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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 Unit

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

Authors
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: November 12, 2012
Publication Date: December 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: 12/20/2014
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