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

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Synucleins are a family of homologous proteins principally known for their involvement in neurodegeneration. gamma-Synuclein is highly expressed in human white adipose tissue and increased in obesity. Here we show that gamma-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 gamma-synuclein-null mutant mice display increased lipolysis, lipid oxidation, and energy expenditure, and reduced adipocyte hypertrophy. Knockdown of gamma-synuclein in adipocytes causes redistribution of the key lipolytic enzyme ATGL to lipid droplets and increases lipolysis. gamma-Synuclein-deficient adipocytes also contain fewer SNARE complexes of a type involved in lipid droplet fusion. We hypothesize that gamma-synuclein may deliver SNAP-23 to the SNARE complexes under lipogenic conditions. Via these independent but complementary roles, gamma-synuclein may coordinately modulate lipid storage by influencing lipolysis and lipid droplet formation. Our data reveal gamma-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
JournalPNAS
Volume109
Issue number51
Early online date3 Dec 2012
DOIs
Publication statusPublished - 18 Dec 2012

Keywords

  • overexpression
  • gene
  • droplets
  • alpha-synuclein
  • in-vitro
  • adipose triglyceride lipase
  • behavior
  • dopamine
  • resistance
  • mutations

Cite this

Millership, S., Ninkina, N., Guschina, I. A., Norton, J., Brambilla, R., Oort, P. J., ... Buchman, V. L. (2012). Increased lipolysis and altered lipid homeostasis protect γ-synuclein-null mutant mice from diet-induced obesity. PNAS, 109(51), 20943-20948. https://doi.org/10.1073/pnas.1210022110

Increased lipolysis and altered lipid homeostasis protect γ-synuclein-null mutant mice from diet-induced obesity. / Millership, Steven; Ninkina, Natalia; Guschina, Irina A.; Norton, Jessica; Brambilla, Ricardo; Oort, Pieter J.; Adams, Sean H.; Dennis, Rowena J.; Voshol, Peter J.; Rochford, Justin J.; Buchman, Vladimir L.

In: PNAS, Vol. 109, No. 51, 18.12.2012, p. 20943-20948.

Research output: Contribution to journalArticle

Millership, S, Ninkina, N, Guschina, IA, Norton, J, Brambilla, R, Oort, PJ, Adams, SH, Dennis, RJ, Voshol, PJ, Rochford, JJ & Buchman, VL 2012, 'Increased lipolysis and altered lipid homeostasis protect γ-synuclein-null mutant mice from diet-induced obesity', PNAS, vol. 109, no. 51, pp. 20943-20948. https://doi.org/10.1073/pnas.1210022110
Millership S, Ninkina N, Guschina IA, Norton J, Brambilla R, Oort PJ et al. Increased lipolysis and altered lipid homeostasis protect γ-synuclein-null mutant mice from diet-induced obesity. PNAS. 2012 Dec 18;109(51):20943-20948. https://doi.org/10.1073/pnas.1210022110
Millership, Steven ; Ninkina, Natalia ; Guschina, Irina A. ; Norton, Jessica ; Brambilla, Ricardo ; Oort, Pieter J. ; Adams, Sean H. ; Dennis, Rowena J. ; Voshol, Peter J. ; Rochford, Justin J. ; Buchman, Vladimir L. / Increased lipolysis and altered lipid homeostasis protect γ-synuclein-null mutant mice from diet-induced obesity. In: PNAS. 2012 ; Vol. 109, No. 51. pp. 20943-20948.
@article{2525938635c745b980234d6a9cb43c33,
title = "Increased lipolysis and altered lipid homeostasis protect γ-synuclein-null mutant mice from diet-induced obesity",
abstract = "Synucleins are a family of homologous proteins principally known for their involvement in neurodegeneration. gamma-Synuclein is highly expressed in human white adipose tissue and increased in obesity. Here we show that gamma-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 gamma-synuclein-null mutant mice display increased lipolysis, lipid oxidation, and energy expenditure, and reduced adipocyte hypertrophy. Knockdown of gamma-synuclein in adipocytes causes redistribution of the key lipolytic enzyme ATGL to lipid droplets and increases lipolysis. gamma-Synuclein-deficient adipocytes also contain fewer SNARE complexes of a type involved in lipid droplet fusion. We hypothesize that gamma-synuclein may deliver SNAP-23 to the SNARE complexes under lipogenic conditions. Via these independent but complementary roles, gamma-synuclein may coordinately modulate lipid storage by influencing lipolysis and lipid droplet formation. Our data reveal gamma-synuclein as a regulator of lipid handling in adipocytes, the function of which is particularly important in conditions of nutrient excess.",
keywords = "overexpression, gene, droplets, alpha-synuclein, in-vitro, adipose triglyceride lipase, behavior, dopamine, resistance, mutations",
author = "Steven Millership and Natalia Ninkina and Guschina, {Irina A.} and Jessica Norton and Ricardo Brambilla and Oort, {Pieter J.} and Adams, {Sean H.} and Dennis, {Rowena J.} and Voshol, {Peter J.} and Rochford, {Justin J.} and Buchman, {Vladimir L.}",
year = "2012",
month = "12",
day = "18",
doi = "10.1073/pnas.1210022110",
language = "English",
volume = "109",
pages = "20943--20948",
journal = "PNAS",
issn = "0027-8424",
publisher = "NATL ACAD SCIENCES",
number = "51",

}

TY - JOUR

T1 - Increased lipolysis and altered lipid homeostasis protect γ-synuclein-null mutant mice from diet-induced obesity

AU - Millership, Steven

AU - Ninkina, Natalia

AU - Guschina, Irina A.

AU - Norton, Jessica

AU - Brambilla, Ricardo

AU - Oort, Pieter J.

AU - Adams, Sean H.

AU - Dennis, Rowena J.

AU - Voshol, Peter J.

AU - Rochford, Justin J.

AU - Buchman, Vladimir L.

PY - 2012/12/18

Y1 - 2012/12/18

N2 - Synucleins are a family of homologous proteins principally known for their involvement in neurodegeneration. gamma-Synuclein is highly expressed in human white adipose tissue and increased in obesity. Here we show that gamma-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 gamma-synuclein-null mutant mice display increased lipolysis, lipid oxidation, and energy expenditure, and reduced adipocyte hypertrophy. Knockdown of gamma-synuclein in adipocytes causes redistribution of the key lipolytic enzyme ATGL to lipid droplets and increases lipolysis. gamma-Synuclein-deficient adipocytes also contain fewer SNARE complexes of a type involved in lipid droplet fusion. We hypothesize that gamma-synuclein may deliver SNAP-23 to the SNARE complexes under lipogenic conditions. Via these independent but complementary roles, gamma-synuclein may coordinately modulate lipid storage by influencing lipolysis and lipid droplet formation. Our data reveal gamma-synuclein as a regulator of lipid handling in adipocytes, the function of which is particularly important in conditions of nutrient excess.

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

KW - overexpression

KW - gene

KW - droplets

KW - alpha-synuclein

KW - in-vitro

KW - adipose triglyceride lipase

KW - behavior

KW - dopamine

KW - resistance

KW - mutations

U2 - 10.1073/pnas.1210022110

DO - 10.1073/pnas.1210022110

M3 - Article

VL - 109

SP - 20943

EP - 20948

JO - PNAS

JF - PNAS

SN - 0027-8424

IS - 51

ER -