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

ABSTRACT: Synucleins are a family of homologous proteins principally known for their involvement in neurodegeneration. ?-Synuclein is highly expressed in human white adipose tissue and increased in obesity. Here we show that ?-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 ?-synuclein-null mutant mice display increased lipolysis, lipid oxidation, and energy expenditure, and reduced adipocyte hypertrophy. Knockdown of ?-synuclein in adipocytes causes redistribution of the key lipolytic enzyme ATGL to lipid droplets and increases lipolysis. ?-Synuclein-deficient adipocytes also contain fewer SNARE complexes of a type involved in lipid droplet fusion. We hypothesize that ?-synuclein may deliver SNAP-23 to the SNARE complexes under lipogenic conditions. Via these independent but complementary roles, ?-synuclein may coordinately modulate lipid storage by influencing lipolysis and lipid droplet formation. Our data reveal ?-synuclein as a regulator of lipid handling in adipocytes, the function of which is particularly important in conditions of nutrient excess.

SUBMITTER: Millership S

PROVIDER: S-EPMC3529034 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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

Millership Steven S Ninkina Natalia N Guschina Irina A IA Norton Jessica J Brambilla Riccardo R Oort Pieter J PJ Adams Sean H SH Dennis Rowena J RJ Voshol Peter J PJ Rochford Justin J JJ Buchman Vladimir L VL

Proceedings of the National Academy of Sciences of the United States of America 20121203 51

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 ...[more]

PMID: 23213245

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Project description:BackgroundElucidation of lipid metabolism and accumulation mechanisms is of paramount importance to understanding obesity and unveiling therapeutic targets. In vitro cell models have been extensively used for these purposes, yet, they do not entirely reflect the in vivo setup. Conventional lipomas, characterized by the presence of mature adipocytes and increased adipogenesis, could overcome the drawbacks of cell cultures. Also, they have the unique advantage of easily accessible matched controls in the form of subcutaneous adipose tissue (SAT) from the same individual. We aimed to determine whether lipomas are a good model to understand lipid accumulation.MethodsWe histologically compared lipomas and control SAT, followed by assessment of the lipidome using high-resolution 1H NMR spectroscopy and ESI-IT mass spectrometry. RNA-sequencing was used to obtain the transcriptome of lipomas and the matched SAT.ResultsWe found a significant increase of small-size (maximal axis?<?70?µm) and very big (maximal axis?>?150?µm) adipocytes within lipomas. This suggests both enhanced adipocyte proliferation and increased lipid accumulation. We further show that there is no significant change in the lipid composition compared to matched SAT. To better delineate the pathophysiology of lipid accumulation, we considered two groups with different genetic backgrounds: (1) lipomas with HMGA2 fusions and (2) without gene fusions. To reduce the search space for genes that are relevant for lipid pathophysiology, we focused on the overlapping differentially expressed (DE) genes between the two groups. Gene Ontology analysis revealed that DE genes are enriched in pathways related to lipid accumulation.ConclusionsWe show that the common shared lipid accumulation mechanism in lipoma is a reduction in lipolysis, with most gene dysregulations leading to a reduced cAMP in the adipocyte. Superficial lipomas could thus be used as a model for lipid accumulation through altered lipolysis as found in obese patients.

Dataset Information

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

Publications

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

Similar Datasets

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