Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease

George D McIlroy, Karla Suchacki, Anke J Roelofs, Wulin Yang, Yanyun Fu, Bo Bai, Robert J Wallace, Cosimo de Bari, William P Cawthorn, Weiping Han, Mirela Delibegovic, Justin J. Rochford (Corresponding Author)

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Abstract

Objective
Mutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mice with germline disruption to Bscl2 recapitulate the effects of BSCL2 disruption in humans. Here we examined whether loss of Bscl2 specifically in developing adipocytes in vivo is sufficient to prevent adipose tissue development and cause all features observed with congenital BSCL2 disruption.

Methods
We generated and characterised a novel mouse model of Bscl2 deficiency in developing adipocytes (Ad-B2(-/-)) using the adipose-specific Adiponectin-Cre line.

Results
We demonstrate that Ad-B2(-/-) mice display early onset lipodystrophy, in common with congenital Bscl2 null mice and CGL2 patients. However, glucose intolerance, insulin resistance, and severe hepatic steatosis are not apparent. Food intake and energy expenditure are unchanged, but Ad-B2(-/-) mice exhibit significantly altered substrate utilisation. We also find differential effects of seipin loss between specific adipose depots revealing new insights regarding their varied characteristics. When fed a high-fat diet, Ad-B2(-/-) mice entirely fail to expand adipose mass but remain glucose tolerant.

Conclusions
Our findings demonstrate that disruption of Bscl2 specifically in developing adipocytes is sufficient to cause the early-onset generalised lipodystrophy observed in patients with mutations in BSCL2. However, this significant reduction in adipose mass does not cause the overt metabolic dysfunction seen in Bscl2 knockout mice, even following a high-fat diet challenge.
Original languageEnglish
Pages (from-to)55-65
Number of pages11
JournalMolecular Metabolism
Volume10
Early online date31 Jan 2018
DOIs
Publication statusPublished - Apr 2018

Fingerprint

Congenital Generalized Lipodystrophy
Metabolic Diseases
Adipocytes
High Fat Diet
Lipodystrophy
White Adipose Tissue
Glucose Intolerance
Adiponectin
Knockout Mice
Energy Metabolism
Insulin Resistance
Adipose Tissue
Eating
Glucose
Mutation
Liver

Keywords

  • BSCL2
  • seipin
  • CGL2
  • lipodystrophy
  • adipose tissue
  • Browning

Cite this

@article{f55e15f310d74b73a58e46c88fa5a584,
title = "Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease",
abstract = "ObjectiveMutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mice with germline disruption to Bscl2 recapitulate the effects of BSCL2 disruption in humans. Here we examined whether loss of Bscl2 specifically in developing adipocytes in vivo is sufficient to prevent adipose tissue development and cause all features observed with congenital BSCL2 disruption.MethodsWe generated and characterised a novel mouse model of Bscl2 deficiency in developing adipocytes (Ad-B2(-/-)) using the adipose-specific Adiponectin-Cre line.ResultsWe demonstrate that Ad-B2(-/-) mice display early onset lipodystrophy, in common with congenital Bscl2 null mice and CGL2 patients. However, glucose intolerance, insulin resistance, and severe hepatic steatosis are not apparent. Food intake and energy expenditure are unchanged, but Ad-B2(-/-) mice exhibit significantly altered substrate utilisation. We also find differential effects of seipin loss between specific adipose depots revealing new insights regarding their varied characteristics. When fed a high-fat diet, Ad-B2(-/-) mice entirely fail to expand adipose mass but remain glucose tolerant.ConclusionsOur findings demonstrate that disruption of Bscl2 specifically in developing adipocytes is sufficient to cause the early-onset generalised lipodystrophy observed in patients with mutations in BSCL2. However, this significant reduction in adipose mass does not cause the overt metabolic dysfunction seen in Bscl2 knockout mice, even following a high-fat diet challenge.",
keywords = "BSCL2, seipin, CGL2, lipodystrophy, adipose tissue, Browning",
author = "McIlroy, {George D} and Karla Suchacki and Roelofs, {Anke J} and Wulin Yang and Yanyun Fu and Bo Bai and Wallace, {Robert J} and {de Bari}, Cosimo and Cawthorn, {William P} and Weiping Han and Mirela Delibegovic and Rochford, {Justin J.}",
note = "Acknowledgements: The authors would like to thank Dr Cristian Olarte-Sanchez for his help with metabolic studies, James Redmore and James Thorburn for their contributions to data collection and analysis, Alison Richmond, Susan Clark and Ausra Lionikiene for technical support, and staff at the University of Aberdeen's Medical Research Facility and Microscopy & Histology Facility. We are very grateful for the gift of the Adiponectin-Cre mice from Dr. Evan Rosen (Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, USA). Work was supported by the Medical Research Council (GDM/JJR; MR/L002620/1, MC/PC/15077, KS/WPC; MR/M021394/1, AJR/CDB; MR/L022893/1), the Biotechnology and Biological Sciences Research Council (JJR; BB/K017772/1), the British Heart Foundation (MD; PG/14/43/30889, KS/WPC; BHF CoRE Bioinformatics Grant), NHS Grampian Endowments (AJR/CDB/JJR; Grant No. 16/11/032) and the NHS Grampian Rheumatology Department.",
year = "2018",
month = "4",
doi = "10.1016/j.molmet.2018.01.019",
language = "English",
volume = "10",
pages = "55--65",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",

}

TY - JOUR

T1 - Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease

AU - McIlroy, George D

AU - Suchacki, Karla

AU - Roelofs, Anke J

AU - Yang, Wulin

AU - Fu, Yanyun

AU - Bai, Bo

AU - Wallace, Robert J

AU - de Bari, Cosimo

AU - Cawthorn, William P

AU - Han, Weiping

AU - Delibegovic, Mirela

AU - Rochford, Justin J.

N1 - Acknowledgements: The authors would like to thank Dr Cristian Olarte-Sanchez for his help with metabolic studies, James Redmore and James Thorburn for their contributions to data collection and analysis, Alison Richmond, Susan Clark and Ausra Lionikiene for technical support, and staff at the University of Aberdeen's Medical Research Facility and Microscopy & Histology Facility. We are very grateful for the gift of the Adiponectin-Cre mice from Dr. Evan Rosen (Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, USA). Work was supported by the Medical Research Council (GDM/JJR; MR/L002620/1, MC/PC/15077, KS/WPC; MR/M021394/1, AJR/CDB; MR/L022893/1), the Biotechnology and Biological Sciences Research Council (JJR; BB/K017772/1), the British Heart Foundation (MD; PG/14/43/30889, KS/WPC; BHF CoRE Bioinformatics Grant), NHS Grampian Endowments (AJR/CDB/JJR; Grant No. 16/11/032) and the NHS Grampian Rheumatology Department.

PY - 2018/4

Y1 - 2018/4

N2 - ObjectiveMutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mice with germline disruption to Bscl2 recapitulate the effects of BSCL2 disruption in humans. Here we examined whether loss of Bscl2 specifically in developing adipocytes in vivo is sufficient to prevent adipose tissue development and cause all features observed with congenital BSCL2 disruption.MethodsWe generated and characterised a novel mouse model of Bscl2 deficiency in developing adipocytes (Ad-B2(-/-)) using the adipose-specific Adiponectin-Cre line.ResultsWe demonstrate that Ad-B2(-/-) mice display early onset lipodystrophy, in common with congenital Bscl2 null mice and CGL2 patients. However, glucose intolerance, insulin resistance, and severe hepatic steatosis are not apparent. Food intake and energy expenditure are unchanged, but Ad-B2(-/-) mice exhibit significantly altered substrate utilisation. We also find differential effects of seipin loss between specific adipose depots revealing new insights regarding their varied characteristics. When fed a high-fat diet, Ad-B2(-/-) mice entirely fail to expand adipose mass but remain glucose tolerant.ConclusionsOur findings demonstrate that disruption of Bscl2 specifically in developing adipocytes is sufficient to cause the early-onset generalised lipodystrophy observed in patients with mutations in BSCL2. However, this significant reduction in adipose mass does not cause the overt metabolic dysfunction seen in Bscl2 knockout mice, even following a high-fat diet challenge.

AB - ObjectiveMutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mice with germline disruption to Bscl2 recapitulate the effects of BSCL2 disruption in humans. Here we examined whether loss of Bscl2 specifically in developing adipocytes in vivo is sufficient to prevent adipose tissue development and cause all features observed with congenital BSCL2 disruption.MethodsWe generated and characterised a novel mouse model of Bscl2 deficiency in developing adipocytes (Ad-B2(-/-)) using the adipose-specific Adiponectin-Cre line.ResultsWe demonstrate that Ad-B2(-/-) mice display early onset lipodystrophy, in common with congenital Bscl2 null mice and CGL2 patients. However, glucose intolerance, insulin resistance, and severe hepatic steatosis are not apparent. Food intake and energy expenditure are unchanged, but Ad-B2(-/-) mice exhibit significantly altered substrate utilisation. We also find differential effects of seipin loss between specific adipose depots revealing new insights regarding their varied characteristics. When fed a high-fat diet, Ad-B2(-/-) mice entirely fail to expand adipose mass but remain glucose tolerant.ConclusionsOur findings demonstrate that disruption of Bscl2 specifically in developing adipocytes is sufficient to cause the early-onset generalised lipodystrophy observed in patients with mutations in BSCL2. However, this significant reduction in adipose mass does not cause the overt metabolic dysfunction seen in Bscl2 knockout mice, even following a high-fat diet challenge.

KW - BSCL2

KW - seipin

KW - CGL2

KW - lipodystrophy

KW - adipose tissue

KW - Browning

U2 - 10.1016/j.molmet.2018.01.019

DO - 10.1016/j.molmet.2018.01.019

M3 - Article

VL - 10

SP - 55

EP - 65

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

ER -