with the plasma membrane during neurotransmitter release. Gamma-synuclein is highly expressed in human white adipose tissue (WAT) and increased in obesity. Here we show that gamma-synuclein is nutritionally regulated in murine adipocytes whilst its loss protects mice from high fat diet (HFD)-induced obesity and associated metabolic complications. This is coupled with decreased adipocyte hypertrophy, increased lipolysis, lipid oxidation and energy expenditure in HFD-fed gamma-synuclein null mutant compared to wild-type mice. Adipocytes from these gamma-synuclein deficient animals also contain more ATGL, a key lipolytic enzyme, and fewer SNARE complexes, an important component of lipid droplet fusion machinery. Together our data suggest that gamma-synuclein is a novel regulator of lipid handling in adipocytes; this function becoming particularly important in conditions of nutrient excess.

Technical Abstract: Synucleins are a family of homologous proteins principally known for their involvement in neurodegeneration. In neurons a-synuclein promotes assembly of SNARE complexes required for fusion of synaptic vesicles with the plasma membrane during neurotransmitter release. Y-synuclein is highly expressed in human white adipose tissue (WAT) and increased in obesity. Here we show that Y-synuclein is nutritionally regulated in WAT whilst its loss protects mice from high fat diet (HFD)-induced obesity and associated metabolic complications. Compared to HFD-fed wild type mice, HFD-fed Y-synuclein null mutant mice display increased lipolysis, lipid oxidation and energy expenditure, and reduced adipocyte hypertrophy. Knockdown of Y-synuclein in cultured adipocytes causes redistribution of the key lipolytic enzyme ATGL to lipid droplets and increases lipolysis. Y-synuclein deficient adipocytes also contain fewer SNARE complexes of a type involved in lipid droplet fusion. We show that Y-synuclein interacts directly with SNAP-23, a component of these SNARE complexes. However, treatment of cells with oleate disrupts this interaction, consistent with a role for Y-synuclein in delivering SNAP-23 to the SNARE complexes under this lipogenic condition. Thus, we propose that via these dual roles Y-synuclein may co-ordinately affect both lipolysis and lipid droplet formation depending on nutritional status. Our data reveal Y-synuclein as a novel regulator of lipid handling in adipocytes, whose function is particularly important in conditions of nutrient excess.

Last Modified: 8/24/2016
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