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

Steven Millership, Natalia Ninkina, Irina A. Guschina, Jessica Norton, Ricardo Brambilla, Pieter J. Oort, Sean H. Adams, Rowena J. Dennis, Peter J. Voshol, Justin J. Rochford, Vladimir L. Buchman

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Abstract

Synucleins are a family of homologous proteins principally known for their involvement in neurodegeneration. γ-Synuclein is highly expressed in human white adipose tissue and increased in obesity. Here we show that γ-synuclein is nutritionally regulated in white adipose tissue whereas its loss partially protects mice from high-fat diet (HFD)-induced obesity and ameliorates some of the associated metabolic complications. Compared with HFD-fed WT mice, HFD-fed γ-synuclein-null mutant mice display increased lipolysis, lipid oxidation, and energy expenditure, and reduced adipocyte hypertrophy. Knockdown of γ-synuclein in adipocytes causes redistribution of the key lipolytic enzyme ATGL to lipid droplets and increases lipolysis. γ-Synuclein-deficient adipocytes also contain fewer SNARE complexes of a type involved in lipid droplet fusion. We hypothesize that γ-synuclein may deliver SNAP-23 to the SNARE complexes under lipogenic conditions. Via these independent but complementary roles, γ-synuclein may coordinately modulate lipid storage by influencing lipolysis and lipid droplet formation. Our data reveal γ-synuclein as a regulator of lipid handling in adipocytes, the function of which is particularly important in conditions of nutrient excess.

Original languageEnglish
Pages (from-to)20943-20948
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number51
DOIs
Publication statusPublished - Dec 18 2012

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    Millership, S., Ninkina, N., Guschina, I. A., 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 γ-synuclein-null mutant mice from diet-induced obesity. Proceedings of the National Academy of Sciences of the United States of America, 109(51), 20943-20948. https://doi.org/10.1073/pnas.1210022110